Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

Children’s Research Hospital

Malaria infection caused by Plasmodium falciparum, even after a one-time illness, can cause long-term bone loss, researchers report.

Parasite byproducts remain in the bone marrow and induce MyD88-dependent inflammatory responses in osteoclast and osteoblast precursors, resulting in bone resorption.

Researchers found that treatment with the vitamin D3 analog alfacalcidol can prevent bone loss related to malaria, at least in animals.

They suggest that bone therapies combined with anti-malarial drugs may prevent bone loss in infected individuals.

Cevayir Coban, MD, from Osaka University in Japan, and colleagues reported their findings in Science Immunology.

"Although chronic inflammatory conditions are known to facilitate bone disorders, our study—for the first time—shows that malaria can do the same thing,” Dr Coban said.

“One may think that the infection has been completely cured by anti-malarial treatment, and be feeling fully recovered,” she said. “However, sustained long-term accumulation of parasite by-products leave the bone in a state of chronic inflammation, leading to long-term bone loss. This is particularly worrisome in the young of age, where it may cause growth problems and osteoporotic, fragile bones."

To study the effect of Plasmodium infection on bone, the team used two mouse models, Plasmodium yoelii nonlethal (PyNL) and Plasmodium chabaudi chabaudi (Pcc).

PyNL infection invades reticulocytes and resembles Plasmodium vivax infection in humans. Pcc infection more closely resembles Plasmodium falciparum infection in humans. The investigators used Pcc infection to evaluate the effect of low-level chronic infection on bone homeostasis.

They infected 6-week-old adult mice with these parasite species and assessed changes in bone during the acute, convalescent, and chronic phases of infection.

Both parasites caused significantly reduced trabecular bone volume and increased trabecular bone spacing in infected mice. This continued for over 60 days after parasite clearance.

Michelle Lee, a PhD candidate and the first author of the study explains, "We found that Plasmodium products continuously accumulate in the bone marrow niche, which turns the bone noticeably black in color, and results in it being ‘eaten-up’ by bone resorbing cells known as osteoclasts, eventually disrupting bone homeostasis".

The research team also investigated the impact of malaria infection on bone growth at a young age by infecting 3-week-old mice with PyNL. These mice had significantly shorter femurs and lower trabecular bone volume compared with uninfected litter mates 3 weeks after infection, when the mice were 6 weeks old.

A key finding of the study, investigators report, is that although Plasmodium infection resolves systemically, a state of chronic inflammation evolves in the bone marrow that may be associated with continued accumulation of Plasmodium byproducts—proteins, hemozoin, and nucleic acids—in the bone marrow. These byproducts are capable of modulating immune responses.

The team also evaluated whether vitamin D supplementation would alleviate bone loss caused by Plasmodium. They treated mice with alfacalcidol, which is used to treat osteoporosis. Treatment with lower doses of oral alfacalcidol was sufficient to prevent malaria-induced bone loss, while higher doses enhanced bone growth despite infection.

This work was supported by the Grants-in-Aid for Scientific Research, the Japan Agency for Medical Research and Development, the Uehara Memorial and Yamada Science, the Grant-in-Aid for Young Scientists, and a Japanese Government Scholarship (Ministry of Education, Culture, Sports, Science and Technology). 

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

A 32-year-old woman comes to your office for help with her recurrent migraines, which she’s had since her early 20s. She is otherwise healthy and active. She is frustrated by the frequency of her migraines and the resulting debilitation. She has tried prophylactic medications in the past but stopped taking them because of the adverse effects. What do you recommend for treatment?

Daily preventive medication can be helpful for patients whose chronic migraines have a significant impact on their lives. Many have a goal of reducing headache frequency, severity, and/or disability, while avoiding acute medication escalation.² An estimated 38% of patients with migraine are appropriate candidates for prophylactic therapy, but only 3% to 13% are taking preventive medications.³

Evidence-based guidelines from the American Academy of Neurology and the American Headache Society state that antiepileptic drugs (divalproex sodium, sodium valproate, topiramate) and many ß-blockers (metoprolol, propranolol, timolol) are effective and should be recommended for migraine prevention.² Medications such as antidepressants (amitriptyline, venlafaxine) and other ß-blockers (atenolol, nadolol) are probably effective and can be considered.² However, adverse effects—including somnolence—are listed as “frequent” with amitriptyline and “occasional to frequent” with topiramate.⁴

Researchers have investigated melatonin before. But a 2010 double-blind, crossover RCT of 46 patients with two to seven migraine attacks per month found no significant difference in reduction of headache frequency between extended-release melatonin (2 mg taken 1 h before bed) and placebo over an eight-week period.⁵

STUDY SUMMARY

More than 50% reduction in headache frequency

This RCT, conducted in Brazil, compared the effectiveness of melatonin to amitriptyline and placebo for migraine prevention in 196 adults (ages 18 to 65) with chronic migraine.¹ Eligible patients had a history of at least three migraine attacks or four migraine headache days per month. Patients were randomized to take identical-appearing melatonin (3 mg), amitriptyline (25 mg), or placebo nightly. The investigators appear to have concealed allocation adequately and used double-blinding.

The primary outcome was the number of headache days per month, compared to baseline. Secondary endpoints included reduction in migraine intensity, duration, number of analgesics used, and percentage of patients with more than 50% reduction in migraine headache days.

