Honeybees (Apis mellifera, A. cerana, A. dorsata, A. floria, A. andreniformis, A. koschevnikov, and A. laborisa) play a key role in propagating numerous plants, flower nectar, and flower pollen as well as in pollinating approximately one-third of common agricultural crops, including fruits, vegetables, nuts, and seeds (Time magazine; Proc. Biol. Sci. 2007;274[1608]:303-13). Indeed, the honeybee is the lone insect that produces food regularly consumed by human beings (Am. J. Ther. 2014;21:304-23). Honey, which contains more than 180 compounds, is produced by honeybees from flower nectar. This sweet food product is supersaturated in sugar, and also contains phenolic acids, flavonoids, ascorbic acid, alpha-tocopherol, carotenoids, the enzymes glucose oxidase and catalase, organic and amino acids, and proteins (J. Food Sci. 2008;73:R117-24). Honey has been used since ancient times in Ayurvedic medicine to treat diabetes and has long been used to treat infected wounds (Ayu 2012;33:178-82; Clin. Infect. Dis. 2009;49:1541-9). Currently, honey is used in Ayurvedic medicine to treat acne, and it is incorporated in various cosmetic formulations such as facial washes, skin moisturizers, and hair conditioners (Ayu 2012;33:178-82).

History

For at least 2,700 years, traditional medical practice has included the use of topically applied honey for various conditions, with many modern researchers retrospectively attributing this usage to the antibacterial activity of honey (Am. J. Ther. 2014;21:304-23; Clin. Infect. Dis. 2008;46:1677-82). Honey served as a potent anti-inflammatory and antibacterial agent in folk remedies in ancient Egypt, Greece, and Rome, with written references to the medical application of bee products dating back to ancientEgypt, India, and China (Am. J. Ther. 2014;21:304-23; Cancer Res. 1993;53:1255-61; Evid. Based Complement. Alternat. Med. 2013;2013:697390)). For more than 4,000 years, honey has been used in Ayurvedic medicine, and its use has been traced to the Xin dynasty in China (Am. J. Ther. 2014;21:304-23). The antibacterial characteristics of honey were first reported in 1892 (IUBMB Life 2012;64:48-55). Russia and Germany used honey for wound treatment through World War I. The traditional medical application of honey began to subside with the advent of antibiotics in the 1940s(Burns 2013; 39:1514-25; Int. J. Clin. Pract. 2007;61:1705-7).

Chemistry

Myriad biological functions are associated with honey (antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral) and ascribed mainly to its constituent phenolic compounds, such as flavonoids, including chrysin (J. Food Sci. 2008;73:R117-24). Indeed, medical grade honeys such as manuka honey (a monofloral honey derived from Leptospermum scoparium, a member of the Myrtaceae family, native to New Zealand) and Medihoney® (a standardized mix of Australian and New Zealand honeys) are rich in flavonoids (Int. J. Clin. Pract. 2007;61:1705-7;J. Int. Acad. Periodontol. 2004;6:63-7; Evid. Based Complement. Alternat. Med. 2009;6:165-73;J. Agric. Food Chem. 2012;60:7229-37). Honey has a pH ranging from 3.2 to 4.5 and an acidity level that stymies the growth of many microorganisms (Burns 2013;39:1514-25; J. Clin. Nurs. 2008;17:2604-23; Nurs. Times. 2006;102:40-2; Br. J. Community Nurs. 2004;Suppl:S21-7 ).

Antibacterial activity

In 2008, Kwakman et al. found that within 24 hours, 10%-40% (vol/vol) medical grade honey (Revamil) destroyed antibiotic-susceptible and antibiotic-resistant isolates of Staphylococcus aureus,S. epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca. After 2 days of honey application, they also observed a 100-fold decrease in forearm skin colonization in healthy volunteers, with the number of positive skin cultures declining by 76%. The researchers concluded that Revamil exhibits significant potential to prevent or treat infections, including those spawned by multidrug-resistant bacteria (Clin. Infect. Dis. 2008;46:1677-82). Honey has been demonstrated to be clinically effective in treating several kinds of wound infections, reducing skin colonization of multiple bacteria, including methicillin-resistant S. aureus (Clin. Infect. Dis. 2008;46:1677-82) and enhancing wound healing, without provoking adverse effects ( Clin. Infect. Dis. 2009;49:1541-9). Manuka honey and Medihoney are the main forms of medical grade honey used in clinical practice. Nonmedical grade honey may contain viable bacterial spores (including clostridia), and manifest less predictable antibacterial properties (Clin. Infect. Dis. 2009;49:1541-9).

Honey is used in over-the-counter products as a moisturizing agent and in hair-conditioning products based on its strong humectant properties. It is also used in home remedies to treat burns, wounds, eczema, and dermatitis, especially in Asia (Ayu 2012;33:178-8).

Seborrheic dermatitis/dandruff

In 2001, Al-Waili assessed the potential of topically applied crude honey (90% honey diluted in warm water) to treat chronic seborrheic dermatitis of the scalp, face, and chest in 30 patients (20 males and 10 females, aged 15-60 years). Over the initial 4 weeks of treatment, honey was gently rubbed onto lesions every other day for 2-3 minutes at a time, with the ointment left on for 3 hours before gentle warm-water rinsing. Then, in a 6-month prophylactic phase, the participants were divided into a once-weekly treatment group and a control group. Skin lesions healed completely within 2 weeks in the treatment group, after significant reductions in itching and scaling in just the first week. Subjective improvements in hair loss were also reported. Relapse was observed in 12 of the 15 subjects in the control group within 2-4 months of therapy cessation and none in the treatment group. The author concluded that weekly use of crude honey significantly improves seborrheic dermatitis symptoms and related hair loss (Eur. J. Med. Res. 2001;6:306-8).

Wound healing

In February 2013, Jull published a review of 25 randomized and quasirandomized trials evaluating honey in the treatment of acute or chronic wounds, finding that honey might delay healing in partial- and full-thickness burns, compared with early excision and grafting, but it does not significantly enhance healing of chronic venous leg ulcers. They suggested that while honey may prove to be more effective than some conventional dressings for such ulcers, evidence is currently insufficient to support this claim ( Cochrane Database Syst. Rev. 2013;2:CD005083). Later that year, Vandamme et al. identified 55 studies in a literature review suggesting that honey stimulates healing of burns, ulcers, and other wounds. They also found, despite some methodologic concerns, that honey exerts antibacterial activity in burn treatment and deodorizing, debridement, anti-inflammatory, and analgesic activity ( Burns 2013;39:1514-25).

Conclusion

Honey has a long history of traditional medicinal use and has been found to display significant biologic activity, including antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral. The antibacterial properties of honey are particularly compelling. While more research, in the form of randomized, controlled trials, is needed prior to incorporating bee products into the dermatologic armamentarium as first-line therapies, the potential of honey usage for skin care is promising.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (McGraw-Hill, April 2002), and a book for consumers, “The Skin Type Solution” (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Honeybees (Apis mellifera, A. cerana, A. dorsata, A. floria, A. andreniformis, A. koschevnikov, and A. laborisa) play a key role in propagating numerous plants, flower nectar, and flower pollen as well as in pollinating approximately one-third of common agricultural crops, including fruits, vegetables, nuts, and seeds (Time magazine; Proc. Biol. Sci. 2007;274[1608]:303-13). Indeed, the honeybee is the lone insect that produces food regularly consumed by human beings (Am. J. Ther. 2014;21:304-23). Honey, which contains more than 180 compounds, is produced by honeybees from flower nectar. This sweet food product is supersaturated in sugar, and also contains phenolic acids, flavonoids, ascorbic acid, alpha-tocopherol, carotenoids, the enzymes glucose oxidase and catalase, organic and amino acids, and proteins (J. Food Sci. 2008;73:R117-24). Honey has been used since ancient times in Ayurvedic medicine to treat diabetes and has long been used to treat infected wounds (Ayu 2012;33:178-82; Clin. Infect. Dis. 2009;49:1541-9). Currently, honey is used in Ayurvedic medicine to treat acne, and it is incorporated in various cosmetic formulations such as facial washes, skin moisturizers, and hair conditioners (Ayu 2012;33:178-82).

History

For at least 2,700 years, traditional medical practice has included the use of topically applied honey for various conditions, with many modern researchers retrospectively attributing this usage to the antibacterial activity of honey (Am. J. Ther. 2014;21:304-23; Clin. Infect. Dis. 2008;46:1677-82). Honey served as a potent anti-inflammatory and antibacterial agent in folk remedies in ancient Egypt, Greece, and Rome, with written references to the medical application of bee products dating back to ancientEgypt, India, and China (Am. J. Ther. 2014;21:304-23; Cancer Res. 1993;53:1255-61; Evid. Based Complement. Alternat. Med. 2013;2013:697390)). For more than 4,000 years, honey has been used in Ayurvedic medicine, and its use has been traced to the Xin dynasty in China (Am. J. Ther. 2014;21:304-23). The antibacterial characteristics of honey were first reported in 1892 (IUBMB Life 2012;64:48-55). Russia and Germany used honey for wound treatment through World War I. The traditional medical application of honey began to subside with the advent of antibiotics in the 1940s(Burns 2013; 39:1514-25; Int. J. Clin. Pract. 2007;61:1705-7).

Chemistry

Myriad biological functions are associated with honey (antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral) and ascribed mainly to its constituent phenolic compounds, such as flavonoids, including chrysin (J. Food Sci. 2008;73:R117-24). Indeed, medical grade honeys such as manuka honey (a monofloral honey derived from Leptospermum scoparium, a member of the Myrtaceae family, native to New Zealand) and Medihoney® (a standardized mix of Australian and New Zealand honeys) are rich in flavonoids (Int. J. Clin. Pract. 2007;61:1705-7;J. Int. Acad. Periodontol. 2004;6:63-7; Evid. Based Complement. Alternat. Med. 2009;6:165-73;J. Agric. Food Chem. 2012;60:7229-37). Honey has a pH ranging from 3.2 to 4.5 and an acidity level that stymies the growth of many microorganisms (Burns 2013;39:1514-25; J. Clin. Nurs. 2008;17:2604-23; Nurs. Times. 2006;102:40-2; Br. J. Community Nurs. 2004;Suppl:S21-7 ).

Antibacterial activity

In 2008, Kwakman et al. found that within 24 hours, 10%-40% (vol/vol) medical grade honey (Revamil) destroyed antibiotic-susceptible and antibiotic-resistant isolates of Staphylococcus aureus,S. epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca. After 2 days of honey application, they also observed a 100-fold decrease in forearm skin colonization in healthy volunteers, with the number of positive skin cultures declining by 76%. The researchers concluded that Revamil exhibits significant potential to prevent or treat infections, including those spawned by multidrug-resistant bacteria (Clin. Infect. Dis. 2008;46:1677-82). Honey has been demonstrated to be clinically effective in treating several kinds of wound infections, reducing skin colonization of multiple bacteria, including methicillin-resistant S. aureus (Clin. Infect. Dis. 2008;46:1677-82) and enhancing wound healing, without provoking adverse effects ( Clin. Infect. Dis. 2009;49:1541-9). Manuka honey and Medihoney are the main forms of medical grade honey used in clinical practice. Nonmedical grade honey may contain viable bacterial spores (including clostridia), and manifest less predictable antibacterial properties (Clin. Infect. Dis. 2009;49:1541-9).

Honey is used in over-the-counter products as a moisturizing agent and in hair-conditioning products based on its strong humectant properties. It is also used in home remedies to treat burns, wounds, eczema, and dermatitis, especially in Asia (Ayu 2012;33:178-8).

Seborrheic dermatitis/dandruff

In 2001, Al-Waili assessed the potential of topically applied crude honey (90% honey diluted in warm water) to treat chronic seborrheic dermatitis of the scalp, face, and chest in 30 patients (20 males and 10 females, aged 15-60 years). Over the initial 4 weeks of treatment, honey was gently rubbed onto lesions every other day for 2-3 minutes at a time, with the ointment left on for 3 hours before gentle warm-water rinsing. Then, in a 6-month prophylactic phase, the participants were divided into a once-weekly treatment group and a control group. Skin lesions healed completely within 2 weeks in the treatment group, after significant reductions in itching and scaling in just the first week. Subjective improvements in hair loss were also reported. Relapse was observed in 12 of the 15 subjects in the control group within 2-4 months of therapy cessation and none in the treatment group. The author concluded that weekly use of crude honey significantly improves seborrheic dermatitis symptoms and related hair loss (Eur. J. Med. Res. 2001;6:306-8).

Wound healing

In February 2013, Jull published a review of 25 randomized and quasirandomized trials evaluating honey in the treatment of acute or chronic wounds, finding that honey might delay healing in partial- and full-thickness burns, compared with early excision and grafting, but it does not significantly enhance healing of chronic venous leg ulcers. They suggested that while honey may prove to be more effective than some conventional dressings for such ulcers, evidence is currently insufficient to support this claim ( Cochrane Database Syst. Rev. 2013;2:CD005083). Later that year, Vandamme et al. identified 55 studies in a literature review suggesting that honey stimulates healing of burns, ulcers, and other wounds. They also found, despite some methodologic concerns, that honey exerts antibacterial activity in burn treatment and deodorizing, debridement, anti-inflammatory, and analgesic activity ( Burns 2013;39:1514-25).

Conclusion

Honey has a long history of traditional medicinal use and has been found to display significant biologic activity, including antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral. The antibacterial properties of honey are particularly compelling. While more research, in the form of randomized, controlled trials, is needed prior to incorporating bee products into the dermatologic armamentarium as first-line therapies, the potential of honey usage for skin care is promising.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (McGraw-Hill, April 2002), and a book for consumers, “The Skin Type Solution” (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Honeybees (Apis mellifera, A. cerana, A. dorsata, A. floria, A. andreniformis, A. koschevnikov, and A. laborisa) play a key role in propagating numerous plants, flower nectar, and flower pollen as well as in pollinating approximately one-third of common agricultural crops, including fruits, vegetables, nuts, and seeds (Time magazine; Proc. Biol. Sci. 2007;274[1608]:303-13). Indeed, the honeybee is the lone insect that produces food regularly consumed by human beings (Am. J. Ther. 2014;21:304-23). Honey, which contains more than 180 compounds, is produced by honeybees from flower nectar. This sweet food product is supersaturated in sugar, and also contains phenolic acids, flavonoids, ascorbic acid, alpha-tocopherol, carotenoids, the enzymes glucose oxidase and catalase, organic and amino acids, and proteins (J. Food Sci. 2008;73:R117-24). Honey has been used since ancient times in Ayurvedic medicine to treat diabetes and has long been used to treat infected wounds (Ayu 2012;33:178-82; Clin. Infect. Dis. 2009;49:1541-9). Currently, honey is used in Ayurvedic medicine to treat acne, and it is incorporated in various cosmetic formulations such as facial washes, skin moisturizers, and hair conditioners (Ayu 2012;33:178-82).

