Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Vessel-sealing devices and hemostatic adjuvants are expanding the surgical armamentarium. These products provide a spectrum of alternatives that can serve you and your surgical patient well when traditional techniques for obtaining hemostasis fail to provide a satisfactory result. (Keep in mind, however, that technology is no substitute for excellent technique!)

In this article, we highlight three common scenarios in which topical hemostatic agents may be useful during gynecologic surgery. In addition, in the sidebar, five surgeons describe the hemostatic products they rely on most often—and tell why.

Following hysterectomy, persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to the site of bladder mobilization, may be managed with the aid of a topical hemostatic agent—in this case, a fibrin sealant.

When the site of bleeding is difficult to reach

CASE 1: Oozing at the site of bladder mobilization

You perform total hysterectomy in a 44-year-old woman who has uterine fibroids. After the procedure, you notice persistent oozing along the anterior vaginal margin, distal to the cuff and adjacent to where the bladder was mobilized.

How do you manage the oozing?

Wide mobilization of the bladder is a vital step in the safe performance of hysterectomy. Adhesions may complicate the process if the patient has had previous abdominal surgery, infection, or inflammation. Following mobilization of the bladder and removal of the uterus, bleeding may be visible along the adventitia of the posterior bladder wall or along the anterior surface of the vagina, distal to the cuff, as it is in this case (see the illustration).

Judicious application of an energy source is an option, but thermal injury to the bladder is a concern. A good alternative is proper placement of a hemostatic suture, but it can sometimes be difficult to avoid incorporating the bladder or injuring or obstructing the nearby ureter.

In this case, the location of the bleeding deep in the operative field poses a challenge, because of limited exposure and the proximity of the bladder and ureters. Virtually any hemostatic agent would work well in this circumstance (TABLE). For example, a flowable agent or fibrin sealant could be thoroughly applied to the area during a minimally invasive or open procedure and would naturally conform to the irregularities in the tissue, particularly the junction between the vagina and bladder flap.

A pliable product such as Surgicel Nu-Knit or Fibrillar would also work well in these circumstances, although successful application during laparoscopy may depend on the size of the trocar. For example, Nu-Knit would require trimming to a size suitable for passage through a trocar, made easier by moistening with saline. The weave of Fibrillar makes it more challenging to pass, intact, through a trocar; rolling the material into a cylindrical shape may reduce its diameter and allow it to pass more easily.

CASE 1: Resolved

You apply a fibrin sealant to the site of bleeding, and the oozing abates. Once complete hemostasis is ensured, you conclude the surgery and transfer the patient to recovery, where she does well.

Profiles in hemostasis: Strengths and weaknesses of topical agent

Controlling bleeding without injuring underlying tissue

CASE 2: After adhesiolysis, bleeding at multiple sites

You perform adnexectomy on a 47-year-old woman who has a large (7 to 8 cm), benign ovarian mass. As you operate, you discover that the lesion is adherent to the sigmoid mesentery and the posterior aspect of the uterus; it is also adherent to the pelvic sidewall, directly along the course of the ureter. Although you are able to release the various adhesive attachments, persistent bleeding is noted at multiple pinpoint areas along the mesentery, uterine serosa, and pelvic sidewall, even after the application of direct pressure.

What do you do next?

Although cautery can be used liberally on the uterus, its application to mesentery carries a risk of injury to the mesenteric vessels and bowel wall. Caution is advised when you are attempting to control bleeding on the peritoneum overlying the ureter, whether you are using suture ligature or an energy source. Ideally, you should identify the ureter using a retroperitoneal approach and mobilize it laterally before employing any of these techniques.

There are several potential approaches to the bleeding described in Case 2, all of them involving hemostatic adjuvants. The first decision you need to make, however, is whether to address each region separately or all sites in unison. If you opt to address them together—either during an open procedure or laparoscopy—a fibrin sealant (e.g., Evicel, Tisseel) is one option. It can be applied using a dripping technique or aerosolization, either of which allows for broad application of a thin film of the agent. The limitation of this approach is the volume of agent required to resolve the bleeding, with a potential need for multiple doses to completely coat the area.

Because fibrin sealants function independently of the patient’s coagulation cascade, they are particularly useful in the presence of disseminated intravascular coagulation (DIC) and other coagulopathies that might limit the effectiveness of preparations that require the patient’s own serum.

An alternative approach to Case 2 is to apply an oxidized regenerated cellulose (ORC) derivative directly to the affected areas. Various forms are available (e.g., Surgicel Fibrillar, Surgicel Nu-Knit). These ORC products can be cut and customized to the area in need of hemostasis, allowing each site to be addressed individually. These agents typically remain adherent after they are applied due to the nature of the interaction between the product, blood, and tissue.