Compared to placebo, headache days per month were reduced in both the melatonin group (6.2 d vs 4.6 d, respectively; mean difference [MD], –1.6) and the amitriptyline group (6.2 d vs 5 d, respectively; MD, –1.2) at 12 weeks, based on intention-to-treat analysis. Mean headache intensity (0-10 pain scale) was also lower at 12 weeks in the melatonin group (4.8 vs 3.6; MD, –1.2) and in the amitriptyline group (4.8 vs 3.5; MD, –1.3), compared to placebo.

Headache duration (hours/month) at 12 weeks was reduced in both groups (MD, –4.4 h for amitriptyline and –4.8 h for melatonin), as was the number of analgesics used (MD for amitriptyline and for melatonin, –1) when compared to placebo. There was no significant difference between the melatonin and amitriptyline groups for these outcomes.

Patients taking melatonin were more likely to have more than 50% improvement in headache frequency compared to those taking amitriptyline (54% vs 39%; number needed to treat [NNT], 7). Melatonin worked much better than placebo (54% vs 20%; NNT, 3).

Adverse events were reported more often in the amitriptyline group than in the melatonin group (46 vs 16), with daytime sleepiness being the most frequent complaint (41% of patients in the amitriptyline group vs 18% of the melatonin group; number needed to harm [NNH], 5). There was no significant difference in adverse events between melatonin and placebo (16 vs 17). Melatonin resulted in weight loss (mean, –0.14 kg), whereas those taking amitriptyline gained weight (+0.97 kg).

WHAT’S NEW

Effective alternative with minimal adverse effects

Melatonin is an accessible and affordable option for prevention of migraine. The 3-mg dosing reduces headache frequency—measured by both the number of migraine headache days per month and the percentage of patients with a more than 50% reduction in headache events—as well as headache intensity, with minimal adverse effects.

CAVEATS

Product consistency, missing study data

This trial used 3-mg dosing, so it is not clear if other doses are also effective. In addition, melatonin’s OTC status means there could be a lack of consistency in quality/actual doses between brands.

Furthermore, in this trial, neither the amitriptyline nor the melatonin dose was titrated according to patient response or adverse effects, as it might be in clinical practice. As a result, we are not sure of the actual lowest effective dose or if greater effect (with continued minimal adverse effects) could be achieved with higher doses.

Lastly, 69% to 75% of patients in the treatment groups completed the 16-week trial, and the researchers reported using three different analytic techniques to estimate missing data. (For example, the primary endpoint analysis included data for 90.8% of randomized patients [178 of 196], and the authors treated all missing data as nonheadache days.) It is unclear how the missing data would affect the outcome—although in this type of analysis, it would tend toward a null effect.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible

There are really no challenges to implementing this practice changer; melatonin is readily available and is affordable.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[5]:320-322).

VANCOUVER – Not too long ago, clinicians at McMaster University in Hamilton, Ont., noticed that ulipristal acetate seemed to reduce pelvic pain in women who were taking it to shrink fibroids and reduce bleeding and other symptoms.

Fibroids aren’t usually painful, however, so they had a hunch it was helping with pain from other causes and decided to take a closer look.

[email protected]

VANCOUVER – Not too long ago, clinicians at McMaster University in Hamilton, Ont., noticed that ulipristal acetate seemed to reduce pelvic pain in women who were taking it to shrink fibroids and reduce bleeding and other symptoms.

Fibroids aren’t usually painful, however, so they had a hunch it was helping with pain from other causes and decided to take a closer look.

[email protected]

VANCOUVER – Not too long ago, clinicians at McMaster University in Hamilton, Ont., noticed that ulipristal acetate seemed to reduce pelvic pain in women who were taking it to shrink fibroids and reduce bleeding and other symptoms.

Fibroids aren’t usually painful, however, so they had a hunch it was helping with pain from other causes and decided to take a closer look.

[email protected]

WASHINGTON – A new way to semiquantitatively score chest x-rays that takes into account lung density and consolidation may be a useful adjunct to current methods for assessing severity of acute respiratory distress syndrome.

The score, know as the Radiographic Assessment of Lung Edema (RALE) score, showed good correlations with lung edema, the severity of acute respiratory distress syndrome (ARDS), and response to fluid management resulting in reduced pulmonary edema, Melissa A. Warren, MD, said at an international conference of the American Thoracic Society.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

WASHINGTON – A new way to semiquantitatively score chest x-rays that takes into account lung density and consolidation may be a useful adjunct to current methods for assessing severity of acute respiratory distress syndrome.

The score, know as the Radiographic Assessment of Lung Edema (RALE) score, showed good correlations with lung edema, the severity of acute respiratory distress syndrome (ARDS), and response to fluid management resulting in reduced pulmonary edema, Melissa A. Warren, MD, said at an international conference of the American Thoracic Society.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

WASHINGTON – A new way to semiquantitatively score chest x-rays that takes into account lung density and consolidation may be a useful adjunct to current methods for assessing severity of acute respiratory distress syndrome.

The score, know as the Radiographic Assessment of Lung Edema (RALE) score, showed good correlations with lung edema, the severity of acute respiratory distress syndrome (ARDS), and response to fluid management resulting in reduced pulmonary edema, Melissa A. Warren, MD, said at an international conference of the American Thoracic Society.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

PARIS – Does heart failure’s name doom any progress against the disease?