History

For at least 2,700 years, traditional medical practice has included the use of topically applied honey for various conditions, with many modern researchers retrospectively attributing this usage to the antibacterial activity of honey (Am. J. Ther. 2014;21:304-23; Clin. Infect. Dis. 2008;46:1677-82). Honey served as a potent anti-inflammatory and antibacterial agent in folk remedies in ancient Egypt, Greece, and Rome, with written references to the medical application of bee products dating back to ancientEgypt, India, and China (Am. J. Ther. 2014;21:304-23; Cancer Res. 1993;53:1255-61; Evid. Based Complement. Alternat. Med. 2013;2013:697390)). For more than 4,000 years, honey has been used in Ayurvedic medicine, and its use has been traced to the Xin dynasty in China (Am. J. Ther. 2014;21:304-23). The antibacterial characteristics of honey were first reported in 1892 (IUBMB Life 2012;64:48-55). Russia and Germany used honey for wound treatment through World War I. The traditional medical application of honey began to subside with the advent of antibiotics in the 1940s(Burns 2013; 39:1514-25; Int. J. Clin. Pract. 2007;61:1705-7).

Chemistry

Myriad biological functions are associated with honey (antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral) and ascribed mainly to its constituent phenolic compounds, such as flavonoids, including chrysin (J. Food Sci. 2008;73:R117-24). Indeed, medical grade honeys such as manuka honey (a monofloral honey derived from Leptospermum scoparium, a member of the Myrtaceae family, native to New Zealand) and Medihoney® (a standardized mix of Australian and New Zealand honeys) are rich in flavonoids (Int. J. Clin. Pract. 2007;61:1705-7;J. Int. Acad. Periodontol. 2004;6:63-7; Evid. Based Complement. Alternat. Med. 2009;6:165-73;J. Agric. Food Chem. 2012;60:7229-37). Honey has a pH ranging from 3.2 to 4.5 and an acidity level that stymies the growth of many microorganisms (Burns 2013;39:1514-25; J. Clin. Nurs. 2008;17:2604-23; Nurs. Times. 2006;102:40-2; Br. J. Community Nurs. 2004;Suppl:S21-7 ).

Antibacterial activity

In 2008, Kwakman et al. found that within 24 hours, 10%-40% (vol/vol) medical grade honey (Revamil) destroyed antibiotic-susceptible and antibiotic-resistant isolates of Staphylococcus aureus,S. epidermidis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, and Klebsiella oxytoca. After 2 days of honey application, they also observed a 100-fold decrease in forearm skin colonization in healthy volunteers, with the number of positive skin cultures declining by 76%. The researchers concluded that Revamil exhibits significant potential to prevent or treat infections, including those spawned by multidrug-resistant bacteria (Clin. Infect. Dis. 2008;46:1677-82). Honey has been demonstrated to be clinically effective in treating several kinds of wound infections, reducing skin colonization of multiple bacteria, including methicillin-resistant S. aureus (Clin. Infect. Dis. 2008;46:1677-82) and enhancing wound healing, without provoking adverse effects ( Clin. Infect. Dis. 2009;49:1541-9). Manuka honey and Medihoney are the main forms of medical grade honey used in clinical practice. Nonmedical grade honey may contain viable bacterial spores (including clostridia), and manifest less predictable antibacterial properties (Clin. Infect. Dis. 2009;49:1541-9).

Honey is used in over-the-counter products as a moisturizing agent and in hair-conditioning products based on its strong humectant properties. It is also used in home remedies to treat burns, wounds, eczema, and dermatitis, especially in Asia (Ayu 2012;33:178-8).

Seborrheic dermatitis/dandruff

In 2001, Al-Waili assessed the potential of topically applied crude honey (90% honey diluted in warm water) to treat chronic seborrheic dermatitis of the scalp, face, and chest in 30 patients (20 males and 10 females, aged 15-60 years). Over the initial 4 weeks of treatment, honey was gently rubbed onto lesions every other day for 2-3 minutes at a time, with the ointment left on for 3 hours before gentle warm-water rinsing. Then, in a 6-month prophylactic phase, the participants were divided into a once-weekly treatment group and a control group. Skin lesions healed completely within 2 weeks in the treatment group, after significant reductions in itching and scaling in just the first week. Subjective improvements in hair loss were also reported. Relapse was observed in 12 of the 15 subjects in the control group within 2-4 months of therapy cessation and none in the treatment group. The author concluded that weekly use of crude honey significantly improves seborrheic dermatitis symptoms and related hair loss (Eur. J. Med. Res. 2001;6:306-8).

Wound healing

In February 2013, Jull published a review of 25 randomized and quasirandomized trials evaluating honey in the treatment of acute or chronic wounds, finding that honey might delay healing in partial- and full-thickness burns, compared with early excision and grafting, but it does not significantly enhance healing of chronic venous leg ulcers. They suggested that while honey may prove to be more effective than some conventional dressings for such ulcers, evidence is currently insufficient to support this claim ( Cochrane Database Syst. Rev. 2013;2:CD005083). Later that year, Vandamme et al. identified 55 studies in a literature review suggesting that honey stimulates healing of burns, ulcers, and other wounds. They also found, despite some methodologic concerns, that honey exerts antibacterial activity in burn treatment and deodorizing, debridement, anti-inflammatory, and analgesic activity ( Burns 2013;39:1514-25).

Conclusion

Honey has a long history of traditional medicinal use and has been found to display significant biologic activity, including antibacterial, antioxidant, antitumor, anti-inflammatory, antibrowning, and antiviral. The antibacterial properties of honey are particularly compelling. While more research, in the form of randomized, controlled trials, is needed prior to incorporating bee products into the dermatologic armamentarium as first-line therapies, the potential of honey usage for skin care is promising.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (McGraw-Hill, April 2002), and a book for consumers, “The Skin Type Solution” (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Broken down
Ms. E, age 20, is a college student who has had major depressive disorder for several years and a genetic bone disease (osteogenesis imperfecta, mixed type III and IV). She pres­ents with depression, anxiety, and suicidal ideation. She reports recent worsening of her depressive symptoms, including anhedonia, excessive sleep, difficulty concentrating, and feeling overwhelmed, hopeless, and worth­less. She also describes frequent thoughts of suicide with the plan of putting herself in oncoming traffic, although she has no history of suicide attempts.

Previously, her primary care physician prescribed lorazepam, 0.5 mg, as needed for anxiety, and sertraline, 100 mg/d, for depres­sion and anxiety. She experienced only partial improvement in symptoms, however.

In addition to depressive symptoms, Ms. E describes manic symptoms lasting for as long as 3 to 5 days, including decreased need for sleep, increased energy, pressured speech, racing thoughts, distractibility, spending excessive money on cosmetics, and risking her safety—given her skeletal disorder— by participating in high-impact stage-combat classes. She denies auditory and visual hallucinations, homicidal ideation, and delusions.

The medical history is significant for osteogenesis imperfecta, which has caused 62 fractures and required 16 surgeries. Ms. E is a theater major who, despite her short stature and wheelchair use, reports enjoying her acting career and says she does not feel demoralized by her medical condition. She describes overcoming her physical disabili­ties with pride and confidence. However, her recent worsening mood symptoms have left her unable to concentrate and feeling over­whelmed with school.

Ms. E is voluntarily admitted to an inpatient psychiatric unit with a diagnosis of bipolar I disorder with rapid cycling, most recent epi­sode mixed. Because of her bone fragility, the treatment team considers what would be an appropriate course of drug treatment to con­trol bipolar symptoms while minimizing risk of bone loss.

Which medications are associated with decreased bone mineral density?
   a) citalopram
   b) haloperidol
   c) carbamazepine
   d) paliperidone
   e) all of the above

The authors’ observations
Osteogenesis imperfecta is a genetic condi­tion caused by mutations in genes impli­cated in collagen production. As a result, bones are brittle and prone to fracture. Different classes of psychotropics have been shown to increase risk of bone frac­tures through a variety of mechanisms. Clinicians often must choose appropri­ate pharmacotherapy for patients at high risk of fracture, including postmenopausal women, older patients, malnourished per­sons, and those with hormonal deficien­cies leading to osteoporosis.

To assist our clinical decision-making, we reviewed the literature to establish appropriate management of a patient with increased bone fragility and new-onset bipolar disorder. We considered all classes of medications used to treat bipolar disor­der, including antipsychotics, antidepres­sants, lithium, and anticonvulsants.

Antipsychotics
In population-based studies, prolactin-elevating antipsychotics have been associ­ated with decreased bone mineral density and increased risk of fracture.¹ Additional studies on geriatric and non-geriatric popu­lations have supported these findings.^2,3

The mechanism through which fracture risk is increased likely is related to antipsy­chotics’ effect on serum prolactin and corti­sol levels. Antipsychotics act as antagonists on D2 receptors in the hypothalamic tubero-infundibular pathway, therefore preventing inhibition of prolactin. Long-term elevation in serum prolactin can cause loss of bone mineral density through secondary hypo­gonadism and direct effects on target tis­sues. Additional modifying factors include smoking and estrogen use.

The degree to which antipsychotics increase fracture risk might be related to the degree of serum prolactin elevation.⁴ Antipsychotics previously have been grouped by the degree of prolactin eleva­tion, categorizing them as high, medium, and low or no potential to elevate serum prolactin.⁴ Based on this classification, typical antipsychotics, risperidone, and paliperidone have the highest potential to elevate prolactin. Accordingly, antipsychot­ics with the lowest fracture risk are those that have the lowest risk of serum prolactin elevation: ziprasidone, asenapine, quetiap­ine, and clozapine. Aripiprazole may lower prolactin in some patients. This is sup­ported by studies noting reduced bone min­eral density^5,6 and increased risk of fracture¹ with high-potential vs low- or no-potential antipsychotics. Because of these findings, it is crucial to consider the potential risk of prolactin elevation when treating patients at increased risk of fracture. Providers should consider low/no potential antipsy­chotic medications before considering those with medium or high potential (Table).

Antidepressants
In a meta-analysis, antidepressants were shown to increase fracture risk by 70% to 90%.² However, the relative risk varies by antidepressant class. Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are associated with a higher risk of fracture compared with tri­cyclic antidepressants (TCAs).⁷ In addition, antidepressants with a high affinity for the serotonin transporter, including citalopram, fluoxetine, fluvoxamine, paroxetine, sertra­line, and imipramine, have been associated with greater risk of osteoporotic fracture compared with those with low affinity.⁸

The mechanisms by which antidepres­sants increase fracture risk are complex, although the strongest evidence implicates a direct effect on bone metabolism via the 5-HTT receptor. This receptor, found on osteoblasts and osteoclasts, plays an impor­tant role in bone metabolism; it is through this receptor that SSRIs might inhibit osteo­blasts and promote osteoclast activity, thereby disrupting bone microarchitecture. Additional studies are needed to further describe the mechanism of the association among antidepressants, bone mineral den­sity, and fracture risk.

Fracture risk is associated with dura­tion of use rather than dosage. Population-based studies show a higher fracture risk for new users of TCAs compared with continuous users, and the risk of fracture with SSRIs seems to increase slightly over time.⁹ No association has been identified between fracture risk and antidepressant dosage. According to the literature, drugs with low affinity for the serotonin trans­porter, such as maprotiline and mirtazap­ine, likely are the safest antidepressants for patients at increased risk of fracture. Options also include other TCAs and any antidepressant with low affinity for the serotonin receptor.^7,8 

Lithium
Studies on lithium and bone mineral den­sity have shown mixed results. Older stud­ies found that lithium had a negative or no effect on bone mineral density or the para­thyroid hormone level.¹⁰ More recent inves­tigations, however, suggest that the drug has a protective effect on bone mineral den­sity, although this has not been replicated in all studies.

In a mouse model, lithium has been shown to enhance bone formation and improve bone mass, at least in part by activation of the Wnt signaling pathway through an inhibitory effect on glycogen synthase kinase-3β.¹¹ In humans, lithium-treated adults had lower serum alkaline phosphate, osteocalcin, and C-telopeptide levels compared with controls, suggesting a state of decreased bone remodeling and increased turnover.¹² There is a paucity of clinical data on the effect of lithium on frac­ture risk. Additional studies are necessary to elucidate lithium’s mechanism on bone mineral density and determine the magni­tude of the clinical effect.

Anticonvulsants
The association among anticonvulsants, decreased bone mineral density, and increased risk of fracture is well-established in the literature.¹³ However, causality is dif­ficult to determine, because many studies were of patients with a seizure disorder, who often have additional risk factors for fracture, including seizure-related trauma, drowsiness, and slowed reflexes.

Mechanisms through which anticon­vulsants increase fracture risk include increased bone resorption, secondary hypo­parathyroidism, and pseudohypoparathy­roidism. Markers of bone resorption were elevated in patients receiving an antiepi­leptic.¹⁴ This effect might be enhanced by co-administration of cytochrome P450 (CYP450) enzyme-inducing anticon­vulsants and CYP450 enzyme-inhibiting medications, such as valproate. Long-term treatment with valproate may produce reduction of bone mass and increased risk of fractures; however, other studies dis­agree with this finding.¹⁵

In addition to CYP450-inducing effects, phenytoin, carbamezapine, and phenobar­bital can increase catabolism of vitamin D, which is associated with osteomalacia.¹⁴ This results in decreased intestinal absorp­tion of calcium, hypocalcemia, and sec­ondary hyperparathyroidism, which also increases fracture risk. Anticonvulsants also might increase resistance to pseudo­hypoparathyroidism and inhibit calcitonin secretion.

Lamotrigine has not been shown to interfere with bone accrual¹⁶ and may be a safer mood stabilizer for patients at high risk of fracture. For patients at increased risk of fracture, it is important to select an anticonvulsant wisely to minimize frac­ture risk.

How would you treat Ms. E during her hospitalization for bipolar disorder?
   a) carbamazepine
   b) lithium
   c) risperidone
   d) mirtazapine

TREATMENT Minimizing polypharmacy
Because many pharmacotherapeutic options for managing bipolar disorder can increase the risk of fracture, clinicians must be aware of the relative risk of each class of medication and each individual drug. We initiated lithium, 300 mg, 3 times a day, to stabilize Ms. E’s mood. Although clinical data are inconclusive regarding lithium’s effect on fracture risk, we felt that the benefit of acute mood stabiliza­tion outweighed the risk of decreased bone mineral index.

We selected aripiprazole, 10 mg/d, as an adjunctive treatment because of its minimal effect on serum prolactin levels.⁴ We con­sidered prescribing an antidepressant but decided against it because we were concerned about manic switching.

Polypharmacy is another important con­sideration for Ms. E. Several studies have identified polypharmacy, particularly with antipsychotics, as an independent risk factor for fracture.³ Therefore, we sought to minimize the number of medications Ms. E receives. Although lithium monotherapy is an option, we thought that her mood symptoms were severe enough that the risk of inadequately treating her bipolar symptoms outweighed the additional risk of fracture from dual ther­apy with lithium and aripiprazole. Untreated or inadequately treated depression is associ­ated with a higher fracture risk. Therefore, we avoided prescribing >2 medications to mitigate any excessive risk of fracture from polypharmacy.

Bottom Line
Different classes of medications—antipsychotics, anticonvulsants, antidepressants, and lithium—used for treating bipolar disorder have been shown to increase risk of bone fracture through a variety of mechanisms. Anticonvulsants and prolactin-elevating antipsychotics are associated with increased fracture risk; evidence on lithium is mixed. Fracture risk with antidepressants is associated with duration of use, rather than dosage.

Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

ANSWER

This ECG is consistent with coarse atrial fibrillation with a rapid ventricular response and a nonspecific T-wave abnormality. The patient’s presentation is strongly suggestive of lone atrial fibrillation: This was the first incidence, it occurred in the absence of an existing heart condition, and it presented with an abrupt onset of increased heart rate and dyspnea.