A liquid or foam hemostatic agent (e.g., Surgiflo, Floseal, topical thrombin) could also be employed in this case, but application can be a challenge on a large area with a heterogeneous topography because of the tendency of such agents to migrate under the force of gravity, pooling away from the source of bleeding.

Is combining agents a good idea?

Although they are not typically approved for use in combination, sequential application of hemostatic agents may be considered when bleeding persists.

All hemostatic agents work best in combination with the application of pressure. It usually is advisable to use moist gauze for this purpose because it can be lifted away without significant adherence to the underlying hemostatic complex, avoiding clot

disruption.

CASE 2: Resolved

You opt to use an ORC product, customizing it to fit each bleeding site, and apply direct pressure. When hemostasis has been achieved at all sites, you complete the operation. The patient has an uneventful postoperative course.

Protect structures along the pelvic sidewall

CASE 3: When the application of pressure isn’t enough

While performing a left salpingo-oophorectomy for a 12-cm ovarian lesion, you use a retroperitoneal approach to identify the structures along the pelvic sidewall. During identification of the ureter, you encounter bleeding from a small vessel in the adjacent fatty areolar tissue. After a period of observation, during which you apply pressure to the area of concern, bleeding persists.

What hemostatic agent do you employ to stop it?

The careful application of steady pressure is often enough to safely control bleeding in the area of the pelvic sidewall. In the event that pressure alone fails to resolve the bleeding, however, it is critical to choose a remedy that avoids injuring the ureter, iliac vessels, and infundibulopelvic ligament. Wide exposure of the space may allow for direct identification of the point of bleeding and precise application of cautery, a hemoclip, or a tie. When this approach is not feasible, other solutions must be sought.

When traditional hemostatic techniques fail in delicate anatomic sites, such as the periureteral area, hemostatic agents are an effective option that can minimize the risk of injury to surrounding vital structures. The contour of the space calls for a product that can intercalate, such as a foam, sealant, or Surgicel Fibrillar. Direct, precise application to the point of bleeding is critical, and the “bunching up” of a more rigid and bulky agent may limit its application to the area of concern. Use of a moist gauze to apply direct pressure after application of the agent will increase the likelihood of success.

CASE 3: Resolved

You decide to apply a foam hemostatic agent because of its ability to conform to the irregular space. You also continue to apply gentle pressure to the point of bleeding, using a moist gauze. Within minutes, hemostasis is achieved. You are then able to finish the operation.

Other variables to consider

As these three cases illustrate, the use of hemostatic agents to control surgical bleeding requires an individualized approach. The site and amount of bleeding, as well as the patient’s hemodynamic and coagulation status, are key variables to be considered when selecting an agent.

For instance, because of their components, fibrin sealants can function independently of the patient’s coagulation status. ORC products provide a matrix that facilitates platelet aggregration and may be less effective when anti-platelet agents have been used.

It is also appropriate for the surgeon to be familiar with the relative cost of the agents available at his or her institution. In particular, when several agents may be equally effective in a particular set of circumstances, cost may be the determining factor.

Availability of these agents varies from one institution to the next; as a result, it can be challenging to maintain familiarity with all of the products in the marketplace. Having access to a diverse, readily available set of “go to” agents is critical to ensure rapid application in a clinical setting.

The surgeon’s preference also is important, particularly in regard to the ease of preparation and handling. Some agents may not be as suitable for minimally invasive procedures (see TABLE). For others, special laparoscopic applicators are available.

When using a hemostatic agent, it pays to consider the duration of its effect in the surgical site. Both the quantity of the agent that is applied and characteristics of the local operative site influence how quickly the agent degrades. Keep this in mind when imaging studies are planned for the early postoperative period. An ORC preparation, for example, may appear with small pockets of air that resemble an abscess. Effective communication with the radiology team is critical to avoid the misinterpretation of findings.

Choosing a topical agent? First, consider surgical technique.

Curious to discover the preferences and practices of surgeons likely to utilize topical hemostatic agents, OBG Management polled several experienced and expert surgeons, including members of the journal’s Board of Editors and Virtual Board of Editors. Their diverse responses offer a snapshot of gynecologic surgical practice in 2012—but all agree that hemostatic products are no substitute for sound surgical technique.
JANELLE YATES, SENIOR EDITOR

We want to hear from you! Tell us what you think.

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Dr. Scott Freeman’s useful discussion of targeting acute risk factors in suicidal patients (“Suicide assessment: Targeting acute risk factors,” Current Psychiatry, January 2012, p. 52-57) ends by resolving the clinical vignette with a summary of hospital treatment. Apart from failing to indicate any psychotherapeutic inroads, Dr. Freeman seems to support prescribing clonazepam, 0.5 mg twice daily and 1 mg at bedtime. Clonazepam apparently “worked” by alleviating the patient’s anxiety and insomnia, but defied any pharmacologic rationale insofar as clonazepam has a slow onset and long half-life, making 3 doses per day irrational. This treatment strategy also risks problems of cumulative excess in the long run after discharge.