That was the provocative premise advanced by Lynne Warner Stevenson, MD, who suggested that efforts to prevent, diagnose, and treat the disease would go better if it could only jettison that unfortunate word “failure,” its hard-wired albatross.

Dr. Stevenson offered several potentially superior alternatives, including cardiac insufficiency, heart dysfunction, and her favorite, cardiomyopathy.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

PARIS – Does heart failure’s name doom any progress against the disease?

That was the provocative premise advanced by Lynne Warner Stevenson, MD, who suggested that efforts to prevent, diagnose, and treat the disease would go better if it could only jettison that unfortunate word “failure,” its hard-wired albatross.

Dr. Stevenson offered several potentially superior alternatives, including cardiac insufficiency, heart dysfunction, and her favorite, cardiomyopathy.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

PARIS – Does heart failure’s name doom any progress against the disease?

That was the provocative premise advanced by Lynne Warner Stevenson, MD, who suggested that efforts to prevent, diagnose, and treat the disease would go better if it could only jettison that unfortunate word “failure,” its hard-wired albatross.

Dr. Stevenson offered several potentially superior alternatives, including cardiac insufficiency, heart dysfunction, and her favorite, cardiomyopathy.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Community-based palliative care reduces emergency department visits

By Bryan J. Huang, MD, FHM

Retrospective cohort study showed that patients receiving community-based palliative care were less likely to seek ED care. The reduction was greater for older patients and for patients living in areas of higher socioeconomic status.

Time to intubation after cardiac arrest: Earlier may not be better

By Sarah Horman, MD

In a retrospective, observational, cohort study of 86,628 adults with in-hospital cardiac arrest, intubation during the first 15 minutes was associated with decreased survival, compared with no intubation.

Reference: Andersen, LW, Granfeldt, A, Callaway, CW, et al. Association between Tracheal intubation during adult in-hospital cardiac arrest and survival. JAMA. 2017;317(5):494-506.

DNR orders often not transferred to ED from outside care facilities

By Leslie M. Martin, MD

Prospective chart review of patients presenting from extended care facilities to an urban trauma center found hospital staff did a poor job of noting do not resuscitate preferences, and extended care facilities were inconsistent in providing their patients’ DNR forms.

Reference: McQuown CM, Frey JA, Amireh A, Chaudhary A. Transfer of do not resuscitate orders to the emergency department from extended care facilities. Am J Emerg Med. Published on 4 Feb 2017. doi: 10.1016/j.ajem.2017.02.007.

A quasi-experimental, before-after trial examining the impact of an emergency department mechanical ventilator protocol on clinical outcomes and lung-protective ventilation in acute respiratory distress syndrome

By William James Frederick III, MD, PhD

A single center, quasi-experimental, before-after trial shows a lung-protective mechanical ventilation protocol for emergency department and intensive care patients with Acute Respiratory Distress Syndrome reduced mortality and increased ventilator-free days.

Reference: Fuller BM, Ferguson IT, Mohr NM, et al. A Quasi-Experimental, Before-After Trial Examining the Impact of an Emergency Department Mechanical Ventilator Protocol on Clinical Outcomes and Lung-Protective Ventilation in Acute Respiratory Distress Syndrome. Crit Care Med. 2017;45(4);645-52.

Community-based palliative care reduces emergency department visits

By Bryan J. Huang, MD, FHM

Retrospective cohort study showed that patients receiving community-based palliative care were less likely to seek ED care. The reduction was greater for older patients and for patients living in areas of higher socioeconomic status.

Time to intubation after cardiac arrest: Earlier may not be better

By Sarah Horman, MD

In a retrospective, observational, cohort study of 86,628 adults with in-hospital cardiac arrest, intubation during the first 15 minutes was associated with decreased survival, compared with no intubation.

Reference: Andersen, LW, Granfeldt, A, Callaway, CW, et al. Association between Tracheal intubation during adult in-hospital cardiac arrest and survival. JAMA. 2017;317(5):494-506.

DNR orders often not transferred to ED from outside care facilities

By Leslie M. Martin, MD

Prospective chart review of patients presenting from extended care facilities to an urban trauma center found hospital staff did a poor job of noting do not resuscitate preferences, and extended care facilities were inconsistent in providing their patients’ DNR forms.

Reference: McQuown CM, Frey JA, Amireh A, Chaudhary A. Transfer of do not resuscitate orders to the emergency department from extended care facilities. Am J Emerg Med. Published on 4 Feb 2017. doi: 10.1016/j.ajem.2017.02.007.

A quasi-experimental, before-after trial examining the impact of an emergency department mechanical ventilator protocol on clinical outcomes and lung-protective ventilation in acute respiratory distress syndrome

By William James Frederick III, MD, PhD

A single center, quasi-experimental, before-after trial shows a lung-protective mechanical ventilation protocol for emergency department and intensive care patients with Acute Respiratory Distress Syndrome reduced mortality and increased ventilator-free days.

Reference: Fuller BM, Ferguson IT, Mohr NM, et al. A Quasi-Experimental, Before-After Trial Examining the Impact of an Emergency Department Mechanical Ventilator Protocol on Clinical Outcomes and Lung-Protective Ventilation in Acute Respiratory Distress Syndrome. Crit Care Med. 2017;45(4);645-52.