Lone atrial fibrillation most commonly occurs in men in their 40s and 50s. It is vagally mediated, occurring during sleep or relaxation and after food and/or alcohol consumption.

The patient was cardioverted to normal sinus rhythm in the ED without difficulty, and follow-up was arranged. 

ANSWER

This ECG is consistent with coarse atrial fibrillation with a rapid ventricular response and a nonspecific T-wave abnormality. The patient’s presentation is strongly suggestive of lone atrial fibrillation: This was the first incidence, it occurred in the absence of an existing heart condition, and it presented with an abrupt onset of increased heart rate and dyspnea.

Lone atrial fibrillation most commonly occurs in men in their 40s and 50s. It is vagally mediated, occurring during sleep or relaxation and after food and/or alcohol consumption.

The patient was cardioverted to normal sinus rhythm in the ED without difficulty, and follow-up was arranged. 

ANSWER

This ECG is consistent with coarse atrial fibrillation with a rapid ventricular response and a nonspecific T-wave abnormality. The patient’s presentation is strongly suggestive of lone atrial fibrillation: This was the first incidence, it occurred in the absence of an existing heart condition, and it presented with an abrupt onset of increased heart rate and dyspnea.

Lone atrial fibrillation most commonly occurs in men in their 40s and 50s. It is vagally mediated, occurring during sleep or relaxation and after food and/or alcohol consumption.

The patient was cardioverted to normal sinus rhythm in the ED without difficulty, and follow-up was arranged. 

I’ve never lived in a world without e-mail. No, I’m not one of those millennial kids; e-mail has been around for a long time. Sending messages between computers dates to the 1960s, but most people consider 1971 to be the birth of e-mail. That’s when Ray Tomlinson added the @ symbol to separate users’ names from their e-mail addresses.

Today, e-mail is ubiquitous. You can e-mail your mother, your colleagues, or your cable company. You can even e-mail the president of the United States. Other than the pope and most physicians, there aren’t many people you cannot e-mail. (Although, interestingly, you can reach His Holiness on Twitter @Pontifex.)

We physicians have historically had a few good reasons to avoid e-mailing patients, but many of those objections are unwarranted. As part the meaningful use EHR incentive program from the Centers for Medicare & Medicaid Services, secure messaging will now be required to be eligible for rewards. Although many physicians cite security as a concern, most electronic medical record systems now have patient portals that allow for secure, safe messaging. Encroachment into private time, however, is still a concern for many physicians.

At Kaiser Permanente (KP), we’ve been using secure e-mails with our patients for more than 5 years. When we started, I had some of the same concerns as most doctors: When am I going to have time to do this? What types of questions will patients send? As it turns out, the system has been wildly popular for patients. In 2013 alone, we replied to more than 14 million patient messages. We encourage our patients to use e-mail to stay connected with us, because it leads to improved patient experiences and improved outcomes.

Managing e-mail in-boxes is difficult work, and we KP physicians constantly try to find ways to be more efficient. E-mail does sometimes encroach on my personal time, but I’ve discovered that’s okay. As it turns out, e-mail encroaches on my entrepreneurial brother’s personal time, my financial planner’s personal time, and my plumber’s personal time. Being always connected is a modern luxury and a curse. It’s also part of being a professional.

Here are some steps I’ve taken to manage my patient e-mails. First, I always remember that this electronic message is connected to a real person with real worry. Second, I remember how appreciative patients are to get a message from their doctor. E-mail a patient after 8 p.m., and they will never forget you. Third, clearly delineate time to take care of business. It never feels burdensome in part because I am in control. I choose to e-mail patients not because I have to but because I’m that doctor and it makes me feel good.

This weekend, for example, I did patient messages in a Jackson Hole, Wyo., coffee shop while on vacation. Just as I opened my computer, I noticed a young guy in a fleece jacket next to me checking his e-mail while his wife and two kids enjoyed muffins and hot cocoa. While I was waiting for my wife, Susan, to order our lattes, I overheard him make a call to his office: “Yes, I’m out, but why don’t you e-mail me that and I’ll get right back to you.”

I’m right with you, buddy, I think. I use my token and the wifi there in Wyoming to access my patient e-mails. There are only five. The messages are like most I receive: “I have a new spot,” or “The cream you gave me isn’t working,” or “My acne is better, so should I reduce the spironolactone?” I hammer replies out in 10 minutes.

My wife returns with lattes and opens the local paper while I review 14 biopsy results from 2 days ago. For most of them, I use a template and the secure e-mail to send patients their results. I then send a few notes to some patients, advising them to follow up with me for excisional surgeries.

The work I was doing was not additive; the questions my patients sent would have had to be addressed at some time. In fact, if they had called, then they would have left a message with a nurse who would have sent a message to me, which I would have had to reply to, and then send the message back to the nurse who would have to reply to the patient.

Despite our love/hate relationship with it, e-mail has been one of the great innovations of the 20th century, and it is the primary form of communication in the business world. According to one study, more than 100 billion business e-mails were sent and received every day in 2013. Yet, fewer than one-third of physicians use e-mail to communicate with their patients.Personally, I have found patients to be generally understanding, courteous, and appreciative of e-mail. Of course, there are a few who don’t follow good etiquette. (One of my primary care colleagues relates a story of a patient who e-mailed her every time she had a bowel movement. Gastroenteritis can significantly add to e-mail burden, apparently.)

There’s no doubt that e-mail will soon become the primary way to communicate with patients. Based on our experience at KP, this will ultimately be to the benefit of both doctors and patients. A June 2014 survey by Catalyst Healthcare Research showed that 93% of patients preferred to see a physician who offers e-mail communication with his or her patients. More than one-quarter of those respondents said they’d be willing to pay a $25 charge for such communication. It’s not surprising; as with all businesses, not just medicine, that patients want more channels of communication, not fewer. Fortunately for them, many of today’s medical residents are being trained to use electronic communication with patients. For instance, a 2013 study published in the Postgraduate Medical Journal found that 57% of residents used e-mail to communicate with patients.

My wife finished reading the Jackson Hole Daily newspaper and outlined our hike to Taggart Lake. And I finished answering my messages. The guy sitting next to me is still tapping away at his keyboard. I make eye contact and say, “Almost done?” “Yup,” he replies, “Better for me to just knock it out now, because I’ll just have to deal with it on Monday.” I agree.

Susan and I pack up and head for the trail, which is thankfully connection free. Let’s just hope we don’t run into any bears.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

I’ve never lived in a world without e-mail. No, I’m not one of those millennial kids; e-mail has been around for a long time. Sending messages between computers dates to the 1960s, but most people consider 1971 to be the birth of e-mail. That’s when Ray Tomlinson added the @ symbol to separate users’ names from their e-mail addresses.

Today, e-mail is ubiquitous. You can e-mail your mother, your colleagues, or your cable company. You can even e-mail the president of the United States. Other than the pope and most physicians, there aren’t many people you cannot e-mail. (Although, interestingly, you can reach His Holiness on Twitter @Pontifex.)

We physicians have historically had a few good reasons to avoid e-mailing patients, but many of those objections are unwarranted. As part the meaningful use EHR incentive program from the Centers for Medicare & Medicaid Services, secure messaging will now be required to be eligible for rewards. Although many physicians cite security as a concern, most electronic medical record systems now have patient portals that allow for secure, safe messaging. Encroachment into private time, however, is still a concern for many physicians.

At Kaiser Permanente (KP), we’ve been using secure e-mails with our patients for more than 5 years. When we started, I had some of the same concerns as most doctors: When am I going to have time to do this? What types of questions will patients send? As it turns out, the system has been wildly popular for patients. In 2013 alone, we replied to more than 14 million patient messages. We encourage our patients to use e-mail to stay connected with us, because it leads to improved patient experiences and improved outcomes.

Managing e-mail in-boxes is difficult work, and we KP physicians constantly try to find ways to be more efficient. E-mail does sometimes encroach on my personal time, but I’ve discovered that’s okay. As it turns out, e-mail encroaches on my entrepreneurial brother’s personal time, my financial planner’s personal time, and my plumber’s personal time. Being always connected is a modern luxury and a curse. It’s also part of being a professional.

Here are some steps I’ve taken to manage my patient e-mails. First, I always remember that this electronic message is connected to a real person with real worry. Second, I remember how appreciative patients are to get a message from their doctor. E-mail a patient after 8 p.m., and they will never forget you. Third, clearly delineate time to take care of business. It never feels burdensome in part because I am in control. I choose to e-mail patients not because I have to but because I’m that doctor and it makes me feel good.

This weekend, for example, I did patient messages in a Jackson Hole, Wyo., coffee shop while on vacation. Just as I opened my computer, I noticed a young guy in a fleece jacket next to me checking his e-mail while his wife and two kids enjoyed muffins and hot cocoa. While I was waiting for my wife, Susan, to order our lattes, I overheard him make a call to his office: “Yes, I’m out, but why don’t you e-mail me that and I’ll get right back to you.”

I’m right with you, buddy, I think. I use my token and the wifi there in Wyoming to access my patient e-mails. There are only five. The messages are like most I receive: “I have a new spot,” or “The cream you gave me isn’t working,” or “My acne is better, so should I reduce the spironolactone?” I hammer replies out in 10 minutes.

My wife returns with lattes and opens the local paper while I review 14 biopsy results from 2 days ago. For most of them, I use a template and the secure e-mail to send patients their results. I then send a few notes to some patients, advising them to follow up with me for excisional surgeries.

The work I was doing was not additive; the questions my patients sent would have had to be addressed at some time. In fact, if they had called, then they would have left a message with a nurse who would have sent a message to me, which I would have had to reply to, and then send the message back to the nurse who would have to reply to the patient.

Despite our love/hate relationship with it, e-mail has been one of the great innovations of the 20th century, and it is the primary form of communication in the business world. According to one study, more than 100 billion business e-mails were sent and received every day in 2013. Yet, fewer than one-third of physicians use e-mail to communicate with their patients.Personally, I have found patients to be generally understanding, courteous, and appreciative of e-mail. Of course, there are a few who don’t follow good etiquette. (One of my primary care colleagues relates a story of a patient who e-mailed her every time she had a bowel movement. Gastroenteritis can significantly add to e-mail burden, apparently.)

There’s no doubt that e-mail will soon become the primary way to communicate with patients. Based on our experience at KP, this will ultimately be to the benefit of both doctors and patients. A June 2014 survey by Catalyst Healthcare Research showed that 93% of patients preferred to see a physician who offers e-mail communication with his or her patients. More than one-quarter of those respondents said they’d be willing to pay a $25 charge for such communication. It’s not surprising; as with all businesses, not just medicine, that patients want more channels of communication, not fewer. Fortunately for them, many of today’s medical residents are being trained to use electronic communication with patients. For instance, a 2013 study published in the Postgraduate Medical Journal found that 57% of residents used e-mail to communicate with patients.

My wife finished reading the Jackson Hole Daily newspaper and outlined our hike to Taggart Lake. And I finished answering my messages. The guy sitting next to me is still tapping away at his keyboard. I make eye contact and say, “Almost done?” “Yup,” he replies, “Better for me to just knock it out now, because I’ll just have to deal with it on Monday.” I agree.

Susan and I pack up and head for the trail, which is thankfully connection free. Let’s just hope we don’t run into any bears.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

I’ve never lived in a world without e-mail. No, I’m not one of those millennial kids; e-mail has been around for a long time. Sending messages between computers dates to the 1960s, but most people consider 1971 to be the birth of e-mail. That’s when Ray Tomlinson added the @ symbol to separate users’ names from their e-mail addresses.

Today, e-mail is ubiquitous. You can e-mail your mother, your colleagues, or your cable company. You can even e-mail the president of the United States. Other than the pope and most physicians, there aren’t many people you cannot e-mail. (Although, interestingly, you can reach His Holiness on Twitter @Pontifex.)

We physicians have historically had a few good reasons to avoid e-mailing patients, but many of those objections are unwarranted. As part the meaningful use EHR incentive program from the Centers for Medicare & Medicaid Services, secure messaging will now be required to be eligible for rewards. Although many physicians cite security as a concern, most electronic medical record systems now have patient portals that allow for secure, safe messaging. Encroachment into private time, however, is still a concern for many physicians.

At Kaiser Permanente (KP), we’ve been using secure e-mails with our patients for more than 5 years. When we started, I had some of the same concerns as most doctors: When am I going to have time to do this? What types of questions will patients send? As it turns out, the system has been wildly popular for patients. In 2013 alone, we replied to more than 14 million patient messages. We encourage our patients to use e-mail to stay connected with us, because it leads to improved patient experiences and improved outcomes.

Managing e-mail in-boxes is difficult work, and we KP physicians constantly try to find ways to be more efficient. E-mail does sometimes encroach on my personal time, but I’ve discovered that’s okay. As it turns out, e-mail encroaches on my entrepreneurial brother’s personal time, my financial planner’s personal time, and my plumber’s personal time. Being always connected is a modern luxury and a curse. It’s also part of being a professional.

Here are some steps I’ve taken to manage my patient e-mails. First, I always remember that this electronic message is connected to a real person with real worry. Second, I remember how appreciative patients are to get a message from their doctor. E-mail a patient after 8 p.m., and they will never forget you. Third, clearly delineate time to take care of business. It never feels burdensome in part because I am in control. I choose to e-mail patients not because I have to but because I’m that doctor and it makes me feel good.

This weekend, for example, I did patient messages in a Jackson Hole, Wyo., coffee shop while on vacation. Just as I opened my computer, I noticed a young guy in a fleece jacket next to me checking his e-mail while his wife and two kids enjoyed muffins and hot cocoa. While I was waiting for my wife, Susan, to order our lattes, I overheard him make a call to his office: “Yes, I’m out, but why don’t you e-mail me that and I’ll get right back to you.”

I’m right with you, buddy, I think. I use my token and the wifi there in Wyoming to access my patient e-mails. There are only five. The messages are like most I receive: “I have a new spot,” or “The cream you gave me isn’t working,” or “My acne is better, so should I reduce the spironolactone?” I hammer replies out in 10 minutes.

My wife returns with lattes and opens the local paper while I review 14 biopsy results from 2 days ago. For most of them, I use a template and the secure e-mail to send patients their results. I then send a few notes to some patients, advising them to follow up with me for excisional surgeries.

The work I was doing was not additive; the questions my patients sent would have had to be addressed at some time. In fact, if they had called, then they would have left a message with a nurse who would have sent a message to me, which I would have had to reply to, and then send the message back to the nurse who would have to reply to the patient.

Despite our love/hate relationship with it, e-mail has been one of the great innovations of the 20th century, and it is the primary form of communication in the business world. According to one study, more than 100 billion business e-mails were sent and received every day in 2013. Yet, fewer than one-third of physicians use e-mail to communicate with their patients.Personally, I have found patients to be generally understanding, courteous, and appreciative of e-mail. Of course, there are a few who don’t follow good etiquette. (One of my primary care colleagues relates a story of a patient who e-mailed her every time she had a bowel movement. Gastroenteritis can significantly add to e-mail burden, apparently.)

There’s no doubt that e-mail will soon become the primary way to communicate with patients. Based on our experience at KP, this will ultimately be to the benefit of both doctors and patients. A June 2014 survey by Catalyst Healthcare Research showed that 93% of patients preferred to see a physician who offers e-mail communication with his or her patients. More than one-quarter of those respondents said they’d be willing to pay a $25 charge for such communication. It’s not surprising; as with all businesses, not just medicine, that patients want more channels of communication, not fewer. Fortunately for them, many of today’s medical residents are being trained to use electronic communication with patients. For instance, a 2013 study published in the Postgraduate Medical Journal found that 57% of residents used e-mail to communicate with patients.