Aggressive pharmacotherapy may be the hallmark of modern acute hospital treatment, but surely it should incorporate careful understanding of specific medications’ pharmacodynamics, especially when relying on benzodiazepines. Needless to say, beginning a psychological process in the hospital also appears to have been shortchanged.

Sara Hartley, MD
Lecturer, Clinical Skills Program
University of California,
Berkeley-University of California,
San Francisco Joint Medical Program
Berkeley, CA

Dr. Freeman responds

I appreciate Dr. Hartley’s interest in my article. Although I agree with her that psychotherapy is an integral part of any treatment plan, the clinical vignette was used only to emphasize the need to aggressively and quickly start antidepressant and, more importantly, anxiolytic pharmacologic treatment in acutely suicidal patients with severe anxiety and depression.

With regard to clonazepam’s pharmacokinetics, although it does have a long half-life, it is only weakly lipophilic compared with other long-acting benzodiazepines such as diazepam. In fact, clonazepam has been shown to be less lipophilic than lorazepam,¹ meaning it has a much smaller volume of distribution and less accumulation in peripheral adipose tissue. Therefore, one would not be concerned about significant drug accumulation leading to unexpected toxicity with a less lipophilic agent such as clonazepam.

I do not agree that dosing clonazepam 3 times a day, especially in an acute crisis, is “irrational,” as Dr. Hartley suggests. According to the package insert, although clonazepam is recommended to be administered twice daily for panic disorder, it can be given 3 times a day for seizure disorders.²

Scott A. Freeman, MD
Medical Director
Schizophrenia and Bipolar Disorder Inpatient Unit
McLean Hospital
Belmont, MA

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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

Helping hospitalized geriatric patients maintain an appropriate sleep-wake cycle can be a challenge. Older patients’ circadian rhythm may be affected by several factors—eg, obstructive sleep apnea and restless leg syndrome—that contribute to disrupted sleep and daytime fatigue. Some patients may have dementing illnesses that could dysregulate sleep. Many older patients experience delirium during hospitalization, of which sleep-wake cycle disturbances are a hallmark. Finally, geriatric patients’ natural sleep pattern often does not mimic a hospital’s typical schedule.

Sleep medication side effects

Medications used to promote sleep can cause side effects in geriatric patients. Benzodiazepine use by older adults is discouraged because these medications could cause falls or contribute to delirium. Non-benzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone pose a similar risk. Medications containing diphenhydramine predispose patients to deliriogenic effects via their anticholinergic properties. Tricyclic antidepressants carry risks, such as delirium secondary to anticholinergic effects, orthostatic hypotension, falls from α-1 blockade, and cardiac arrythmias.

Atypical antipsychotics sometimes are used off-label to help initiate sleep, but they carry a “black-box” warning regarding sudden death from cardiovascular events in geriatric patients with dementia. Hydroxyzine and trazodone also are associated with side effects such as orthostatic hypotension and daytime sedation, and are not always effective.

Melatonin is a hormone secreted by the pineal gland in response to darkness, under the control of the suprachiasmatic nucleus (SCN), and is thought to promote sleep via synchronizing effects on the SCN.¹ Melatonin is available as an over-the-counter dietary supplement and via prescription in dosages of 1 or 3 mg. The typical effective dose is 3 to 9 mg.¹ Patients should take melatonin in the mid-evening, ideally between 7 pm and 8 pm, and effects become evident after a few days. Side effects are rare; the most common are headache and nausea. Daytime sedation and vivid dreams also have been reported. Melatonin can be used safely in conjunction with other sleep aids and its major drug-drug interactions involve enhancing the effects of other sedatives.²

We have found melatonin to be effective for treating sleep disturbances in older hospitalized patients. Its effectiveness may stem from the high incidence of dysregulated or calcified pineal glands in geriatric patients, which leads to a marked reduction in melatonin secretion.³ Recent evidence also suggests melatonin may reduce the incidence of delirium in older adults, and it has been proposed as a delirium treatment in post-operative and intensive care unit settings.⁴

Disclosure

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

Since the discovery of chlordiazepoxide in the 1950s, benzodiazepines have revolutionized the treatment of anxiety and insomnia, largely because of their improved safety profile compared with barbiturates, formerly the preferred sedative-hypnotic.¹ In addition to their anxiolytic and sedative-hypnotic effects, benzodiazepines exhibit anterograde amnesia, anticonvulsant, and muscle relaxant properties.¹ Psychiatrists use benzodiazepines to treat anxiety and sleep disorders, acute agitation, alcohol withdrawal, catatonia, and psychotropic side effects such as akathisia. This article highlights the evidence for using benzodiazepines in anxiety and other disorders and why they generally should not be used for obsessive-compulsive disorder and posttraumatic stress disorder (Box 1).