Community-based palliative care reduces emergency department visits

By Bryan J. Huang, MD, FHM

Retrospective cohort study showed that patients receiving community-based palliative care were less likely to seek ED care. The reduction was greater for older patients and for patients living in areas of higher socioeconomic status.

Time to intubation after cardiac arrest: Earlier may not be better

By Sarah Horman, MD

In a retrospective, observational, cohort study of 86,628 adults with in-hospital cardiac arrest, intubation during the first 15 minutes was associated with decreased survival, compared with no intubation.

Reference: Andersen, LW, Granfeldt, A, Callaway, CW, et al. Association between Tracheal intubation during adult in-hospital cardiac arrest and survival. JAMA. 2017;317(5):494-506.

DNR orders often not transferred to ED from outside care facilities

By Leslie M. Martin, MD

Prospective chart review of patients presenting from extended care facilities to an urban trauma center found hospital staff did a poor job of noting do not resuscitate preferences, and extended care facilities were inconsistent in providing their patients’ DNR forms.

Reference: McQuown CM, Frey JA, Amireh A, Chaudhary A. Transfer of do not resuscitate orders to the emergency department from extended care facilities. Am J Emerg Med. Published on 4 Feb 2017. doi: 10.1016/j.ajem.2017.02.007.

A quasi-experimental, before-after trial examining the impact of an emergency department mechanical ventilator protocol on clinical outcomes and lung-protective ventilation in acute respiratory distress syndrome

By William James Frederick III, MD, PhD

A single center, quasi-experimental, before-after trial shows a lung-protective mechanical ventilation protocol for emergency department and intensive care patients with Acute Respiratory Distress Syndrome reduced mortality and increased ventilator-free days.

Reference: Fuller BM, Ferguson IT, Mohr NM, et al. A Quasi-Experimental, Before-After Trial Examining the Impact of an Emergency Department Mechanical Ventilator Protocol on Clinical Outcomes and Lung-Protective Ventilation in Acute Respiratory Distress Syndrome. Crit Care Med. 2017;45(4);645-52.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.

Local anesthesia is a central component of successful interventions in cosmetic dermatology. The number of anesthetic medications and administration techniques has grown in recent years as outpatient cosmetic procedures continue to expand. Pain is a common barrier to cosmetic procedures, and alleviating the fear of painful interventions is critical to patient satisfaction and future visits. To accommodate a multitude of cosmetic interventions, it is important for clinicians to be well versed in applications of topical and regional anesthesia. In this article, we review pain management strategies for use in cosmetic practice.

Local Anesthetics

The sensation of pain is carried to the central nervous system by unmyelinated C nerve fibers. Local anesthetics (LAs) act by blocking fast voltage-gated sodium channels in the cell membrane of the nerve, thereby inhibiting downstream propagation of an action potential and the transmission of painful stimuli.¹ The chemical structure of LAs is fundamental to their mechanism of action and metabolism. Local anesthetics contain a lipophilic aromatic group, an intermediate chain, and a hydrophilic amine group. Broadly, agents are classified as amides or esters depending on the chemical group attached to the intermediate chain.² Amides (eg, lidocaine, bupivacaine, articaine, mepivacaine, prilocaine, levobupivacaine) are metabolized by the hepatic system; esters (eg, procaine, proparacaine, benzocaine, chlorprocaine, tetracaine, cocaine) are metabolized by plasma cholinesterase, which produces para-aminobenzoic acid, a potentially dangerous metabolite that has been implicated in allergic reactions.³

Lidocaine is the most prevalent LA used in dermatology practices. Importantly, lidocaine is a class IB antiarrhythmic agent used in cardiology to treat ventricular arrhythmias.⁴ As an anesthetic, a maximum dose of 4.5 mg/kg can be administered, increasing to 7.0 mg/kg when mixed with epinephrine; with higher doses, there is a risk for central nervous system and cardiovascular toxicity.⁵ Initial symptoms of lidocaine toxicity include dizziness, tinnitus, circumoral paresthesia, blurred vision, and a metallic taste in the mouth.⁶ Systemic absorption of topical anesthetics is heightened across mucosal membranes, and care should be taken when applying over large surface areas.

Allergic reactions to LAs may be local or less frequently systemic. It is important to note that LAs tend to show cross-reactivity within their class rather than across different classes.⁷ Reactions can be classified as type I or type IV. Type I (IgE-mediated) reactions evolve in minutes to hours, affecting the skin and possibly leading to respiratory and circulatory collapse. Delayed reactions to LAs have increased in recent years, with type IV contact allergy most frequently found in connection with benzocaine and lidocaine.⁸

Topical Anesthesia

Topical anesthetics are effective and easy to use and are particularly valuable in patients with needle phobia. In certain cases, these medications may be applied by the patient prior to arrival, thereby reducing visit time. Topical agents act on nerve fibers running through the dermis; therefore, efficacy is dependent on successful penetration through the stratum corneum and viable epidermis. To enhance absorption, agents may be applied under an occlusive dressing.

Topical anesthetics are most commonly used for injectable fillers, ablative and nonablative laser resurfacing, laser hair removal, and tattoo removal. The eutectic mixture of 2.5% lidocaine and 2.5% prilocaine as well as topical 4% or 5% lidocaine are the most commonly used US Food and Drug Administration–approved products for topical anesthesia. In addition, several compounded pharmacy products are available.