My wife finished reading the Jackson Hole Daily newspaper and outlined our hike to Taggart Lake. And I finished answering my messages. The guy sitting next to me is still tapping away at his keyboard. I make eye contact and say, “Almost done?” “Yup,” he replies, “Better for me to just knock it out now, because I’ll just have to deal with it on Monday.” I agree.

Susan and I pack up and head for the trail, which is thankfully connection free. Let’s just hope we don’t run into any bears.

Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego, and volunteer clinical assistant professor at the University of California, San Diego. Dr. Benabio is @dermdoc on Twitter.

Mr. R, 75, is having difficulty sleeping. When he goes to bed, he lies there for what seems like forever, unable to fall asleep. He feels “so tired” and ends up taking naps during the day, but he cannot break this cycle. He has tried using over-the-counter products with little relief.

Mr. R’s primary care physician prescribes zaleplon, 10 mg/d, and asks him to call the clinic in 2 weeks to discuss his progress. He takes zaleplon as directed for several nights and begins to feel “sluggish” during the day, both mentally and physically, despite reporting an increase in the overall amount of sleep at night.

Sedative-hypnotic drugs are among the most commonly used medica­tions in the United States. Use of these drugs, as well as anxiolytics, has increased from 2.8% between 1988 and 1994 to 4.7% between 2007 and 2010, according to the Department of Health and Human Services.¹ In 2011, drugs categorized as sedative-hypnotics or antipsychotics were involved in 6.1% of all human exposures identified in the American Association of Poison Control Centers’ National Poison Data System.² Therefore, an understanding of clinical and pharmacological variables related to safe and effective use is important for clinicians prescribing and monitoring therapy with these agents.

Neuropsychiatric disorders are prevalent among geriatric patients and are associated with age-related physiologic changes in the CNS.³ Such changes involve:  
   • neuroanatomy (brain atrophy, decreased neuronal density, increased plaque formation)  
   • neurotransmitters (reduced cholinergic transmission, decreased synthesis of dopamine and catecholamines), and   
   • neurophysiology (reduced cerebral blood flow).

These physiologic processes manifest as alterations in mental status, reflexes, sen­sation, gait, balance, and sleep. Examples of sleep changes among geriatric patients include decreased sleep efficiency, more fre­quent awakenings, and more variable sleep duration.^3,4 Sleep disorders also may be related to mental disorders and other medi­cal conditions.⁵ For example, the prevalence of sleep-related respiratory disorders, such as obstructive sleep apnea and central sleep apnea, increases with age.⁶

Sleep disorders are common among geri­atric patients. In a large epidemiologic study of sleep complaints in patients age ≥65, more than one-half of patients had at least 1 sleep complaint (ie, difficulty falling asleep, trou­ble waking up, early awakening, need for naps, and feeling ill-rested).⁷ As many as 34% of patients reported symptoms of insom­nia. In an analysis of National Ambulatory Medical Survey Data over 6 years, 24.8% to 27.9% of sleep-related medical office visits were attributed to patients age ≥65.⁸

Pharmacology in aging
Prescribing sedative-hypnotic drugs is not routinely recommended for older patients with a sleep disorder. Geriatric patients, com­pared with younger patients, are at higher risk of iatrogenic complications because of polypharmacy, comorbidities, relative renal and hepatic insufficiency, and other physi­ologic changes leading to alterations in drug exposure and metabolism (Table 1).^9-12

Aging is associated with changes in body composition, including an increase in total body fat and decrease in lean body mass and total body water. These changes, as well as a prolonged GI transit time, decrease in active gut transporters, decreased blood perfusion, and decrease in plasma proteins such as albumin (because of reduced liver function or malnutrition), may lead to alteration in drug absorption patterns and may increase the volume of distribution for lipophilic drugs. Additionally, the elimination half-life of some drugs may increase with age because of larger volumes of distribution and reduction in hepatic or renal clearance.

The clinical significance of these changes is not well established. Although the process of drug absorption can change with age, the amount of drug absorbed might not be significantly affected. An increase in the vol­ume of distribution and reduction in drug metabolism and clearance might lead to increasing amounts of circulating drug and duration of drug exposure, putting geriat­ric patients at an increased risk for adverse effects and drug toxicity.⁹

Among these mechanisms, Dolder et al¹¹ hypothesized that drug metabolism cata­lyzed by cytochrome P450 (CYP) enzymes and renal excretion may be of greatest con­cern. Although in vitro studies suggest that concentration of CYP enzymes does not decline with age, in vivo studies have dem­onstrated reduced CYP activity in geriatric patients.^11,12 Theoretically, a reduction in CYP activity would increase the bioavail­ability of drugs, especially those that are subject to extensive first-pass (ie, hepatic) metabolism, and may lead to a reduction in systemic clearance.

Independent of metabolic changes, geriatric patients are at risk of reduced renal clearance because of age-related changes in glomerular filtration rate. Pharmacodynamic changes might be observed in older patients and could be a concern even in the setting of unaltered pharmacokinetic factors.9 These changes usually require administering smaller drug dosages.

Sedative-hypnotic medications
Sedative-hypnotic agents include several barbiturates, benzodiazepines (BZDs), non-BZD benzodiazepine-receptor ago­nists (BzRAs), a melatonin-receptor agonist (ie, ramelteon), and an orexin-receptor antagonist (ie, suvorexant).^13,14Table 2^14-29 summarizes selected sedative-hypnotic drugs. Additional drug classes used to treat insomnia include:
   • sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine)
   • antiepileptic drugs (gabapentin, tiagabine)
   • atypical antipsychotics (quetiapine, olanzapine).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, zaleplon, zolpidem, ramelteon, and suvorexant. Not all of these drugs are recommended for use in geriatric patients. Barbiturates, for example, should be avoided.³⁰

Pharmacokinetic characteristics vary among drugs and drug classes. Choice of pharmacotherapy should account for patient and drug characteristics and the specific sleep complaint. Sleep disorders may be var­iously characterized as difficulty with sleep initiation, duration, consolidation, or qual­ity.¹³ Therefore, onset and duration of effect are important drug-related considerations. Sedative-hypnotic drugs with a short time-to-onset may be ideal for patients with sleep-onset insomnia.

The drugs’ duration of effect (eg, presence of active metabolites, long elimination half-life) also must be reviewed. A long elimi­nation half-life may lead to increased drug exposure and unwanted side effects such as residual daytime drowsiness. Despite this, sedative-hypnotic drugs with a longer duration of effect (eg, intermediate- or long-acting drugs) may be best for patients with insomnia defined by difficulty maintaining sleep.

Benzodiazepines vary in their time to onset of effect, rate of elimination, and metabolism.^15-21 BZDs that are FDA- approved for use as sedative-hypnotics are listed in Table 2.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_max), ranging from 0.5 hours (flurazepam) to 2 hours (estazolam, quaz­epam, triazolam). The elimination half-life varies widely among these medications, from 1.5 hours (triazolam) to >100 hours (flurazepam). Flurazepam’s long half-life is attributable to its active major metabo­lite. Although most BZDs are metabolized hepatically, temazepam is subject to mini­mal hepatic metabolism.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem dosage forms; sublingual formulations have the shortest onset of effect. Eszopiclone and zaleplon have low protein binding com­pared with zolpidem. Elimination half-lives vary among drugs with the shortest attrib­uted to zaleplon (1 hour) and longest to eszopiclone (6 hours). All BzRAs are subject to extensive hepatic metabolism. 

Ramelteon. Singular in its class, ramelteon is a treatment option for insomnia.²⁹ This drug has a short onset of effect, moder­ate protein binding, and extensive hepatic metabolism. Ramelteon is primarily excreted in the urine as its metabolites, and the drug half-life is relatively short.

Suvorexant is the latest addition to the sedative-hypnotic armamentarium, approved by the FDA in August 2014 for dif­ficulty with sleep onset and/or sleep main­tenance.¹⁴ As an orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. Suvorexant exhibits moderately rapid absorption with time to peak concen­tration ranging from 30 minutes to 6 hours in fasting conditions; absorption is delayed when taken with or soon after a meal. The drug is highly protein bound and extensively metabolized, primarily through CYP3A. The manufacturer recommends dose reduc­tion (5 mg at bedtime) in patients taking moderate CYP3A inhibitors and avoiding suvorexant in patients taking strong CYP3A inhibitors. Suvorexant is primarily excreted through feces and the mean half-life is rela­tively long.

Considering these characteristics and age-related physiologic changes, the practi­tioner should be concerned about drugs that undergo extensive hepatic metabolism. Age-related reductions in CYP activity may lead to an increase in drug bioavailability and a decrease in the systemic clearance,¹¹ which might be associated with an increase in elimination half-life and duration of action. Dosage adjustments are recommended for several BZDs (lower initial and maximum dosages for most agents) and BzRAs.^17-28 No dosage adjustments for ramelteon or suvorexant in geriatric patients have been specified^14,29; the manufacturers for both products assert that no differences in safety and efficacy have been observed between older and younger adult patients.

Alternative and complementary medications
Several non-prescription products, includ­ing over-the-counter drugs (eg, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine in patients with chronic insomnia, and tolerance to its hypnotic effect has been reported with repeated use.³¹ Concerns about anticholinergic toxicity and CNS depression limit its use in geriatric patients. Among herbal therapies, melatonin may have the strongest evidence for its ability to allevi­ate sleep disorders in geriatric patients³²; however, meta-analyses have demonstrated small effects of melatonin on sleep latency and minimal differences in wake time after sleep onset and total sleep time.¹³

Clinical practice guidelines
Non-pharmacotherapeutic interventions, such as behavioral (eg, sleep hygiene mea­sures) and psychological therapy, are rec­ommended for initial management of sleep disorders in geriatric patients.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-hypnotic drugs, tricyclic antide­pressants, and antihistamines. The American Academy of Sleep Medicine (AASM) recom­mends an initial treatment period of 2 to 4 weeks, followed by re-evaluation of con­tinued need for treatment.¹³ The AASM recommends short- or intermediate-acting BzRAs or ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^14-29

Barbiturates, chloral hydrate, and non-barbiturate, non-BZD drugs such as mep­robamate are not recommended because of potential significant adverse effects and tolerance/dependence, and low therapeu­tic index. The AASM advises caution when using prescription drugs off-label for insom­nia (eg, antidepressants, antiepileptics, antipsychotics) and recommends avoiding them, if possible, because of limited evi­dence supporting their use.¹³

Safety concerns
Two commonly used references contain rec­ommendations for sedative-hypnotic medi­cation use in geriatric patients.^30,34 According to Gallagher et al’s³⁴ Screening Tool of Older Person’s Prescriptions (STOPP), long-term (>1 month) use of long-acting BZDs (eg, flurazepam, diazepam) and prolonged use (>1 week) of first-generation antihistamines (eg, diphenhydramine, doxylamine) should be avoided in patients age ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, neuroleptics, or first-generation antihistamines may contrib­ute to postural imbalance; therefore these agents are not recommended in older patients at risk for falls.

In the 2012 American Geriatrics Society (AGS) Beers Criteria, the AGS recommends avoiding barbiturates in older adults because of the high rate of physical depen­dence, tolerance to sleep effects, and over­dose risk at low dosages.³⁰ The AGS also recommends avoiding BZDs, stating that older adults have increased sensitivity to these agents and are at an increased risk of cognitive impairment, delirium, falls, frac­tures, and motor vehicle accidents when taking these drugs. Non-BZD BzRAs also should not be prescribed to patients with a history of falls or fractures, unless safer alternatives are not available.

The FDA has issued several advisory reports regarding sedative-hypnotic drugs. In 2007, all manufacturers of sedative-hypnotic drugs were required to modify their product labeling to include stronger language about potential risks.35 Among these changes, warnings for ana­phylaxis and complex sleep-related behav­iors were added. Also, the FDA requested that manufacturers of sedative-hypnotic drugs develop and provide patient medi­cation guides, advising consumers on the potential risks and precautions associated with these drugs. More recently, the FDA announced changes to dosing recommen­dations for zolpidem-containing products because of the risk of impaired mental alertness36; manufacturers were required to lower the recommended dosages for each product.

Manufacturers of FDA-approved sedative-hypnotic drugs urge caution when prescribing these medications for geriatric patients, citing the potential for increased sensitivity, manifesting as marked excite­ment, depression, or confusion (eg, barbi­turates), and greater risk for dosage-related adverse effects (eg, oversedation, dizziness, confusion, impaired psychomotor perfor­mance, ataxia).^17-29

Use in clinical practice
Several variables should be considered when evaluating appropriateness of phar­macotherapy, including characteristics of the drug and the patient. Geriatric patients may be prone to comorbidities resulting from age-related physiologic changes. These diseases may be confounding (ie, contributing to sleep disorders); examples include medical illnesses, such as hyperthyroidism and arthritis, and psychiatric illnesses, such as depression and anxiety.³⁷ Other conditions, such as renal and hepatic dysfunction, may lead to alteration in drug exposure. These condi­tions should be assessed through routine renal function tests (eg, serum creatinine and glomerular filtration rate) and liver function tests (eg, serum albumin and liver transaminases).

Multiple comorbidities suggest a higher likelihood of polypharmacy, leading to other drug-related issues (eg, drug-drug interactions). Although these issues may guide therapy by restricting medication options, their potential contribution to the underlying sleep complaints should be con­sidered.³⁷ Several drugs commonly used by geriatric patients may affect wakefulness (eg, analgesics, antidepressants, and anti­hypertensives [sedating], and thyroid hor­mones, corticosteroids, and CNS stimulants [alerting]).

CASE CONTINUED
In Mr. R’s case, zaleplon was initiated at 10 mg/d. Because of his age and the nature of his sleep disorder, the choice of sedative-hypnotic was suitable; however, the prescribed dosage was inappropriate. The sluggishness Mr. R experienced likely was a manifestation of increased exposure to the drug. According to manufacturer and AASM recommendations, a more appropriate dosage is 5 mg/d.^13,23 Mr. R’s medical history and current medica­tions, and his hepatic and renal function, should be assessed. If Mr. R continues to have issues with sleep initiation, zaleplon, 5 mg at bedtime, should be considered.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

Acknowledgement
Vicki L. Ellingrod, PharmD, FCCP, is the series editor of Savvy Psychopharmacology.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. R, 75, is having difficulty sleeping. When he goes to bed, he lies there for what seems like forever, unable to fall asleep. He feels “so tired” and ends up taking naps during the day, but he cannot break this cycle. He has tried using over-the-counter products with little relief.

Mr. R’s primary care physician prescribes zaleplon, 10 mg/d, and asks him to call the clinic in 2 weeks to discuss his progress. He takes zaleplon as directed for several nights and begins to feel “sluggish” during the day, both mentally and physically, despite reporting an increase in the overall amount of sleep at night.

Sedative-hypnotic drugs are among the most commonly used medica­tions in the United States. Use of these drugs, as well as anxiolytics, has increased from 2.8% between 1988 and 1994 to 4.7% between 2007 and 2010, according to the Department of Health and Human Services.¹ In 2011, drugs categorized as sedative-hypnotics or antipsychotics were involved in 6.1% of all human exposures identified in the American Association of Poison Control Centers’ National Poison Data System.² Therefore, an understanding of clinical and pharmacological variables related to safe and effective use is important for clinicians prescribing and monitoring therapy with these agents.