Box 1

Pharmacokinetic properties

Most benzodiazepines are considered to have similar efficacy; therefore, selection is based on pharmacokinetic considerations. Table 1 compares the indication, onset, and half-life of 12 commonly used benzodiazepines.^2-6 Although Table 1 lists approximate equivalent doses, studies report inconsistent data. These are approximations only and should not be used independently to make therapy decisions.

Table 1

Oral benzodiazepines: Indications, onset, half-life, and equivalent doses

A diverse range of indications

Alcohol withdrawal. Benzodiazepines are the treatment of choice for alcohol withdrawal syndrome, particularly to prevent seizures.⁷ Research supports symptom-triggered therapy using the revised Clinical Institute Withdrawal Assessment for Alcohol. Benzodiazepines reduce CNS sympathetic hyperactivity to mitigate withdrawal from alcohol by decreasing tachycardia, tremor, insomnia, agitation, and anxiety. Furthermore, these agents provide prophylaxis against serious sequelae such as seizures and delirium.

Insomnia. The American Academy of Sleep Medicine considers benzodiazepine receptor agonists (BzRAs, which include benzodiazepines and non-benzodiazepines) and ramelteon first-line pharmacotherapy for primary insomnia.⁸ However, pharmacologic treatment should be short-term. Agents with short to intermediate half-lives and rapid onset, such as triazolam, can aid sleep initiation. Those with longer half-lives, such as temazepam, could address sleep maintenance. If a patient does not respond to the initial agent, try another medication within the same class, because patients may respond differently. Use lower starting doses in geriatric patients.⁹ Closely monitor for adverse effects, rebound insomnia, and potential abuse or tolerance. Identify comorbid conditions and medications that may impair sleep, and address them accordingly.

Psychological and behavioral treatments given over 4 to 8 weeks can yield stable sleep improvements for up to 2 years. If available, these interventions may be considered first-line for treating insomnia because of their lasting effects compared with BzRAs.¹⁰

Generalized anxiety disorder (GAD). Benzodiazepines effectively treat GAD because they work quickly and are well tolerated. However, there are better first-line treatment options when considering efficacy studies and dependence and tolerance concerns. One effect-size comparison of 21 double-blind, placebo-controlled trials showed that the efficacy of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and pregabalin are comparable to benzodiazepines.¹¹ Benzodiazepines can be used in the first 2 to 3 weeks after initiating antidepressants to alleviate and prevent worsening of anxiety that may occur at the start of antidepressant therapy. Recent treatment guidelines recommend benzodiazepines as a second-line treatment or for treatment-resistant GAD in patients who do not have a substance abuse history.^12,13

Panic disorder. Efficacy of benzodiazepines for panic disorder is comparable to SSRIs, SNRIs, and tricyclic antidepressants (TCAs). SSRIs and SNRIs are considered first-line treatments for panic disorder because of their favorable side effect profile.¹⁴ In practice, benzodiazepines often are combined with SSRIs, SNRIs, or TCAs. A randomized controlled trial demonstrated that paroxetine and clonazepam (mean dose 1.6 mg/d at 5 weeks) resulted in a more rapid response compared with paroxetine alone, although this difference lasted only a few weeks.¹⁵ Furthermore, this study suggested that brief treatment with clonazepam followed by a taper is as effective as sustained treatment with paroxetine and clonazepam.¹⁵

There is a lack of high-quality data on combining cognitive-behavioral therapy (CBT) and benzodiazepines for panic disorder, although a Cochrane Review found that adding a benzodiazepine to CBT did not lead to a significant difference in response compared with psychotherapy alone.¹⁶ A recent randomized controlled trial demonstrated that tapering benzodiazepines combined with CBT was associated with successful discontinuation of the drug and prevented return of panic symptoms.¹⁷

Social anxiety. A meta-analysis found that for treating social anxiety, benzodiazepines have better efficacy than SSRIs, monoamine oxidase inhibitors, and anticonvulsants.¹⁸ Longer-acting benzodiazepines may be more effective than shorter-acting agents. One study of patients with social anxiety showed a 38% response rate for alprazolam vs 20% for placebo over 12 weeks, and a similar 10-week study demonstrated a 73% recovery rate with clonazepam vs 22% for placebo.¹⁹ In addition, studies have observed that patients can be maintained on clonazepam for up to 2 years without symptom relapse and will tolerate slow-taper discontinuation.^18,20 Sedation and drowsiness can be lessened by limiting clonazepam doses to 2 to 3 mg/d.