After 60 minutes of application of the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine, a 3-mm depth of analgesia is reached, and after 120 minutes, a 4.5-mm depth is reached.⁹ It elicits a biphasic vascular response of vasoconstriction and blanching followed by vasodilation and erythema.¹⁰ Most adverse events are mild and transient, but allergic contact dermatitis and contact urticaria have been reported.^11-13 In older children and adults, the maximum application area is 200 cm², with a maximum dose of 20 g used for no longer than 4 hours.

The 4% or 5% lidocaine cream uses a liposomal delivery system, which is designed to improve cutaneous penetration and has been shown to provide longer durations of anesthesia than nonliposomal lidocaine preparations.¹⁴ Application should be performed 30 to 60 minutes prior to a procedure. In a study comparing the eutectic mixture of 2.5% lidocaine and 2.5% prilocaine versus lidocaine cream 5% for pain control during laser hair removal with a 1064-nm Nd:YAG laser, no significant differences were found.¹⁵ The maximum application area is 100 cm² in children weighing less than 20 kg. A study of healthy adults demonstrated safety with the use of 30 to 60 g of occluded liposomal lidocaine cream 4%.¹⁶

In addition to US Food and Drug Administration–approved products, several compounded pharmacy products are available for topical anesthesia. These formulations include benzocaine-lidocaine-tetracaine gel, tetracaine-adrenaline-cocaine solution, and lidocaine-epinephrine-tetracaine solution. A triple-anesthetic gel, benzocaine-lidocaine-tetracaine is widely used in cosmetic practice. The product has been shown to provide adequate anesthesia for laser resurfacing after 20 minutes without occlusion.¹⁷ Of note, compounded anesthetics lack standardization, and different pharmacies may follow their own individual protocols.

Regional Anesthesia

Regional nerve blockade is a useful option for more widespread or complex interventions. Using regional nerve blockade, effective analgesia can be delivered to a target area while avoiding the toxicity and pain associated with numerous anesthetic infiltrations. In addition, there is no distortion of the tissue architecture, allowing for improved visual evaluation during the procedure. Recently, hyaluronic acid fillers have been compounded with lidocaine as a means of reducing procedural pain.

Blocks for Dermal Fillers

Forehead
For dermal filler injections of the glabellar and frontalis lines, anesthesia of the forehead may be desired. The supraorbital and supratrochlear nerves supply this area. The supraorbital nerve can be injected at the supraorbital notch, which is measured roughly 2.7 cm from the glabella. The orbital rim should be palpated with the nondominant hand, and 1 to 2 mL of anesthetic should be injected just below the rim (Figure 1). The supratrochlear nerve is located roughly 1.7 cm from the midline and can be similarly injected under the orbital rim with 1 to 2 mL of anesthetic (Figure 1).

Lateral Temple Region
Anesthesia of the zygomaticotemporal nerve can be used to reduce pain from dermal filler injections of the lateral canthal and temporal areas. The nerve is identified by first palpating the zygomaticofrontal suture. A long needle is then inserted posteriorly, immediately behind the concave surface of the lateral orbital rim, and 1 to 2 mL of anesthetic is injected (Figure 1).

Malar Region
Blockade of the zygomaticofacial nerve is commonly performed in conjunction with the zygomaticotemporal nerve and provides anesthesia to the malar region for cheek augmentation procedures. To identify the target area, the junction of the lateral and inferior orbital rim should be palpated. With the needle placed just lateral to this point, 1 to 2 mL of anesthetic is injected (Figure 1).

Blocks for Perioral Fillers

Upper Lips/Nasolabial Folds
Bilateral blockade of the infraorbital nerves provides anesthesia to the upper lip and nasolabial folds prior to filler injections. The infraorbital nerve can be targeted via an intraoral route where it exits the maxilla at the infraorbital foramen. The nerve is anesthetized by palpating the infraorbital ridge and injecting 3 to 5 mL of anesthetic roughly 1 cm below this point on the vertical axis of the midpupillary line (Figure 1). The external nasal nerve, thought to be a branch of cranial nerve V, also may be targeted if there is inadequate anesthesia from the infraorbital block. This nerve is reached by injecting at the osseocartilaginous junction of the nasal bones (Figure 1).

Lower Lips
Blockade of the mental nerve provides anesthesia to the lower lips for augmentation procedures. The mental nerve can be targeted on each side at the mental foramen, which is located below the root of the lower second premolar. Aiming roughly 1 cm below the gumline, 3 to 5 mL of anesthetic is injected intraorally (Figure 1). A transcutaneous approach toward the same target also is possible, though this technique risks visible bruising. Alternatively, the upper or lower lips can be anesthetized using 4 to 5 submucosal injections at evenly spaced intervals between the canine teeth.¹⁸

Blocks for Palmoplantar Hyperhidrosis

The treatment of palmoplantar hyperhidrosis benefits from regional blocks. Botulinum toxin has been well established as an effective therapy for the condition.^19-21 Given the sensitivity of palmoplantar sites, it is valuable to achieve effective analgesia of the region prior to dermal injections of botulinum toxin.