Neuropsychiatric disorders are prevalent among geriatric patients and are associated with age-related physiologic changes in the CNS.³ Such changes involve:  
   • neuroanatomy (brain atrophy, decreased neuronal density, increased plaque formation)  
   • neurotransmitters (reduced cholinergic transmission, decreased synthesis of dopamine and catecholamines), and   
   • neurophysiology (reduced cerebral blood flow).

These physiologic processes manifest as alterations in mental status, reflexes, sen­sation, gait, balance, and sleep. Examples of sleep changes among geriatric patients include decreased sleep efficiency, more fre­quent awakenings, and more variable sleep duration.^3,4 Sleep disorders also may be related to mental disorders and other medi­cal conditions.⁵ For example, the prevalence of sleep-related respiratory disorders, such as obstructive sleep apnea and central sleep apnea, increases with age.⁶

Sleep disorders are common among geri­atric patients. In a large epidemiologic study of sleep complaints in patients age ≥65, more than one-half of patients had at least 1 sleep complaint (ie, difficulty falling asleep, trou­ble waking up, early awakening, need for naps, and feeling ill-rested).⁷ As many as 34% of patients reported symptoms of insom­nia. In an analysis of National Ambulatory Medical Survey Data over 6 years, 24.8% to 27.9% of sleep-related medical office visits were attributed to patients age ≥65.⁸

Pharmacology in aging
Prescribing sedative-hypnotic drugs is not routinely recommended for older patients with a sleep disorder. Geriatric patients, com­pared with younger patients, are at higher risk of iatrogenic complications because of polypharmacy, comorbidities, relative renal and hepatic insufficiency, and other physi­ologic changes leading to alterations in drug exposure and metabolism (Table 1).^9-12

Aging is associated with changes in body composition, including an increase in total body fat and decrease in lean body mass and total body water. These changes, as well as a prolonged GI transit time, decrease in active gut transporters, decreased blood perfusion, and decrease in plasma proteins such as albumin (because of reduced liver function or malnutrition), may lead to alteration in drug absorption patterns and may increase the volume of distribution for lipophilic drugs. Additionally, the elimination half-life of some drugs may increase with age because of larger volumes of distribution and reduction in hepatic or renal clearance.

The clinical significance of these changes is not well established. Although the process of drug absorption can change with age, the amount of drug absorbed might not be significantly affected. An increase in the vol­ume of distribution and reduction in drug metabolism and clearance might lead to increasing amounts of circulating drug and duration of drug exposure, putting geriat­ric patients at an increased risk for adverse effects and drug toxicity.⁹

Among these mechanisms, Dolder et al¹¹ hypothesized that drug metabolism cata­lyzed by cytochrome P450 (CYP) enzymes and renal excretion may be of greatest con­cern. Although in vitro studies suggest that concentration of CYP enzymes does not decline with age, in vivo studies have dem­onstrated reduced CYP activity in geriatric patients.^11,12 Theoretically, a reduction in CYP activity would increase the bioavail­ability of drugs, especially those that are subject to extensive first-pass (ie, hepatic) metabolism, and may lead to a reduction in systemic clearance.

Independent of metabolic changes, geriatric patients are at risk of reduced renal clearance because of age-related changes in glomerular filtration rate. Pharmacodynamic changes might be observed in older patients and could be a concern even in the setting of unaltered pharmacokinetic factors.9 These changes usually require administering smaller drug dosages.

Sedative-hypnotic medications
Sedative-hypnotic agents include several barbiturates, benzodiazepines (BZDs), non-BZD benzodiazepine-receptor ago­nists (BzRAs), a melatonin-receptor agonist (ie, ramelteon), and an orexin-receptor antagonist (ie, suvorexant).^13,14Table 2^14-29 summarizes selected sedative-hypnotic drugs. Additional drug classes used to treat insomnia include:
   • sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine)
   • antiepileptic drugs (gabapentin, tiagabine)
   • atypical antipsychotics (quetiapine, olanzapine).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, zaleplon, zolpidem, ramelteon, and suvorexant. Not all of these drugs are recommended for use in geriatric patients. Barbiturates, for example, should be avoided.³⁰

Pharmacokinetic characteristics vary among drugs and drug classes. Choice of pharmacotherapy should account for patient and drug characteristics and the specific sleep complaint. Sleep disorders may be var­iously characterized as difficulty with sleep initiation, duration, consolidation, or qual­ity.¹³ Therefore, onset and duration of effect are important drug-related considerations. Sedative-hypnotic drugs with a short time-to-onset may be ideal for patients with sleep-onset insomnia.

The drugs’ duration of effect (eg, presence of active metabolites, long elimination half-life) also must be reviewed. A long elimi­nation half-life may lead to increased drug exposure and unwanted side effects such as residual daytime drowsiness. Despite this, sedative-hypnotic drugs with a longer duration of effect (eg, intermediate- or long-acting drugs) may be best for patients with insomnia defined by difficulty maintaining sleep.

Benzodiazepines vary in their time to onset of effect, rate of elimination, and metabolism.^15-21 BZDs that are FDA- approved for use as sedative-hypnotics are listed in Table 2.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_max), ranging from 0.5 hours (flurazepam) to 2 hours (estazolam, quaz­epam, triazolam). The elimination half-life varies widely among these medications, from 1.5 hours (triazolam) to >100 hours (flurazepam). Flurazepam’s long half-life is attributable to its active major metabo­lite. Although most BZDs are metabolized hepatically, temazepam is subject to mini­mal hepatic metabolism.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem dosage forms; sublingual formulations have the shortest onset of effect. Eszopiclone and zaleplon have low protein binding com­pared with zolpidem. Elimination half-lives vary among drugs with the shortest attrib­uted to zaleplon (1 hour) and longest to eszopiclone (6 hours). All BzRAs are subject to extensive hepatic metabolism. 

Ramelteon. Singular in its class, ramelteon is a treatment option for insomnia.²⁹ This drug has a short onset of effect, moder­ate protein binding, and extensive hepatic metabolism. Ramelteon is primarily excreted in the urine as its metabolites, and the drug half-life is relatively short.

Suvorexant is the latest addition to the sedative-hypnotic armamentarium, approved by the FDA in August 2014 for dif­ficulty with sleep onset and/or sleep main­tenance.¹⁴ As an orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. Suvorexant exhibits moderately rapid absorption with time to peak concen­tration ranging from 30 minutes to 6 hours in fasting conditions; absorption is delayed when taken with or soon after a meal. The drug is highly protein bound and extensively metabolized, primarily through CYP3A. The manufacturer recommends dose reduc­tion (5 mg at bedtime) in patients taking moderate CYP3A inhibitors and avoiding suvorexant in patients taking strong CYP3A inhibitors. Suvorexant is primarily excreted through feces and the mean half-life is rela­tively long.

Considering these characteristics and age-related physiologic changes, the practi­tioner should be concerned about drugs that undergo extensive hepatic metabolism. Age-related reductions in CYP activity may lead to an increase in drug bioavailability and a decrease in the systemic clearance,¹¹ which might be associated with an increase in elimination half-life and duration of action. Dosage adjustments are recommended for several BZDs (lower initial and maximum dosages for most agents) and BzRAs.^17-28 No dosage adjustments for ramelteon or suvorexant in geriatric patients have been specified^14,29; the manufacturers for both products assert that no differences in safety and efficacy have been observed between older and younger adult patients.

Alternative and complementary medications
Several non-prescription products, includ­ing over-the-counter drugs (eg, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine in patients with chronic insomnia, and tolerance to its hypnotic effect has been reported with repeated use.³¹ Concerns about anticholinergic toxicity and CNS depression limit its use in geriatric patients. Among herbal therapies, melatonin may have the strongest evidence for its ability to allevi­ate sleep disorders in geriatric patients³²; however, meta-analyses have demonstrated small effects of melatonin on sleep latency and minimal differences in wake time after sleep onset and total sleep time.¹³

Clinical practice guidelines
Non-pharmacotherapeutic interventions, such as behavioral (eg, sleep hygiene mea­sures) and psychological therapy, are rec­ommended for initial management of sleep disorders in geriatric patients.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-hypnotic drugs, tricyclic antide­pressants, and antihistamines. The American Academy of Sleep Medicine (AASM) recom­mends an initial treatment period of 2 to 4 weeks, followed by re-evaluation of con­tinued need for treatment.¹³ The AASM recommends short- or intermediate-acting BzRAs or ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^14-29

Barbiturates, chloral hydrate, and non-barbiturate, non-BZD drugs such as mep­robamate are not recommended because of potential significant adverse effects and tolerance/dependence, and low therapeu­tic index. The AASM advises caution when using prescription drugs off-label for insom­nia (eg, antidepressants, antiepileptics, antipsychotics) and recommends avoiding them, if possible, because of limited evi­dence supporting their use.¹³

Safety concerns
Two commonly used references contain rec­ommendations for sedative-hypnotic medi­cation use in geriatric patients.^30,34 According to Gallagher et al’s³⁴ Screening Tool of Older Person’s Prescriptions (STOPP), long-term (>1 month) use of long-acting BZDs (eg, flurazepam, diazepam) and prolonged use (>1 week) of first-generation antihistamines (eg, diphenhydramine, doxylamine) should be avoided in patients age ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, neuroleptics, or first-generation antihistamines may contrib­ute to postural imbalance; therefore these agents are not recommended in older patients at risk for falls.

In the 2012 American Geriatrics Society (AGS) Beers Criteria, the AGS recommends avoiding barbiturates in older adults because of the high rate of physical depen­dence, tolerance to sleep effects, and over­dose risk at low dosages.³⁰ The AGS also recommends avoiding BZDs, stating that older adults have increased sensitivity to these agents and are at an increased risk of cognitive impairment, delirium, falls, frac­tures, and motor vehicle accidents when taking these drugs. Non-BZD BzRAs also should not be prescribed to patients with a history of falls or fractures, unless safer alternatives are not available.

The FDA has issued several advisory reports regarding sedative-hypnotic drugs. In 2007, all manufacturers of sedative-hypnotic drugs were required to modify their product labeling to include stronger language about potential risks.35 Among these changes, warnings for ana­phylaxis and complex sleep-related behav­iors were added. Also, the FDA requested that manufacturers of sedative-hypnotic drugs develop and provide patient medi­cation guides, advising consumers on the potential risks and precautions associated with these drugs. More recently, the FDA announced changes to dosing recommen­dations for zolpidem-containing products because of the risk of impaired mental alertness36; manufacturers were required to lower the recommended dosages for each product.

Manufacturers of FDA-approved sedative-hypnotic drugs urge caution when prescribing these medications for geriatric patients, citing the potential for increased sensitivity, manifesting as marked excite­ment, depression, or confusion (eg, barbi­turates), and greater risk for dosage-related adverse effects (eg, oversedation, dizziness, confusion, impaired psychomotor perfor­mance, ataxia).^17-29

Use in clinical practice
Several variables should be considered when evaluating appropriateness of phar­macotherapy, including characteristics of the drug and the patient. Geriatric patients may be prone to comorbidities resulting from age-related physiologic changes. These diseases may be confounding (ie, contributing to sleep disorders); examples include medical illnesses, such as hyperthyroidism and arthritis, and psychiatric illnesses, such as depression and anxiety.³⁷ Other conditions, such as renal and hepatic dysfunction, may lead to alteration in drug exposure. These condi­tions should be assessed through routine renal function tests (eg, serum creatinine and glomerular filtration rate) and liver function tests (eg, serum albumin and liver transaminases).

Multiple comorbidities suggest a higher likelihood of polypharmacy, leading to other drug-related issues (eg, drug-drug interactions). Although these issues may guide therapy by restricting medication options, their potential contribution to the underlying sleep complaints should be con­sidered.³⁷ Several drugs commonly used by geriatric patients may affect wakefulness (eg, analgesics, antidepressants, and anti­hypertensives [sedating], and thyroid hor­mones, corticosteroids, and CNS stimulants [alerting]).

CASE CONTINUED
In Mr. R’s case, zaleplon was initiated at 10 mg/d. Because of his age and the nature of his sleep disorder, the choice of sedative-hypnotic was suitable; however, the prescribed dosage was inappropriate. The sluggishness Mr. R experienced likely was a manifestation of increased exposure to the drug. According to manufacturer and AASM recommendations, a more appropriate dosage is 5 mg/d.^13,23 Mr. R’s medical history and current medica­tions, and his hepatic and renal function, should be assessed. If Mr. R continues to have issues with sleep initiation, zaleplon, 5 mg at bedtime, should be considered.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

Acknowledgement
Vicki L. Ellingrod, PharmD, FCCP, is the series editor of Savvy Psychopharmacology.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. R, 75, is having difficulty sleeping. When he goes to bed, he lies there for what seems like forever, unable to fall asleep. He feels “so tired” and ends up taking naps during the day, but he cannot break this cycle. He has tried using over-the-counter products with little relief.

Mr. R’s primary care physician prescribes zaleplon, 10 mg/d, and asks him to call the clinic in 2 weeks to discuss his progress. He takes zaleplon as directed for several nights and begins to feel “sluggish” during the day, both mentally and physically, despite reporting an increase in the overall amount of sleep at night.

Sedative-hypnotic drugs are among the most commonly used medica­tions in the United States. Use of these drugs, as well as anxiolytics, has increased from 2.8% between 1988 and 1994 to 4.7% between 2007 and 2010, according to the Department of Health and Human Services.¹ In 2011, drugs categorized as sedative-hypnotics or antipsychotics were involved in 6.1% of all human exposures identified in the American Association of Poison Control Centers’ National Poison Data System.² Therefore, an understanding of clinical and pharmacological variables related to safe and effective use is important for clinicians prescribing and monitoring therapy with these agents.

Neuropsychiatric disorders are prevalent among geriatric patients and are associated with age-related physiologic changes in the CNS.³ Such changes involve:  
   • neuroanatomy (brain atrophy, decreased neuronal density, increased plaque formation)  
   • neurotransmitters (reduced cholinergic transmission, decreased synthesis of dopamine and catecholamines), and   
   • neurophysiology (reduced cerebral blood flow).

These physiologic processes manifest as alterations in mental status, reflexes, sen­sation, gait, balance, and sleep. Examples of sleep changes among geriatric patients include decreased sleep efficiency, more fre­quent awakenings, and more variable sleep duration.^3,4 Sleep disorders also may be related to mental disorders and other medi­cal conditions.⁵ For example, the prevalence of sleep-related respiratory disorders, such as obstructive sleep apnea and central sleep apnea, increases with age.⁶

Sleep disorders are common among geri­atric patients. In a large epidemiologic study of sleep complaints in patients age ≥65, more than one-half of patients had at least 1 sleep complaint (ie, difficulty falling asleep, trou­ble waking up, early awakening, need for naps, and feeling ill-rested).⁷ As many as 34% of patients reported symptoms of insom­nia. In an analysis of National Ambulatory Medical Survey Data over 6 years, 24.8% to 27.9% of sleep-related medical office visits were attributed to patients age ≥65.⁸

Pharmacology in aging
Prescribing sedative-hypnotic drugs is not routinely recommended for older patients with a sleep disorder. Geriatric patients, com­pared with younger patients, are at higher risk of iatrogenic complications because of polypharmacy, comorbidities, relative renal and hepatic insufficiency, and other physi­ologic changes leading to alterations in drug exposure and metabolism (Table 1).^9-12

Aging is associated with changes in body composition, including an increase in total body fat and decrease in lean body mass and total body water. These changes, as well as a prolonged GI transit time, decrease in active gut transporters, decreased blood perfusion, and decrease in plasma proteins such as albumin (because of reduced liver function or malnutrition), may lead to alteration in drug absorption patterns and may increase the volume of distribution for lipophilic drugs. Additionally, the elimination half-life of some drugs may increase with age because of larger volumes of distribution and reduction in hepatic or renal clearance.