Akathisia and tremor. Akathisia, a syndrome of motor restlessness and inner turmoil, is associated with antipsychotics but can occur with SSRIs. Reducing the dosage or switching to another, usually less potent agent often can relieve akathisia. When these remedies are not tenable, consider benzodiazepines along with other medications—including beta blockers and anticholinergic agents—with demonstrated efficacy in reducing akathisia symptoms. Lorazepam, diazepam, and clonazepam have demonstrated efficacy for relieving akathisia in comparison studies with placebo, propranolol, and diphenhydramine.^21,22

Drug-induced postural tremor can occur with several psychotropics, including lithium, valproic acid, antidepressants, and antipsychotics. A tremor is considered mild if a patient can drink a glass of water with 1 hand without spilling and severe if holding a glass with 2 hands is difficult. Propranolol is most commonly prescribed for these tremors, but alprazolam and clonazepam have demonstrated efficacy, either as monotherapy or coadministered with a beta blocker.²³

Acute agitation. Agitated patients often have acute psychosis and/or mania or dyscontrol secondary to axis II disorders.²⁴ Patients may be paranoid, hostile, disruptive, and combative. Rapidly initiating medication can prevent the need for more restrictive measures, such as seclusion or restraint. Antipsychotics—especially high-potency agents such as haloperidol—and benzodiazepines, as monotherapy or in combination, are a mainstay treatment. Although treatment protocols favor atypical antipsychotics over typical antipsychotics, benzodiazepines are a viable option because of their anxiolytic and sedative effects. Advantages of benzodiazepine monotherapy include decreased extrapyramidal symptoms, greater patient acceptance/preference, and increased sedation compared with antipsychotics. Lorazepam, 1 to 2 mg intramuscularly (IM) or orally, is well tolerated because of its favorable drug-drug interaction profile and lack of significant cardiac side effects. Benzodiazepines can cause respiratory depression in patients with chronic lung disease and additive sedation secondary to opiates, other sedatives/hypnotics, or alcohol. Behavioral disinhibition is rare and is associated with preexisting CNS pathology or mental retardation.²⁵ The IM olanzapine package insert warns against coadministering IM lorazepam because of additive cardiorespiratory depressive effects and excessive somnolence.²⁶

Catatonia. The characteristic symptoms of catatonia are immobility, negativism, muteness, and failure to eat or drink. Benzodiazepines improve these symptoms in approximately 70% to 80% of catatonic patients with affective disorders. Response rates are lower in catatonia in patients with schizophrenia.²⁷ If catatonia in a patient with psychosis is missed, giving antipsychotics before benzodiazepines may worsen catatonic symptoms or precipitate neuroleptic malignant syndrome in some cases. When you suspect a patient has catatonia, start with lorazepam, 1 to 2 mg IV or IM, and examine the patient for diminishing catatonic signs within 1 to 2 hours. If catatonia signs lessen, begin regularly scheduled lorazepam, with dosing varying by age—be more cautious in geriatric patients—and symptom severity. Titrate benzodiazepines for stuporous patients more slowly (eg, 1 mg 3 times a day as a starting dose) than for excited catatonic patients. Lorazepam can be increased gradually as tolerated; it is not unusual for patients to require up to 8 to 12 mg/d. Electroconvulsive therapy (ECT) is the treatment of choice when catatonic patients respond poorly or partially to high-dose benzodiazepines.^28,29

Benzodiazepine reversal for ECT

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of ECT.³⁰ A multi-center study demonstrated that lorazepam (up to 4 mg/d as needed) in the 48 hours before the first ECT session was not associated with effects on seizure threshold or duration; however, larger lorazepam dosages were associated with briefer EEG seizure duration.³¹ Some patients may not tolerate withholding or tapering benzodiazepines in preparation for ECT. Studies investigating flumazenil for pre-ECT benzodiazepine reversal are lacking. One retrospective analysis showed that flumazenil administration immediately before and after ECT resulted in adequate seizures with no difference in clinical outcome compared with patients who were not receiving benzodiazepines or flumazenil.³²

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.³³Table 2 lists recommended durations for tapering benzodiazepines.^33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.³⁴

Table 2

Recommendations for tapering benzodiazepines

Risks of benzodiazepine use

For most indications, benzodiazepine therapy should be short-term.³⁵ Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.³⁶

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.³⁷ Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.³⁴ Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).³⁸

Box 2

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Drug Abuse resources for medical and health professionals. www.drugabuse.gov/medical-health-professionals.
• American Academy of Sleep Medicine. www.aasmnet.org.