Wrists
Sensory innervation of the palm is provided by the median, ulnar, and radial nerves (Figure 2A). At the wrist, the median nerve lies between the tendons of the flexor carpi radialis muscle and the palmaris longus muscle. To facilitate identification of the palmaris longus muscle, instruct the patient to oppose the thumb and little finger while flexing the wrist. The needle should be inserted between the 2 tendons, just proximal to the wrist creases (Figure 2B). Once the fascia is pierced, 3 to 5 mL of anesthetic is injected.

The ulnar nerve is anesthetized between the ulnar artery and the flexor carpi ulnaris muscle. The artery is identified by palpation, and special care should be taken to avoid intra-arterial injection. The needle is directed toward the radial styloid, and 3 to 5 mL of anesthetic is injected roughly 1 cm proximal to the wrist crease (Figure 2B).

Anesthesia of the radial nerve can be considered a field block given the numerous small branches that supply the hand. These branches are reached by injecting anesthetic roughly 2 to 3 cm proximal to the radial styloid with the needle aimed medially and extending the injection dorsally (Figure 2B). A total of 4 to 6 mL of anesthetic is used.

Ankles
An ankle block provides anesthesia to the dorsal and plantar surfaces of the foot.²² The region is supplied by the superficial peroneal nerve, deep peroneal nerve, sural nerve, saphenous nerve, and branches of the posterior tibial nerve (Figure 3A).

To anesthetize the deep peroneal nerve, the extensor hallucis longus tendon is first identified on the anterior surface of the ankle through dorsiflexion of the toes; the dorsalis pedis artery runs in close proximity. The injection should be placed lateral to the tendon and artery (Figure 3B). The needle should be inserted until bone is reached, withdrawn slightly, and then 3 to 5 mL of anesthetic should be injected. To block the saphenous nerve, the needle can then be directed superficially toward the medial malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C). To block the superficial peroneal nerve, the needle should then be directed toward the lateral malleolus, and 3 to 5 mL should be injected in a subcutaneous wheal (Figure 3C).

The posterior tibial nerve is located posterior to the medial malleolus. The dorsalis pedis artery can be palpated near this location. The needle should be inserted posterior to the artery, extending until bone is reached (Figure 3C). The needle is then withdrawn slightly, and 3 to 5 mL of anesthetic is injected. Finally, the sural nerve is anesthetized between the Achilles tendon and the lateral malleolus, using 5 mL of anesthetic to raise a subcutaneous wheal (Figure 3C).

Conclusion

Proper pain management is integral to ensuring a positive experience for cosmetic patients. Enhanced knowledge of local anesthetic techniques allows the clinician to provide for a variety of procedural indications and patient preferences. As anesthetic strategies are continually evolving, it is important for practitioners to remain informed of these developments.

Avène Complexion Correcting Shield SPF 50+

Pierre Fabre Dermo-Cosmetique USA adds the Avène Complexion Correcting Shield SPF 50+ mineral sunscreen to its physician-dispensed sun care line. This tinted moisturizer, available in 3 shades, provides 24-hour hydration and an effective antioxidant defense against sun-induced free radicals. Avène Complexion Correcting Shield provides an instant blurring effect to camouflage skin imperfections such as large pores, uneven skin tone, redness, fine lines, and wrinkles. For more information, visit www.aveneusa.com.

Coppertone Clearly Sheer Whipped Sunscreen

Bayer introduces Coppertone Clearly Sheer Whipped Sunscreen, a rich and creamy formula available in sun protection factor 30 and 50. Coppertone Clearly Sheer Whipped Sunscreen absorbs quickly to leave skin feeling soft and smooth. It offers broad-spectrum UVA/UVB protection and is water resistant for up to 80 minutes.For more information, visit www.coppertone.com.

DerMend Mature Skin Solutions

Ferndale Healthcare launches DerMend Mature Skin Solutions, an over-the-counter line consisting of 3 products specifically designed for patients aged 50 years and older. The Fragile Skin Moisturizing Formula rejuvenates thin and fragile skin with hyaluronic acid, retinol, glycolic acid, niacinaminde, and 5 ceramides. The Moisturizing Anti-Itch Lotion is steroid free and contains pramoxine hydrochloride 1% to provide temporary relief of itching associated with minor skin irritations. The Moisturizing Bruise Formula (cream or lotion) improves the appearance of bruised skin with a blend of ceramides, glycolic acid, arnica oil, and retinol to restore and rejuvenate the skin’s natural barrier. For more information, visit www.dermend.com.

Jan Marini Sunscreens

Jan Marini Skin Research, Inc, introduces Antioxidant Daily Face Protectant SPF 33 and Marini Physical Protectant SPF 45, both providing broad-spectrum UVA/UVB protection. Antioxidant Daily Face Protectant provides oil control and advanced hydration for daily use to reduce and address damage caused by sun exposure. Marini Physical Protectant utilizes purely physical filters to decrease the risk of premature skin aging and features a universal tint with a sheer matte finish. For more information, visit www.janmarini.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Avène Complexion Correcting Shield SPF 50+

Pierre Fabre Dermo-Cosmetique USA adds the Avène Complexion Correcting Shield SPF 50+ mineral sunscreen to its physician-dispensed sun care line. This tinted moisturizer, available in 3 shades, provides 24-hour hydration and an effective antioxidant defense against sun-induced free radicals. Avène Complexion Correcting Shield provides an instant blurring effect to camouflage skin imperfections such as large pores, uneven skin tone, redness, fine lines, and wrinkles. For more information, visit www.aveneusa.com.