The clinical significance of these changes is not well established. Although the process of drug absorption can change with age, the amount of drug absorbed might not be significantly affected. An increase in the vol­ume of distribution and reduction in drug metabolism and clearance might lead to increasing amounts of circulating drug and duration of drug exposure, putting geriat­ric patients at an increased risk for adverse effects and drug toxicity.⁹

Among these mechanisms, Dolder et al¹¹ hypothesized that drug metabolism cata­lyzed by cytochrome P450 (CYP) enzymes and renal excretion may be of greatest con­cern. Although in vitro studies suggest that concentration of CYP enzymes does not decline with age, in vivo studies have dem­onstrated reduced CYP activity in geriatric patients.^11,12 Theoretically, a reduction in CYP activity would increase the bioavail­ability of drugs, especially those that are subject to extensive first-pass (ie, hepatic) metabolism, and may lead to a reduction in systemic clearance.

Independent of metabolic changes, geriatric patients are at risk of reduced renal clearance because of age-related changes in glomerular filtration rate. Pharmacodynamic changes might be observed in older patients and could be a concern even in the setting of unaltered pharmacokinetic factors.9 These changes usually require administering smaller drug dosages.

Sedative-hypnotic medications
Sedative-hypnotic agents include several barbiturates, benzodiazepines (BZDs), non-BZD benzodiazepine-receptor ago­nists (BzRAs), a melatonin-receptor agonist (ie, ramelteon), and an orexin-receptor antagonist (ie, suvorexant).^13,14Table 2^14-29 summarizes selected sedative-hypnotic drugs. Additional drug classes used to treat insomnia include:
   • sedating antidepressants (trazodone, amitriptyline, doxepin, mirtazapine)
   • antiepileptic drugs (gabapentin, tiagabine)
   • atypical antipsychotics (quetiapine, olanzapine).

FDA-approved agents for treating insomnia include amobarbital, butabarbi­tal, pentobarbital, phenobarbital, secobar­bital, chloral hydrate, diphenhydramine, doxylamine, doxepin, estazolam, fluraz­epam, lorazepam, quazepam, temazepam, triazolam, eszopiclone, zaleplon, zolpidem, ramelteon, and suvorexant. Not all of these drugs are recommended for use in geriatric patients. Barbiturates, for example, should be avoided.³⁰

Pharmacokinetic characteristics vary among drugs and drug classes. Choice of pharmacotherapy should account for patient and drug characteristics and the specific sleep complaint. Sleep disorders may be var­iously characterized as difficulty with sleep initiation, duration, consolidation, or qual­ity.¹³ Therefore, onset and duration of effect are important drug-related considerations. Sedative-hypnotic drugs with a short time-to-onset may be ideal for patients with sleep-onset insomnia.

The drugs’ duration of effect (eg, presence of active metabolites, long elimination half-life) also must be reviewed. A long elimi­nation half-life may lead to increased drug exposure and unwanted side effects such as residual daytime drowsiness. Despite this, sedative-hypnotic drugs with a longer duration of effect (eg, intermediate- or long-acting drugs) may be best for patients with insomnia defined by difficulty maintaining sleep.

Benzodiazepines vary in their time to onset of effect, rate of elimination, and metabolism.^15-21 BZDs that are FDA- approved for use as sedative-hypnotics are listed in Table 2.^14-29 These BZDs have different onsets of effect as evidenced by time to achieve maximum plasma con­centration (T_max), ranging from 0.5 hours (flurazepam) to 2 hours (estazolam, quaz­epam, triazolam). The elimination half-life varies widely among these medications, from 1.5 hours (triazolam) to >100 hours (flurazepam). Flurazepam’s long half-life is attributable to its active major metabo­lite. Although most BZDs are metabolized hepatically, temazepam is subject to mini­mal hepatic metabolism.

Benzodiazepine-receptor agonists. There is substantial variation in the phar­macokinetic characteristics of BzRAs.^15,16,22-28 There also are differences among the zolpi­dem dosage forms; sublingual formulations have the shortest onset of effect. Eszopiclone and zaleplon have low protein binding com­pared with zolpidem. Elimination half-lives vary among drugs with the shortest attrib­uted to zaleplon (1 hour) and longest to eszopiclone (6 hours). All BzRAs are subject to extensive hepatic metabolism. 

Ramelteon. Singular in its class, ramelteon is a treatment option for insomnia.²⁹ This drug has a short onset of effect, moder­ate protein binding, and extensive hepatic metabolism. Ramelteon is primarily excreted in the urine as its metabolites, and the drug half-life is relatively short.

Suvorexant is the latest addition to the sedative-hypnotic armamentarium, approved by the FDA in August 2014 for dif­ficulty with sleep onset and/or sleep main­tenance.¹⁴ As an orexin-receptor antagonist, suvorexant represents a novel pharmaco­logic class. Suvorexant exhibits moderately rapid absorption with time to peak concen­tration ranging from 30 minutes to 6 hours in fasting conditions; absorption is delayed when taken with or soon after a meal. The drug is highly protein bound and extensively metabolized, primarily through CYP3A. The manufacturer recommends dose reduc­tion (5 mg at bedtime) in patients taking moderate CYP3A inhibitors and avoiding suvorexant in patients taking strong CYP3A inhibitors. Suvorexant is primarily excreted through feces and the mean half-life is rela­tively long.

Considering these characteristics and age-related physiologic changes, the practi­tioner should be concerned about drugs that undergo extensive hepatic metabolism. Age-related reductions in CYP activity may lead to an increase in drug bioavailability and a decrease in the systemic clearance,¹¹ which might be associated with an increase in elimination half-life and duration of action. Dosage adjustments are recommended for several BZDs (lower initial and maximum dosages for most agents) and BzRAs.^17-28 No dosage adjustments for ramelteon or suvorexant in geriatric patients have been specified^14,29; the manufacturers for both products assert that no differences in safety and efficacy have been observed between older and younger adult patients.

Alternative and complementary medications
Several non-prescription products, includ­ing over-the-counter drugs (eg, diphenhy-dramine, doxylamine) and herbal therapies (eg, melatonin, valerian), are used for their sedative-hypnotic properties. There is a lack of evidence supporting using diphenhydra-mine in patients with chronic insomnia, and tolerance to its hypnotic effect has been reported with repeated use.³¹ Concerns about anticholinergic toxicity and CNS depression limit its use in geriatric patients. Among herbal therapies, melatonin may have the strongest evidence for its ability to allevi­ate sleep disorders in geriatric patients³²; however, meta-analyses have demonstrated small effects of melatonin on sleep latency and minimal differences in wake time after sleep onset and total sleep time.¹³

Clinical practice guidelines
Non-pharmacotherapeutic interventions, such as behavioral (eg, sleep hygiene mea­sures) and psychological therapy, are rec­ommended for initial management of sleep disorders in geriatric patients.^13,33 In con­junction, the American Medical Directors Association (AMDA) recommends address­ ing underlying causes and exacerbating fac­tors (eg, medical condition or medication).³³ The AMDA recommends avoiding long-term pharmacotherapy and advises caution with BZD-hypnotic drugs, tricyclic antide­pressants, and antihistamines. The American Academy of Sleep Medicine (AASM) recom­mends an initial treatment period of 2 to 4 weeks, followed by re-evaluation of con­tinued need for treatment.¹³ The AASM recommends short- or intermediate-acting BzRAs or ramelteon for initial pharmaco­logic management of primary insomnias and insomnias comorbid with other condi­tions. The AASM also recommends specific dosages of BzRAs and BZDs for geriatric patients, which coincide with manufacturer-recommended dosages (Table 2).^14-29

Barbiturates, chloral hydrate, and non-barbiturate, non-BZD drugs such as mep­robamate are not recommended because of potential significant adverse effects and tolerance/dependence, and low therapeu­tic index. The AASM advises caution when using prescription drugs off-label for insom­nia (eg, antidepressants, antiepileptics, antipsychotics) and recommends avoiding them, if possible, because of limited evi­dence supporting their use.¹³

Safety concerns
Two commonly used references contain rec­ommendations for sedative-hypnotic medi­cation use in geriatric patients.^30,34 According to Gallagher et al’s³⁴ Screening Tool of Older Person’s Prescriptions (STOPP), long-term (>1 month) use of long-acting BZDs (eg, flurazepam, diazepam) and prolonged use (>1 week) of first-generation antihistamines (eg, diphenhydramine, doxylamine) should be avoided in patients age ≥65 because of the risk of sedation, confusion, and anti­cholinergic side effects. STOPP recognizes that any use of BZDs, neuroleptics, or first-generation antihistamines may contrib­ute to postural imbalance; therefore these agents are not recommended in older patients at risk for falls.

In the 2012 American Geriatrics Society (AGS) Beers Criteria, the AGS recommends avoiding barbiturates in older adults because of the high rate of physical depen­dence, tolerance to sleep effects, and over­dose risk at low dosages.³⁰ The AGS also recommends avoiding BZDs, stating that older adults have increased sensitivity to these agents and are at an increased risk of cognitive impairment, delirium, falls, frac­tures, and motor vehicle accidents when taking these drugs. Non-BZD BzRAs also should not be prescribed to patients with a history of falls or fractures, unless safer alternatives are not available.

The FDA has issued several advisory reports regarding sedative-hypnotic drugs. In 2007, all manufacturers of sedative-hypnotic drugs were required to modify their product labeling to include stronger language about potential risks.35 Among these changes, warnings for ana­phylaxis and complex sleep-related behav­iors were added. Also, the FDA requested that manufacturers of sedative-hypnotic drugs develop and provide patient medi­cation guides, advising consumers on the potential risks and precautions associated with these drugs. More recently, the FDA announced changes to dosing recommen­dations for zolpidem-containing products because of the risk of impaired mental alertness36; manufacturers were required to lower the recommended dosages for each product.

Manufacturers of FDA-approved sedative-hypnotic drugs urge caution when prescribing these medications for geriatric patients, citing the potential for increased sensitivity, manifesting as marked excite­ment, depression, or confusion (eg, barbi­turates), and greater risk for dosage-related adverse effects (eg, oversedation, dizziness, confusion, impaired psychomotor perfor­mance, ataxia).^17-29

Use in clinical practice
Several variables should be considered when evaluating appropriateness of phar­macotherapy, including characteristics of the drug and the patient. Geriatric patients may be prone to comorbidities resulting from age-related physiologic changes. These diseases may be confounding (ie, contributing to sleep disorders); examples include medical illnesses, such as hyperthyroidism and arthritis, and psychiatric illnesses, such as depression and anxiety.³⁷ Other conditions, such as renal and hepatic dysfunction, may lead to alteration in drug exposure. These condi­tions should be assessed through routine renal function tests (eg, serum creatinine and glomerular filtration rate) and liver function tests (eg, serum albumin and liver transaminases).

Multiple comorbidities suggest a higher likelihood of polypharmacy, leading to other drug-related issues (eg, drug-drug interactions). Although these issues may guide therapy by restricting medication options, their potential contribution to the underlying sleep complaints should be con­sidered.³⁷ Several drugs commonly used by geriatric patients may affect wakefulness (eg, analgesics, antidepressants, and anti­hypertensives [sedating], and thyroid hor­mones, corticosteroids, and CNS stimulants [alerting]).

CASE CONTINUED
In Mr. R’s case, zaleplon was initiated at 10 mg/d. Because of his age and the nature of his sleep disorder, the choice of sedative-hypnotic was suitable; however, the prescribed dosage was inappropriate. The sluggishness Mr. R experienced likely was a manifestation of increased exposure to the drug. According to manufacturer and AASM recommendations, a more appropriate dosage is 5 mg/d.^13,23 Mr. R’s medical history and current medica­tions, and his hepatic and renal function, should be assessed. If Mr. R continues to have issues with sleep initiation, zaleplon, 5 mg at bedtime, should be considered.

Related Resources
• Institute for Safe Medication Practices. www.ismp.org.
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program. www.fda.gov/Safety/MedWatch/default.htm.

Drug Brand Names
Amitriptyline • Elavil                                   Mirtazapine • Remeron
Amobarbital • Amytal                                  Olanzapine • Zyprexa
Butabarbital • Butisol                                  Pentobarbital • Nembutal
Chloral hydrate • Somnote                          Phenobarbital • Luminal
Diazepam • Valium                                     Quazepam • Doral
Diphenhydramine • Benadryl, others            Quetiapine • Seroquel
Doxepin • Silenor                                       Ramelteon • Rozerem
Doxylamine • Unisom, others                      Secobarbital • Seconal
Estazolam • ProSom                                   Suvorexant • Belsomra
Eszopiclone • Lunesta                                 Temazepam • Restoril
Flurazepam • Dalmane                               Tiagabine • Gabitril
Gabapentin • Neurontin,                             Trazodone • Desyrel
Gralise, Horizant                                        Zaleplon • Sonata
Lorazepam • Ativan                                   Zolpidem • Ambien, Edluar,
Meprobamate • Equanil                                 Intermezzo, Zolpimist

Acknowledgement
Vicki L. Ellingrod, PharmD, FCCP, is the series editor of Savvy Psychopharmacology.

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

At least once during your career, you probably will have to put a value on your practice. The need arises more often than you might think – if you sell it, of course (more on that next month); but also for estate planning, preparation of financial statements, or divorce negotiations; or when an associate joins or leaves your office; or if you have occasion to combine or partner your practice with one or more others, as I will discuss in detail in a future issue.

As you might guess, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in a few hundred words, but three basic yardsticks are essential for a practice appraisal:

Tangible assets: equipment, cash, accounts receivable, and other property owned by the practice.

Liabilities: accounts payable, outstanding loans, and anything else owed to others.

Intangible assets: sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the “equity,” or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons patients come back (if they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferrable. For example, unique skills with a laser, neurotoxins, or filler substances (or extraordinary personal charisma) may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash flow analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider to provide a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings are (and thus its overall value).

Asset-based valuation is the most popular, but by no means the only, method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not the income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll talk about sales and mergers over the next several columns.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Skin & Allergy News.

At least once during your career, you probably will have to put a value on your practice. The need arises more often than you might think – if you sell it, of course (more on that next month); but also for estate planning, preparation of financial statements, or divorce negotiations; or when an associate joins or leaves your office; or if you have occasion to combine or partner your practice with one or more others, as I will discuss in detail in a future issue.

As you might guess, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in a few hundred words, but three basic yardsticks are essential for a practice appraisal:

Tangible assets: equipment, cash, accounts receivable, and other property owned by the practice.

Liabilities: accounts payable, outstanding loans, and anything else owed to others.

Intangible assets: sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the “equity,” or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons patients come back (if they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferrable. For example, unique skills with a laser, neurotoxins, or filler substances (or extraordinary personal charisma) may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash flow analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider to provide a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings are (and thus its overall value).