Drug Brand Names

• Alprazolam • Xanax
• Chlordiazepoxide • Librium, Limbitrol
• Clonazepam • Klonopin
• Clorazepate • Tranxene
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Estazolam • ProSom
• Flumazenil • Romazicon
• Flurazepam • Dalmane
• Haloperidol • Haldol
• Lithium • Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Paroxetine • Paxil
• Pregabalin • Lyrica
• Propranolol • Inderal, InnoPran XL, others
• Quazepam • Doral
• Ramelteon • Rozerem
• Sertraline • Zoloft
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Since the discovery of chlordiazepoxide in the 1950s, benzodiazepines have revolutionized the treatment of anxiety and insomnia, largely because of their improved safety profile compared with barbiturates, formerly the preferred sedative-hypnotic.¹ In addition to their anxiolytic and sedative-hypnotic effects, benzodiazepines exhibit anterograde amnesia, anticonvulsant, and muscle relaxant properties.¹ Psychiatrists use benzodiazepines to treat anxiety and sleep disorders, acute agitation, alcohol withdrawal, catatonia, and psychotropic side effects such as akathisia. This article highlights the evidence for using benzodiazepines in anxiety and other disorders and why they generally should not be used for obsessive-compulsive disorder and posttraumatic stress disorder (Box 1).

Box 1

Pharmacokinetic properties

Most benzodiazepines are considered to have similar efficacy; therefore, selection is based on pharmacokinetic considerations. Table 1 compares the indication, onset, and half-life of 12 commonly used benzodiazepines.^2-6 Although Table 1 lists approximate equivalent doses, studies report inconsistent data. These are approximations only and should not be used independently to make therapy decisions.

Table 1

Oral benzodiazepines: Indications, onset, half-life, and equivalent doses

A diverse range of indications

Alcohol withdrawal. Benzodiazepines are the treatment of choice for alcohol withdrawal syndrome, particularly to prevent seizures.⁷ Research supports symptom-triggered therapy using the revised Clinical Institute Withdrawal Assessment for Alcohol. Benzodiazepines reduce CNS sympathetic hyperactivity to mitigate withdrawal from alcohol by decreasing tachycardia, tremor, insomnia, agitation, and anxiety. Furthermore, these agents provide prophylaxis against serious sequelae such as seizures and delirium.

Insomnia. The American Academy of Sleep Medicine considers benzodiazepine receptor agonists (BzRAs, which include benzodiazepines and non-benzodiazepines) and ramelteon first-line pharmacotherapy for primary insomnia.⁸ However, pharmacologic treatment should be short-term. Agents with short to intermediate half-lives and rapid onset, such as triazolam, can aid sleep initiation. Those with longer half-lives, such as temazepam, could address sleep maintenance. If a patient does not respond to the initial agent, try another medication within the same class, because patients may respond differently. Use lower starting doses in geriatric patients.⁹ Closely monitor for adverse effects, rebound insomnia, and potential abuse or tolerance. Identify comorbid conditions and medications that may impair sleep, and address them accordingly.

Psychological and behavioral treatments given over 4 to 8 weeks can yield stable sleep improvements for up to 2 years. If available, these interventions may be considered first-line for treating insomnia because of their lasting effects compared with BzRAs.¹⁰

Generalized anxiety disorder (GAD). Benzodiazepines effectively treat GAD because they work quickly and are well tolerated. However, there are better first-line treatment options when considering efficacy studies and dependence and tolerance concerns. One effect-size comparison of 21 double-blind, placebo-controlled trials showed that the efficacy of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and pregabalin are comparable to benzodiazepines.¹¹ Benzodiazepines can be used in the first 2 to 3 weeks after initiating antidepressants to alleviate and prevent worsening of anxiety that may occur at the start of antidepressant therapy. Recent treatment guidelines recommend benzodiazepines as a second-line treatment or for treatment-resistant GAD in patients who do not have a substance abuse history.^12,13

Panic disorder. Efficacy of benzodiazepines for panic disorder is comparable to SSRIs, SNRIs, and tricyclic antidepressants (TCAs). SSRIs and SNRIs are considered first-line treatments for panic disorder because of their favorable side effect profile.¹⁴ In practice, benzodiazepines often are combined with SSRIs, SNRIs, or TCAs. A randomized controlled trial demonstrated that paroxetine and clonazepam (mean dose 1.6 mg/d at 5 weeks) resulted in a more rapid response compared with paroxetine alone, although this difference lasted only a few weeks.¹⁵ Furthermore, this study suggested that brief treatment with clonazepam followed by a taper is as effective as sustained treatment with paroxetine and clonazepam.¹⁵

There is a lack of high-quality data on combining cognitive-behavioral therapy (CBT) and benzodiazepines for panic disorder, although a Cochrane Review found that adding a benzodiazepine to CBT did not lead to a significant difference in response compared with psychotherapy alone.¹⁶ A recent randomized controlled trial demonstrated that tapering benzodiazepines combined with CBT was associated with successful discontinuation of the drug and prevented return of panic symptoms.¹⁷

Social anxiety. A meta-analysis found that for treating social anxiety, benzodiazepines have better efficacy than SSRIs, monoamine oxidase inhibitors, and anticonvulsants.¹⁸ Longer-acting benzodiazepines may be more effective than shorter-acting agents. One study of patients with social anxiety showed a 38% response rate for alprazolam vs 20% for placebo over 12 weeks, and a similar 10-week study demonstrated a 73% recovery rate with clonazepam vs 22% for placebo.¹⁹ In addition, studies have observed that patients can be maintained on clonazepam for up to 2 years without symptom relapse and will tolerate slow-taper discontinuation.^18,20 Sedation and drowsiness can be lessened by limiting clonazepam doses to 2 to 3 mg/d.