Coppertone Clearly Sheer Whipped Sunscreen

Bayer introduces Coppertone Clearly Sheer Whipped Sunscreen, a rich and creamy formula available in sun protection factor 30 and 50. Coppertone Clearly Sheer Whipped Sunscreen absorbs quickly to leave skin feeling soft and smooth. It offers broad-spectrum UVA/UVB protection and is water resistant for up to 80 minutes.For more information, visit www.coppertone.com.

DerMend Mature Skin Solutions

Ferndale Healthcare launches DerMend Mature Skin Solutions, an over-the-counter line consisting of 3 products specifically designed for patients aged 50 years and older. The Fragile Skin Moisturizing Formula rejuvenates thin and fragile skin with hyaluronic acid, retinol, glycolic acid, niacinaminde, and 5 ceramides. The Moisturizing Anti-Itch Lotion is steroid free and contains pramoxine hydrochloride 1% to provide temporary relief of itching associated with minor skin irritations. The Moisturizing Bruise Formula (cream or lotion) improves the appearance of bruised skin with a blend of ceramides, glycolic acid, arnica oil, and retinol to restore and rejuvenate the skin’s natural barrier. For more information, visit www.dermend.com.

Jan Marini Sunscreens

Jan Marini Skin Research, Inc, introduces Antioxidant Daily Face Protectant SPF 33 and Marini Physical Protectant SPF 45, both providing broad-spectrum UVA/UVB protection. Antioxidant Daily Face Protectant provides oil control and advanced hydration for daily use to reduce and address damage caused by sun exposure. Marini Physical Protectant utilizes purely physical filters to decrease the risk of premature skin aging and features a universal tint with a sheer matte finish. For more information, visit www.janmarini.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Avène Complexion Correcting Shield SPF 50+

Pierre Fabre Dermo-Cosmetique USA adds the Avène Complexion Correcting Shield SPF 50+ mineral sunscreen to its physician-dispensed sun care line. This tinted moisturizer, available in 3 shades, provides 24-hour hydration and an effective antioxidant defense against sun-induced free radicals. Avène Complexion Correcting Shield provides an instant blurring effect to camouflage skin imperfections such as large pores, uneven skin tone, redness, fine lines, and wrinkles. For more information, visit www.aveneusa.com.

Coppertone Clearly Sheer Whipped Sunscreen

Bayer introduces Coppertone Clearly Sheer Whipped Sunscreen, a rich and creamy formula available in sun protection factor 30 and 50. Coppertone Clearly Sheer Whipped Sunscreen absorbs quickly to leave skin feeling soft and smooth. It offers broad-spectrum UVA/UVB protection and is water resistant for up to 80 minutes.For more information, visit www.coppertone.com.

DerMend Mature Skin Solutions

Ferndale Healthcare launches DerMend Mature Skin Solutions, an over-the-counter line consisting of 3 products specifically designed for patients aged 50 years and older. The Fragile Skin Moisturizing Formula rejuvenates thin and fragile skin with hyaluronic acid, retinol, glycolic acid, niacinaminde, and 5 ceramides. The Moisturizing Anti-Itch Lotion is steroid free and contains pramoxine hydrochloride 1% to provide temporary relief of itching associated with minor skin irritations. The Moisturizing Bruise Formula (cream or lotion) improves the appearance of bruised skin with a blend of ceramides, glycolic acid, arnica oil, and retinol to restore and rejuvenate the skin’s natural barrier. For more information, visit www.dermend.com.

Jan Marini Sunscreens

Jan Marini Skin Research, Inc, introduces Antioxidant Daily Face Protectant SPF 33 and Marini Physical Protectant SPF 45, both providing broad-spectrum UVA/UVB protection. Antioxidant Daily Face Protectant provides oil control and advanced hydration for daily use to reduce and address damage caused by sun exposure. Marini Physical Protectant utilizes purely physical filters to decrease the risk of premature skin aging and features a universal tint with a sheer matte finish. For more information, visit www.janmarini.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

MADRID – Ninety percent of children with acute hematogenous osteomyelitis will do fine after their initial course of antibiotics and don’t require long-term follow-up; and the other 10% can be identified within the first few days of hospitalization, Lawson A. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

The tool that enables physicians to distinguish the 10% of children at high risk for severe orthopedic sequelae is a validated severity of illness score that can be determined within the first several days of hospitalization. The 0-10 score, developed by Dr. Copley and his coinvestigators (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879), awards points for the patient’s initial C-reactive protein level, the C-reactive protein levels on hospital days 2-3 and 4-5, the number of febrile days on antibiotic therapy, the band percentage of WBC, ICU admission, and disseminated disease such as endocarditis, septic pulmonary embolism, and deep venous thrombosis.

[email protected]
 

MADRID – Ninety percent of children with acute hematogenous osteomyelitis will do fine after their initial course of antibiotics and don’t require long-term follow-up; and the other 10% can be identified within the first few days of hospitalization, Lawson A. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

The tool that enables physicians to distinguish the 10% of children at high risk for severe orthopedic sequelae is a validated severity of illness score that can be determined within the first several days of hospitalization. The 0-10 score, developed by Dr. Copley and his coinvestigators (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879), awards points for the patient’s initial C-reactive protein level, the C-reactive protein levels on hospital days 2-3 and 4-5, the number of febrile days on antibiotic therapy, the band percentage of WBC, ICU admission, and disseminated disease such as endocarditis, septic pulmonary embolism, and deep venous thrombosis.