Asset-based valuation is the most popular, but by no means the only, method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not the income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll talk about sales and mergers over the next several columns.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Skin & Allergy News.

At least once during your career, you probably will have to put a value on your practice. The need arises more often than you might think – if you sell it, of course (more on that next month); but also for estate planning, preparation of financial statements, or divorce negotiations; or when an associate joins or leaves your office; or if you have occasion to combine or partner your practice with one or more others, as I will discuss in detail in a future issue.

As you might guess, a medical practice is trickier to value than an ordinary business, and usually requires the services of an experienced professional appraiser. Entire books have been written about the process, so I can’t hope to cover it completely in a few hundred words, but three basic yardsticks are essential for a practice appraisal:

Tangible assets: equipment, cash, accounts receivable, and other property owned by the practice.

Liabilities: accounts payable, outstanding loans, and anything else owed to others.

Intangible assets: sometimes called “good will” – the reputation of the physicians, the location and name recognition of the practice, the loyalty and volume of patients, and other, well, intangibles.

Armed with those numbers, an appraiser can then determine the “equity,” or book value, of the practice.

Valuing tangible assets is comparatively straightforward, but there are several ways to do it, and when reviewing a practice appraisal you should ask which of them was used. Depreciated value is the book value of equipment and supplies as determined by their purchase price, less the amount their value has decreased since purchase. Remaining useful life value estimates how long the equipment can be expected to last. Market (or replacement) value is the amount it would cost on the open market to replace all equipment and supplies.

Intangible assets are more difficult to value. Many components are analyzed, including location, interior and exterior decor, accessibility to patients, age and functional status of equipment, systems in place to promote efficiency, reasons patients come back (if they do), and the overall reputation of the practice in the community. Other important factors include the “payer mix” (what percentage pays cash, how many third-party contracts are in place and how well they pay, etc.), the extent and strength of the referral base, and the presence of clinical studies or other supplemental income streams.

It is also important to determine to what extent intangible assets are transferrable. For example, unique skills with a laser, neurotoxins, or filler substances (or extraordinary personal charisma) may increase your practice’s value to you, but they are worthless to the next owner, and he or she will be unwilling to pay for them unless your services become part of the deal.

Once again, there are many ways to estimate intangible asset value, and once again you should ask which were used. Cash flow analysis works on the assumption that cash flow is a measure of intangible value. Capitalization of earnings puts a value, or capitalization, on the practice’s income streams using a variety of assumptions. Guideline comparison uses various databases to compare your practice with other, similar ones that have changed hands in the past.

Two newer techniques, which some consider to provide a better estimate of intangible assets, are the replacement method, which estimates the costs of starting the practice over again in the current market; and the excess earnings method, which measures how far above average your practice’s earnings are (and thus its overall value).

Asset-based valuation is the most popular, but by no means the only, method available. Income-based valuation looks at the source and strength of a practice’s income stream as a creator of value, as well as whether or not the income stream under a different owner would mirror its present one. This in turn becomes the basis for an understanding of the fair market value of both tangible and intangible assets. Market valuation combines the asset-based and income-based approaches, along with an analysis of sales and mergers of comparable practices in the community, to determine the value of a practice in its local market.

Whatever methods are used, it is important that the appraisal be done by an experienced financial consultant, that all techniques used in the valuation be divulged and explained, and that documentation is supplied to support the conclusions reached. This is especially important if the appraisal will be relied upon in the sale or merger of the practice. I’ll talk about sales and mergers over the next several columns.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Skin & Allergy News.

I got my Medicare card 2 years ago (guess how old I am?). At this year’s physical exam (my first exam under new rules that let Medicare pay for routine annual physicals), the clerk asked me to fill out the “Health-Risk Assessment” form my PCP would need for billing.

This form had two pages. Page 1 listed 26 questions, each to be answered by checking off one of the following six choices: Never, Sometimes, Seldom, Often, Always, and Not Applicable.

Right away you see a problem. If this were an SAT test, say, where I actually cared whether or not I passed, I would summon a proctor and demand to know the difference between “Sometimes” and “Seldom,” or whether “Always” includes when I’m asleep, intoxicated, or filling out forms.

I will not burden you with all 26 questions. Instead, I’ll present several (these are the actual questions, folks, word for word), along with the answers I would have given had I not been hamstrung by the Six Categories. Each question is headed, “In the past 4 weeks.”

Q: How much have you felt little interest or pleasure?

A: I have very much felt little interest, and very little felt much interest. On the other hand, I have much interest in the little pleasure I have felt, and much pleasure in the little interest I have had.

Q: Has your physical and emotional health limited your social activities with family, friends, neighbors or groups?

A: No, but lack of money has.

Q: Have you needed help preparing your own meals?

A: Yes, ever since I got married, but that was more than 4 weeks ago. I can still make omelets, though.

Q: Are you having difficulties driving your car?

A: Do you know Boston drivers?

Q: Have you needed help managing your finances?

A: Not since 2008, and then it was my broker who needed the help.

Q: Have you needed help with household chores?

A: Never do ‘em.

Q: Do you have concerns about your memory?

A: What?

Q: DO YOU HAVE CONCERNS ABOUT YOUR MEMORY?

A: Not so much about what I can’t remember, mostly about what I can.

Q: Do any of your friends/family have concerns about your memory?

A: No, other than whether I’ll remember them in my will.

Q: Have you had sexual problems?

A: Too much. Too little. I forget. But that’s just the last 4 weeks. Six weeks ago was amazing.

Q: Have problems using a telephone?

A: Damn right. Cellular connectivity around here stinks.

Q: Do you exercise for about 20 minutes, 3 or more days a week?

A: I always exercise sometimes. I sometimes exercise always. Could you repeat the question?

Q: Does your home have throw rugs?

A: It has rugs, but nobody throws them.

Q: Does your home have poor lighting?

A: Ever since they outlawed incandescents. When I flip the switch, they’re fully lit by the time I finish breakfast, but by then it’s time to turn them off and go to work.

Q: During the past 4 weeks, how have things been going for you?

A: The Red Sox are doing lousy. Did you have to ask?

The form ends with thanks for taking the time to fill out the form and concludes with this cheery note: “Your responses will help you receive the best health and health care possible.”

When my physical was done, my doctor found the form in my paper pile. “I see you filled it out,” she said.

“By the way,” I asked her. ‘”What do you do with these forms?”

“Absolutely nothing,” she said.

“You don’t have to submit them for tabulation or something?”

“No,” she said.

If you’re not on Medicare yet, this is what you have to look forward to. Always.

Sometimes.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Skin & Allergy News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

[email protected]

I got my Medicare card 2 years ago (guess how old I am?). At this year’s physical exam (my first exam under new rules that let Medicare pay for routine annual physicals), the clerk asked me to fill out the “Health-Risk Assessment” form my PCP would need for billing.

This form had two pages. Page 1 listed 26 questions, each to be answered by checking off one of the following six choices: Never, Sometimes, Seldom, Often, Always, and Not Applicable.

Right away you see a problem. If this were an SAT test, say, where I actually cared whether or not I passed, I would summon a proctor and demand to know the difference between “Sometimes” and “Seldom,” or whether “Always” includes when I’m asleep, intoxicated, or filling out forms.

I will not burden you with all 26 questions. Instead, I’ll present several (these are the actual questions, folks, word for word), along with the answers I would have given had I not been hamstrung by the Six Categories. Each question is headed, “In the past 4 weeks.”

Q: How much have you felt little interest or pleasure?

A: I have very much felt little interest, and very little felt much interest. On the other hand, I have much interest in the little pleasure I have felt, and much pleasure in the little interest I have had.

Q: Has your physical and emotional health limited your social activities with family, friends, neighbors or groups?

A: No, but lack of money has.

Q: Have you needed help preparing your own meals?

A: Yes, ever since I got married, but that was more than 4 weeks ago. I can still make omelets, though.

Q: Are you having difficulties driving your car?

A: Do you know Boston drivers?

Q: Have you needed help managing your finances?

A: Not since 2008, and then it was my broker who needed the help.

Q: Have you needed help with household chores?

A: Never do ‘em.

Q: Do you have concerns about your memory?

A: What?

Q: DO YOU HAVE CONCERNS ABOUT YOUR MEMORY?

A: Not so much about what I can’t remember, mostly about what I can.

Q: Do any of your friends/family have concerns about your memory?

A: No, other than whether I’ll remember them in my will.

Q: Have you had sexual problems?

A: Too much. Too little. I forget. But that’s just the last 4 weeks. Six weeks ago was amazing.

Q: Have problems using a telephone?

A: Damn right. Cellular connectivity around here stinks.

Q: Do you exercise for about 20 minutes, 3 or more days a week?

A: I always exercise sometimes. I sometimes exercise always. Could you repeat the question?

Q: Does your home have throw rugs?

A: It has rugs, but nobody throws them.

Q: Does your home have poor lighting?

A: Ever since they outlawed incandescents. When I flip the switch, they’re fully lit by the time I finish breakfast, but by then it’s time to turn them off and go to work.

Q: During the past 4 weeks, how have things been going for you?

A: The Red Sox are doing lousy. Did you have to ask?

The form ends with thanks for taking the time to fill out the form and concludes with this cheery note: “Your responses will help you receive the best health and health care possible.”

When my physical was done, my doctor found the form in my paper pile. “I see you filled it out,” she said.

“By the way,” I asked her. ‘”What do you do with these forms?”

“Absolutely nothing,” she said.

“You don’t have to submit them for tabulation or something?”

“No,” she said.

If you’re not on Medicare yet, this is what you have to look forward to. Always.

Sometimes.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Skin & Allergy News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

[email protected]

I got my Medicare card 2 years ago (guess how old I am?). At this year’s physical exam (my first exam under new rules that let Medicare pay for routine annual physicals), the clerk asked me to fill out the “Health-Risk Assessment” form my PCP would need for billing.

This form had two pages. Page 1 listed 26 questions, each to be answered by checking off one of the following six choices: Never, Sometimes, Seldom, Often, Always, and Not Applicable.

Right away you see a problem. If this were an SAT test, say, where I actually cared whether or not I passed, I would summon a proctor and demand to know the difference between “Sometimes” and “Seldom,” or whether “Always” includes when I’m asleep, intoxicated, or filling out forms.

I will not burden you with all 26 questions. Instead, I’ll present several (these are the actual questions, folks, word for word), along with the answers I would have given had I not been hamstrung by the Six Categories. Each question is headed, “In the past 4 weeks.”

Q: How much have you felt little interest or pleasure?

A: I have very much felt little interest, and very little felt much interest. On the other hand, I have much interest in the little pleasure I have felt, and much pleasure in the little interest I have had.

Q: Has your physical and emotional health limited your social activities with family, friends, neighbors or groups?

A: No, but lack of money has.

Q: Have you needed help preparing your own meals?

A: Yes, ever since I got married, but that was more than 4 weeks ago. I can still make omelets, though.

Q: Are you having difficulties driving your car?

A: Do you know Boston drivers?

Q: Have you needed help managing your finances?

A: Not since 2008, and then it was my broker who needed the help.

Q: Have you needed help with household chores?

A: Never do ‘em.

Q: Do you have concerns about your memory?

A: What?

Q: DO YOU HAVE CONCERNS ABOUT YOUR MEMORY?

A: Not so much about what I can’t remember, mostly about what I can.

Q: Do any of your friends/family have concerns about your memory?

A: No, other than whether I’ll remember them in my will.

Q: Have you had sexual problems?

A: Too much. Too little. I forget. But that’s just the last 4 weeks. Six weeks ago was amazing.

Q: Have problems using a telephone?

A: Damn right. Cellular connectivity around here stinks.

Q: Do you exercise for about 20 minutes, 3 or more days a week?

A: I always exercise sometimes. I sometimes exercise always. Could you repeat the question?

Q: Does your home have throw rugs?

A: It has rugs, but nobody throws them.

Q: Does your home have poor lighting?

A: Ever since they outlawed incandescents. When I flip the switch, they’re fully lit by the time I finish breakfast, but by then it’s time to turn them off and go to work.

Q: During the past 4 weeks, how have things been going for you?

A: The Red Sox are doing lousy. Did you have to ask?

The form ends with thanks for taking the time to fill out the form and concludes with this cheery note: “Your responses will help you receive the best health and health care possible.”

When my physical was done, my doctor found the form in my paper pile. “I see you filled it out,” she said.

“By the way,” I asked her. ‘”What do you do with these forms?”

“Absolutely nothing,” she said.

“You don’t have to submit them for tabulation or something?”

“No,” she said.

If you’re not on Medicare yet, this is what you have to look forward to. Always.

Sometimes.

Dr. Rockoff practices dermatology in Brookline, Mass., and is a longtime contributor to Skin & Allergy News. He serves on the clinical faculty at Tufts University, Boston, and has taught senior medical students and other trainees for 30 years.

[email protected]

Prescriptions

Credit: CDC

A newly published meta-analysis suggests most anticoagulant therapies produce similar results in patients with venous thromboembolism (VTE).

Using data from 45 randomized trials, investigators compared 8 anticoagulation options and found that most were associated with similar rates of VTE recurrence and bleeding.

They did find that unfractionated heparin (UFH) plus a vitamin K antagonist (VKA) conferred the greatest risk of VTE recurrence.

And rivaroxaban and apixaban were associated with the lowest rates of bleeding.

Two treatments—apixaban and low-molecular-weight heparin (LMWH) plus edoxaban—had the highest probability of being the best therapy. And apixaban had the greatest probability of being the least harmful therapy.

Lana A. Castellucci, MD, of the Ottawa Hospital Research Institute in Ontario, Canada, and her colleagues reported these results in JAMA.

The team conducted this meta-analysis to compare the efficacy and safety of 8 anticoagulation options: rivaroxaban, apixaban, LMWH, LMWH plus dabigatran, LMWH plus edoxaban, LMWH plus a VKA, UFH plus a VKA, and fondaparinux plus a VKA.

A search of the medical literature revealed 45 randomized trials comparing treatment options for VTE. They included a total of 44,989 patients.

VTE recurrence

The investigators first compared the risk of VTE recurrence with LMWH-VKA to all other treatment strategies. They found that 6 of the other options were associated with a lower rate of VTE recurrence than LMWH-VKA.

The only exception was UFH-VKA. During 3 months of treatment, 1.84% of patients who received UFH-VKA had a VTE recurrence, compared to 1.30% of patients treated with LMWH-VKA.

When the investigators used UFH-VKA as the comparator, they found that LMWH-VKA and LMWH alone were the only treatments associated with a reduction in recurrent VTE.

Stepwise comparisons of the remaining treatment strategies did not reveal significant differences in VTE recurrence.

However, the investigators found that LMWH-edoxaban and apixaban had the greatest probability of being the best therapy—at 33.1% and 31.6%, respectively.

Bleeding risk

Compared with LMWH-VKA, rivaroxaban and apixaban were associated with the lowest bleeding risk. The incidence of major bleeding during 3 months of anticoagulation was 0.49% for rivaroxaban, 0.28% for apixaban, and 0.89% for LMWH-VKA.

For all other treatments, the risk of bleeding did not differ significantly from the risk associated with LMWH-VKA.

Additional pairwise comparisons showed that rivaroxaban, apixaban, or both were associated with the lowest bleeding rates compared with UFH-VKA, fondaparinux-VKA, LMWH-dabigatran, and LMWH-edoxaban.