Akathisia and tremor. Akathisia, a syndrome of motor restlessness and inner turmoil, is associated with antipsychotics but can occur with SSRIs. Reducing the dosage or switching to another, usually less potent agent often can relieve akathisia. When these remedies are not tenable, consider benzodiazepines along with other medications—including beta blockers and anticholinergic agents—with demonstrated efficacy in reducing akathisia symptoms. Lorazepam, diazepam, and clonazepam have demonstrated efficacy for relieving akathisia in comparison studies with placebo, propranolol, and diphenhydramine.^21,22

Drug-induced postural tremor can occur with several psychotropics, including lithium, valproic acid, antidepressants, and antipsychotics. A tremor is considered mild if a patient can drink a glass of water with 1 hand without spilling and severe if holding a glass with 2 hands is difficult. Propranolol is most commonly prescribed for these tremors, but alprazolam and clonazepam have demonstrated efficacy, either as monotherapy or coadministered with a beta blocker.²³

Acute agitation. Agitated patients often have acute psychosis and/or mania or dyscontrol secondary to axis II disorders.²⁴ Patients may be paranoid, hostile, disruptive, and combative. Rapidly initiating medication can prevent the need for more restrictive measures, such as seclusion or restraint. Antipsychotics—especially high-potency agents such as haloperidol—and benzodiazepines, as monotherapy or in combination, are a mainstay treatment. Although treatment protocols favor atypical antipsychotics over typical antipsychotics, benzodiazepines are a viable option because of their anxiolytic and sedative effects. Advantages of benzodiazepine monotherapy include decreased extrapyramidal symptoms, greater patient acceptance/preference, and increased sedation compared with antipsychotics. Lorazepam, 1 to 2 mg intramuscularly (IM) or orally, is well tolerated because of its favorable drug-drug interaction profile and lack of significant cardiac side effects. Benzodiazepines can cause respiratory depression in patients with chronic lung disease and additive sedation secondary to opiates, other sedatives/hypnotics, or alcohol. Behavioral disinhibition is rare and is associated with preexisting CNS pathology or mental retardation.²⁵ The IM olanzapine package insert warns against coadministering IM lorazepam because of additive cardiorespiratory depressive effects and excessive somnolence.²⁶

Catatonia. The characteristic symptoms of catatonia are immobility, negativism, muteness, and failure to eat or drink. Benzodiazepines improve these symptoms in approximately 70% to 80% of catatonic patients with affective disorders. Response rates are lower in catatonia in patients with schizophrenia.²⁷ If catatonia in a patient with psychosis is missed, giving antipsychotics before benzodiazepines may worsen catatonic symptoms or precipitate neuroleptic malignant syndrome in some cases. When you suspect a patient has catatonia, start with lorazepam, 1 to 2 mg IV or IM, and examine the patient for diminishing catatonic signs within 1 to 2 hours. If catatonia signs lessen, begin regularly scheduled lorazepam, with dosing varying by age—be more cautious in geriatric patients—and symptom severity. Titrate benzodiazepines for stuporous patients more slowly (eg, 1 mg 3 times a day as a starting dose) than for excited catatonic patients. Lorazepam can be increased gradually as tolerated; it is not unusual for patients to require up to 8 to 12 mg/d. Electroconvulsive therapy (ECT) is the treatment of choice when catatonic patients respond poorly or partially to high-dose benzodiazepines.^28,29

Benzodiazepine reversal for ECT

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of ECT.³⁰ A multi-center study demonstrated that lorazepam (up to 4 mg/d as needed) in the 48 hours before the first ECT session was not associated with effects on seizure threshold or duration; however, larger lorazepam dosages were associated with briefer EEG seizure duration.³¹ Some patients may not tolerate withholding or tapering benzodiazepines in preparation for ECT. Studies investigating flumazenil for pre-ECT benzodiazepine reversal are lacking. One retrospective analysis showed that flumazenil administration immediately before and after ECT resulted in adequate seizures with no difference in clinical outcome compared with patients who were not receiving benzodiazepines or flumazenil.³²

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.³³Table 2 lists recommended durations for tapering benzodiazepines.^33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.³⁴

Table 2

Recommendations for tapering benzodiazepines

Risks of benzodiazepine use

For most indications, benzodiazepine therapy should be short-term.³⁵ Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.³⁶

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.³⁷ Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.³⁴ Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).³⁸

Box 2

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Drug Abuse resources for medical and health professionals. www.drugabuse.gov/medical-health-professionals.
• American Academy of Sleep Medicine. www.aasmnet.org.