[email protected]
 

MADRID – Ninety percent of children with acute hematogenous osteomyelitis will do fine after their initial course of antibiotics and don’t require long-term follow-up; and the other 10% can be identified within the first few days of hospitalization, Lawson A. Copley, MD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.

The tool that enables physicians to distinguish the 10% of children at high risk for severe orthopedic sequelae is a validated severity of illness score that can be determined within the first several days of hospitalization. The 0-10 score, developed by Dr. Copley and his coinvestigators (J Pediatr Orthop. 2016 Oct 12. doi: 10.1097/BPO.0000000000000879), awards points for the patient’s initial C-reactive protein level, the C-reactive protein levels on hospital days 2-3 and 4-5, the number of febrile days on antibiotic therapy, the band percentage of WBC, ICU admission, and disseminated disease such as endocarditis, septic pulmonary embolism, and deep venous thrombosis.

[email protected]
 

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.

CHICAGO – Larotrectinib, an oral inhibitor of tropomyosin receptor kinase (TRK), has durable efficacy across diverse adult and pediatric cancers that harbor a genetic aberration known as TRK fusion, finds an analysis of three trials reported at the annual meeting of the American Society of Clinical Oncology.

Fusion of a TRK gene with an unrelated gene leads to uncontrolled signaling in the TRK pathway, potentially causing tumor growth and addiction to this input, lead author David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center in New York explained in a press briefing.

Susan London/Frontline Medical News

Expert perspective

The data for larotrectinib “really bring us into a new era where treatment is truly based on mutation, not location,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope, in Duarte, Calif. “When I was in training, which was not too long ago, it really would have been a pipe dream to think that we could have treated cancers independent of their site of origin. … With the data presented by Dr. Hyman for larotrectinib, we may now be poised to treat many cancers in a manner that is agnostic of their site of origin and that is instead based on molecular criteria.

Susan London/Frontline Medical News

TRK testing

Several next-generation sequencing–based tests already available clinically can pick up TRK fusions, Dr. Hyman pointed out. “But it is important for the ordering physician to understand whether the tests they are ordering includes fusion detection and, if it’s an option, to select it. Otherwise, they will not find TRK fusions.

“The list price for these tests is in the kind of low thousands of dollars, which equates essentially to a PET scan for the cancer patient,” he noted. In cancers where sequential single-gene testing is already being done as standard of care, there is “minimal” incremental cost of instead using comprehensive testing that would detect TRK fusions.

Oncologists should be aware that obtaining test results can take weeks, Dr. Hyman stressed. “My personal opinion is that this [testing] should be more broadly adopted and should be adopted at a point in the patient’s treatment … [so that they] don’t become too sick, as we see in our own experience as well, and don’t have an opportunity to be treated even when the test results come back positive. So I would generally advocate early testing.”

Study details

For the study, which was funded by Loxo Oncology, the investigators analyzed data from three trials in which patients with advanced TRK fusion–positive solid cancers received larotrectinib (LOXO-101): a phase I trial among 8 adult patients, a phase I/II trial among 12 pediatric patients (SCOUT), and a phase II “basket” trial among 35 adult and adolescent patients (NAVIGATE).

“I want to emphasize that these patients were identified by local testing,” Dr. Hyman noted. “We did not perform central screening to find the TRK fusions, and in fact, 50 different laboratories identified the 55 patients. So this in a sense really represents the real-world identification of these patients.”

In an integrated analysis, the overall rate of confirmed response as assessed by investigators was 76%, with complete response in 12% of patients and partial response in 64%. Two patients had such deep tumor regression that they experienced downstaging enabling them to undergo potentially curative surgery. Efficacy was consistent regardless of tumor type, which TRK gene was affected, and the fusion partner gene.

Median time to response was 1.8 months. “This is actually just a reflection of when the first scan was obtained. But in the clinic, patients reported dramatic improvement of their symptoms within days of beginning therapy,” Dr. Hyman said.

With a median follow-up of 5.8 months, the median duration of response was not yet reached. Fully 79% of responses were still ongoing at 12 months. Median progression-free survival was likewise not reached; the 12-month rate was 63%.

The leading treatment-emergent adverse events were fatigue (38%), dizziness (27%), nausea (26%), and anemia (26%). “This is an extremely well tolerated therapy with only 13% of patients requiring any form of dose modification and not a single patient discontinuing due to adverse events,” he said.

It is unclear why some patients had apparent primary resistance to larotrectinib, but their TRK fusion test results may have been incorrect, Dr. Hyman speculated. Six patients developed acquired resistance to larotrectinib; five of them were found to have an identical resistance mutation, and two went on to receive and have a response to LOXO-195, a next-generation TRK inhibitor that appears to retain activity in the presence of this mutation (Cancer Discov. 2017 June 3. doi: 10.1158/2159-8290.CD-17-0507).

Dr. Hyman disclosed that he has a consulting or advisory role with Atara Biotherapeutics, Chugai Pharma, and CytomX Therapeutics, and that he receives research funding from AstraZeneca and Puma Biotechnology.