Apixaban was associated with the greatest probability of being the least harmful therapy (88.9%).

Considering these results together, Dr Castellucci and her colleagues concluded that most of the VTE treatments studied elicited comparable safety and efficacy outcomes.

However, UFH-VKA may be the least effective strategy for managing VTE, and rivaroxaban and apixaban may be associated with the lowest risk of bleeding.

Prescriptions

Credit: CDC

A newly published meta-analysis suggests most anticoagulant therapies produce similar results in patients with venous thromboembolism (VTE).

Using data from 45 randomized trials, investigators compared 8 anticoagulation options and found that most were associated with similar rates of VTE recurrence and bleeding.

They did find that unfractionated heparin (UFH) plus a vitamin K antagonist (VKA) conferred the greatest risk of VTE recurrence.

And rivaroxaban and apixaban were associated with the lowest rates of bleeding.

Two treatments—apixaban and low-molecular-weight heparin (LMWH) plus edoxaban—had the highest probability of being the best therapy. And apixaban had the greatest probability of being the least harmful therapy.

Lana A. Castellucci, MD, of the Ottawa Hospital Research Institute in Ontario, Canada, and her colleagues reported these results in JAMA.

The team conducted this meta-analysis to compare the efficacy and safety of 8 anticoagulation options: rivaroxaban, apixaban, LMWH, LMWH plus dabigatran, LMWH plus edoxaban, LMWH plus a VKA, UFH plus a VKA, and fondaparinux plus a VKA.

A search of the medical literature revealed 45 randomized trials comparing treatment options for VTE. They included a total of 44,989 patients.

VTE recurrence

The investigators first compared the risk of VTE recurrence with LMWH-VKA to all other treatment strategies. They found that 6 of the other options were associated with a lower rate of VTE recurrence than LMWH-VKA.

The only exception was UFH-VKA. During 3 months of treatment, 1.84% of patients who received UFH-VKA had a VTE recurrence, compared to 1.30% of patients treated with LMWH-VKA.

When the investigators used UFH-VKA as the comparator, they found that LMWH-VKA and LMWH alone were the only treatments associated with a reduction in recurrent VTE.

Stepwise comparisons of the remaining treatment strategies did not reveal significant differences in VTE recurrence.

However, the investigators found that LMWH-edoxaban and apixaban had the greatest probability of being the best therapy—at 33.1% and 31.6%, respectively.

Bleeding risk

Compared with LMWH-VKA, rivaroxaban and apixaban were associated with the lowest bleeding risk. The incidence of major bleeding during 3 months of anticoagulation was 0.49% for rivaroxaban, 0.28% for apixaban, and 0.89% for LMWH-VKA.

For all other treatments, the risk of bleeding did not differ significantly from the risk associated with LMWH-VKA.

Additional pairwise comparisons showed that rivaroxaban, apixaban, or both were associated with the lowest bleeding rates compared with UFH-VKA, fondaparinux-VKA, LMWH-dabigatran, and LMWH-edoxaban.

Apixaban was associated with the greatest probability of being the least harmful therapy (88.9%).

Considering these results together, Dr Castellucci and her colleagues concluded that most of the VTE treatments studied elicited comparable safety and efficacy outcomes.

However, UFH-VKA may be the least effective strategy for managing VTE, and rivaroxaban and apixaban may be associated with the lowest risk of bleeding.

Prescriptions

Credit: CDC

A newly published meta-analysis suggests most anticoagulant therapies produce similar results in patients with venous thromboembolism (VTE).

Using data from 45 randomized trials, investigators compared 8 anticoagulation options and found that most were associated with similar rates of VTE recurrence and bleeding.

They did find that unfractionated heparin (UFH) plus a vitamin K antagonist (VKA) conferred the greatest risk of VTE recurrence.

And rivaroxaban and apixaban were associated with the lowest rates of bleeding.

Two treatments—apixaban and low-molecular-weight heparin (LMWH) plus edoxaban—had the highest probability of being the best therapy. And apixaban had the greatest probability of being the least harmful therapy.

Lana A. Castellucci, MD, of the Ottawa Hospital Research Institute in Ontario, Canada, and her colleagues reported these results in JAMA.

The team conducted this meta-analysis to compare the efficacy and safety of 8 anticoagulation options: rivaroxaban, apixaban, LMWH, LMWH plus dabigatran, LMWH plus edoxaban, LMWH plus a VKA, UFH plus a VKA, and fondaparinux plus a VKA.

A search of the medical literature revealed 45 randomized trials comparing treatment options for VTE. They included a total of 44,989 patients.

VTE recurrence

The investigators first compared the risk of VTE recurrence with LMWH-VKA to all other treatment strategies. They found that 6 of the other options were associated with a lower rate of VTE recurrence than LMWH-VKA.

The only exception was UFH-VKA. During 3 months of treatment, 1.84% of patients who received UFH-VKA had a VTE recurrence, compared to 1.30% of patients treated with LMWH-VKA.

When the investigators used UFH-VKA as the comparator, they found that LMWH-VKA and LMWH alone were the only treatments associated with a reduction in recurrent VTE.

Stepwise comparisons of the remaining treatment strategies did not reveal significant differences in VTE recurrence.

However, the investigators found that LMWH-edoxaban and apixaban had the greatest probability of being the best therapy—at 33.1% and 31.6%, respectively.

Bleeding risk

Compared with LMWH-VKA, rivaroxaban and apixaban were associated with the lowest bleeding risk. The incidence of major bleeding during 3 months of anticoagulation was 0.49% for rivaroxaban, 0.28% for apixaban, and 0.89% for LMWH-VKA.

For all other treatments, the risk of bleeding did not differ significantly from the risk associated with LMWH-VKA.

Additional pairwise comparisons showed that rivaroxaban, apixaban, or both were associated with the lowest bleeding rates compared with UFH-VKA, fondaparinux-VKA, LMWH-dabigatran, and LMWH-edoxaban.

Apixaban was associated with the greatest probability of being the least harmful therapy (88.9%).

Considering these results together, Dr Castellucci and her colleagues concluded that most of the VTE treatments studied elicited comparable safety and efficacy outcomes.

However, UFH-VKA may be the least effective strategy for managing VTE, and rivaroxaban and apixaban may be associated with the lowest risk of bleeding.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a recombinant factor IX product (Rixubis) for use in children with hemophilia B.

Rixubis is indicated for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in these patients.

Rixubis was the first recombinant factor IX product to gain FDA approval for routine prophylaxis and control of bleeding episodes in adults with hemophilia B.

The latest FDA approval is based on results of a trial investigating the efficacy and safety of Rixubis in 23 previously treated male patients younger than 12 years of age who had severe or moderately severe hemophilia B.

The patients received a twice-weekly Rixubis prophylaxis regimen (mean dose 56 IU/kg) for a mean treatment duration of 6 months and a mean of 54 exposure days.

The median annualized bleeding rate was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients (39.1%) experienced no bleeds, and 23 bleeding episodes (88.5%) were treated with 1 to 2 infusions.

There were no reports of inhibitor development, severe allergic reactions, thrombotic events, or treatment-related adverse events.

These data were presented at the 2013 ASH Annual Meeting (abstract 1118).

Common adverse reactions observed in more than 1% of subjects in clinical studies of Rixubis were dysgeusia, pain in an extremity, and a positive test for furin antibody. Rixubis may pose a risk of hypersensitivity reactions, inhibitor development, nephrotic syndrome, and thromboembolic complications.

Rixubis is contraindicated in patients who have known hypersensitivity to the product or its excipients (including hamster protein), patients with disseminated intravascular coagulation, and those with signs of fibrinolysis.

For more details on Rixubis, see the full prescribing information. Rixubis is under development by Baxter International Inc.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a recombinant factor IX product (Rixubis) for use in children with hemophilia B.

Rixubis is indicated for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in these patients.

Rixubis was the first recombinant factor IX product to gain FDA approval for routine prophylaxis and control of bleeding episodes in adults with hemophilia B.

The latest FDA approval is based on results of a trial investigating the efficacy and safety of Rixubis in 23 previously treated male patients younger than 12 years of age who had severe or moderately severe hemophilia B.

The patients received a twice-weekly Rixubis prophylaxis regimen (mean dose 56 IU/kg) for a mean treatment duration of 6 months and a mean of 54 exposure days.

The median annualized bleeding rate was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients (39.1%) experienced no bleeds, and 23 bleeding episodes (88.5%) were treated with 1 to 2 infusions.

There were no reports of inhibitor development, severe allergic reactions, thrombotic events, or treatment-related adverse events.

These data were presented at the 2013 ASH Annual Meeting (abstract 1118).

Common adverse reactions observed in more than 1% of subjects in clinical studies of Rixubis were dysgeusia, pain in an extremity, and a positive test for furin antibody. Rixubis may pose a risk of hypersensitivity reactions, inhibitor development, nephrotic syndrome, and thromboembolic complications.

Rixubis is contraindicated in patients who have known hypersensitivity to the product or its excipients (including hamster protein), patients with disseminated intravascular coagulation, and those with signs of fibrinolysis.

For more details on Rixubis, see the full prescribing information. Rixubis is under development by Baxter International Inc.

Antihemophilic factor

The US Food and Drug Administration (FDA) has approved a recombinant factor IX product (Rixubis) for use in children with hemophilia B.

Rixubis is indicated for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in these patients.

Rixubis was the first recombinant factor IX product to gain FDA approval for routine prophylaxis and control of bleeding episodes in adults with hemophilia B.

The latest FDA approval is based on results of a trial investigating the efficacy and safety of Rixubis in 23 previously treated male patients younger than 12 years of age who had severe or moderately severe hemophilia B.

The patients received a twice-weekly Rixubis prophylaxis regimen (mean dose 56 IU/kg) for a mean treatment duration of 6 months and a mean of 54 exposure days.

The median annualized bleeding rate was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients (39.1%) experienced no bleeds, and 23 bleeding episodes (88.5%) were treated with 1 to 2 infusions.

There were no reports of inhibitor development, severe allergic reactions, thrombotic events, or treatment-related adverse events.

These data were presented at the 2013 ASH Annual Meeting (abstract 1118).

Common adverse reactions observed in more than 1% of subjects in clinical studies of Rixubis were dysgeusia, pain in an extremity, and a positive test for furin antibody. Rixubis may pose a risk of hypersensitivity reactions, inhibitor development, nephrotic syndrome, and thromboembolic complications.

Rixubis is contraindicated in patients who have known hypersensitivity to the product or its excipients (including hamster protein), patients with disseminated intravascular coagulation, and those with signs of fibrinolysis.

For more details on Rixubis, see the full prescribing information. Rixubis is under development by Baxter International Inc.

DNA coiled around histones

Credit: Eric Smith

A protein that helps the innate immune system target bacteria and viruses can fight sepsis by interacting with histones, according to research

published in Science Signaling.

The pattern recognition protein pentraxin 3 (PTX3) is known to activate the body’s immune system in response to sepsis conditions.

But researchers thought the protein might have an additional role in sepsis pathogenesis, in the form of host protection against extracellular histones.

They knew that, during sepsis, histones escape from dead cells and kill nearby healthy cells, causing inflammation.

And the team’s experiments showed that PTX3 forms strong bonds with histones and disrupts their cellular toxicity, specifically by bundling the histones into aggregates that no longer kill healthy cells.

“We observed extraordinarily rapid and tight interaction with histone, which we recognized as coaggregation after a variety of experiments,” said study author Takao Hamakubo, MD, PhD, of the University of Tokyo in Japan.

The researchers also found that mice pretreated with PTX3 and infused with histones showed reduced inflammation.

So the team decided to investigate the effects of PTX3 in 2 mouse models of sepsis. In both models, the protein substantially reduced mortality.

PTX3 worked even when administered hours after a sepsis-inducing procedure called cecal ligation and puncture, in which fecal material is released into the abdomen to generate a strong immune response.

The researchers said these results suggest the host-protective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. And this effect provides a potential basis for treating sepsis by protecting cells from the toxic effects of extracellular histones.

“To our knowledge, this is the first report of coaggregation between different proteins that is protective to the host,” Dr Hamakubo said. “We expect our findings lead to a novel understanding of protein interaction and that they will benefit people who are suffering from severe illness.”

DNA coiled around histones

Credit: Eric Smith

A protein that helps the innate immune system target bacteria and viruses can fight sepsis by interacting with histones, according to research

published in Science Signaling.

The pattern recognition protein pentraxin 3 (PTX3) is known to activate the body’s immune system in response to sepsis conditions.

But researchers thought the protein might have an additional role in sepsis pathogenesis, in the form of host protection against extracellular histones.

They knew that, during sepsis, histones escape from dead cells and kill nearby healthy cells, causing inflammation.

And the team’s experiments showed that PTX3 forms strong bonds with histones and disrupts their cellular toxicity, specifically by bundling the histones into aggregates that no longer kill healthy cells.

“We observed extraordinarily rapid and tight interaction with histone, which we recognized as coaggregation after a variety of experiments,” said study author Takao Hamakubo, MD, PhD, of the University of Tokyo in Japan.

The researchers also found that mice pretreated with PTX3 and infused with histones showed reduced inflammation.

So the team decided to investigate the effects of PTX3 in 2 mouse models of sepsis. In both models, the protein substantially reduced mortality.

PTX3 worked even when administered hours after a sepsis-inducing procedure called cecal ligation and puncture, in which fecal material is released into the abdomen to generate a strong immune response.

The researchers said these results suggest the host-protective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. And this effect provides a potential basis for treating sepsis by protecting cells from the toxic effects of extracellular histones.

“To our knowledge, this is the first report of coaggregation between different proteins that is protective to the host,” Dr Hamakubo said. “We expect our findings lead to a novel understanding of protein interaction and that they will benefit people who are suffering from severe illness.”

DNA coiled around histones

Credit: Eric Smith

A protein that helps the innate immune system target bacteria and viruses can fight sepsis by interacting with histones, according to research

published in Science Signaling.

The pattern recognition protein pentraxin 3 (PTX3) is known to activate the body’s immune system in response to sepsis conditions.

But researchers thought the protein might have an additional role in sepsis pathogenesis, in the form of host protection against extracellular histones.

They knew that, during sepsis, histones escape from dead cells and kill nearby healthy cells, causing inflammation.

And the team’s experiments showed that PTX3 forms strong bonds with histones and disrupts their cellular toxicity, specifically by bundling the histones into aggregates that no longer kill healthy cells.

“We observed extraordinarily rapid and tight interaction with histone, which we recognized as coaggregation after a variety of experiments,” said study author Takao Hamakubo, MD, PhD, of the University of Tokyo in Japan.

The researchers also found that mice pretreated with PTX3 and infused with histones showed reduced inflammation.

So the team decided to investigate the effects of PTX3 in 2 mouse models of sepsis. In both models, the protein substantially reduced mortality.

PTX3 worked even when administered hours after a sepsis-inducing procedure called cecal ligation and puncture, in which fecal material is released into the abdomen to generate a strong immune response.

The researchers said these results suggest the host-protective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. And this effect provides a potential basis for treating sepsis by protecting cells from the toxic effects of extracellular histones.

“To our knowledge, this is the first report of coaggregation between different proteins that is protective to the host,” Dr Hamakubo said. “We expect our findings lead to a novel understanding of protein interaction and that they will benefit people who are suffering from severe illness.”