Drug Brand Names

• Alprazolam • Xanax
• Chlordiazepoxide • Librium, Limbitrol
• Clonazepam • Klonopin
• Clorazepate • Tranxene
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Estazolam • ProSom
• Flumazenil • Romazicon
• Flurazepam • Dalmane
• Haloperidol • Haldol
• Lithium • Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Paroxetine • Paxil
• Pregabalin • Lyrica
• Propranolol • Inderal, InnoPran XL, others
• Quazepam • Doral
• Ramelteon • Rozerem
• Sertraline • Zoloft
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Since the discovery of chlordiazepoxide in the 1950s, benzodiazepines have revolutionized the treatment of anxiety and insomnia, largely because of their improved safety profile compared with barbiturates, formerly the preferred sedative-hypnotic.¹ In addition to their anxiolytic and sedative-hypnotic effects, benzodiazepines exhibit anterograde amnesia, anticonvulsant, and muscle relaxant properties.¹ Psychiatrists use benzodiazepines to treat anxiety and sleep disorders, acute agitation, alcohol withdrawal, catatonia, and psychotropic side effects such as akathisia. This article highlights the evidence for using benzodiazepines in anxiety and other disorders and why they generally should not be used for obsessive-compulsive disorder and posttraumatic stress disorder (Box 1).

Box 1

Pharmacokinetic properties

Most benzodiazepines are considered to have similar efficacy; therefore, selection is based on pharmacokinetic considerations. Table 1 compares the indication, onset, and half-life of 12 commonly used benzodiazepines.^2-6 Although Table 1 lists approximate equivalent doses, studies report inconsistent data. These are approximations only and should not be used independently to make therapy decisions.

Table 1

Oral benzodiazepines: Indications, onset, half-life, and equivalent doses

A diverse range of indications

Alcohol withdrawal. Benzodiazepines are the treatment of choice for alcohol withdrawal syndrome, particularly to prevent seizures.⁷ Research supports symptom-triggered therapy using the revised Clinical Institute Withdrawal Assessment for Alcohol. Benzodiazepines reduce CNS sympathetic hyperactivity to mitigate withdrawal from alcohol by decreasing tachycardia, tremor, insomnia, agitation, and anxiety. Furthermore, these agents provide prophylaxis against serious sequelae such as seizures and delirium.

Insomnia. The American Academy of Sleep Medicine considers benzodiazepine receptor agonists (BzRAs, which include benzodiazepines and non-benzodiazepines) and ramelteon first-line pharmacotherapy for primary insomnia.⁸ However, pharmacologic treatment should be short-term. Agents with short to intermediate half-lives and rapid onset, such as triazolam, can aid sleep initiation. Those with longer half-lives, such as temazepam, could address sleep maintenance. If a patient does not respond to the initial agent, try another medication within the same class, because patients may respond differently. Use lower starting doses in geriatric patients.⁹ Closely monitor for adverse effects, rebound insomnia, and potential abuse or tolerance. Identify comorbid conditions and medications that may impair sleep, and address them accordingly.

Psychological and behavioral treatments given over 4 to 8 weeks can yield stable sleep improvements for up to 2 years. If available, these interventions may be considered first-line for treating insomnia because of their lasting effects compared with BzRAs.¹⁰

Generalized anxiety disorder (GAD). Benzodiazepines effectively treat GAD because they work quickly and are well tolerated. However, there are better first-line treatment options when considering efficacy studies and dependence and tolerance concerns. One effect-size comparison of 21 double-blind, placebo-controlled trials showed that the efficacy of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and pregabalin are comparable to benzodiazepines.¹¹ Benzodiazepines can be used in the first 2 to 3 weeks after initiating antidepressants to alleviate and prevent worsening of anxiety that may occur at the start of antidepressant therapy. Recent treatment guidelines recommend benzodiazepines as a second-line treatment or for treatment-resistant GAD in patients who do not have a substance abuse history.^12,13

Panic disorder. Efficacy of benzodiazepines for panic disorder is comparable to SSRIs, SNRIs, and tricyclic antidepressants (TCAs). SSRIs and SNRIs are considered first-line treatments for panic disorder because of their favorable side effect profile.¹⁴ In practice, benzodiazepines often are combined with SSRIs, SNRIs, or TCAs. A randomized controlled trial demonstrated that paroxetine and clonazepam (mean dose 1.6 mg/d at 5 weeks) resulted in a more rapid response compared with paroxetine alone, although this difference lasted only a few weeks.¹⁵ Furthermore, this study suggested that brief treatment with clonazepam followed by a taper is as effective as sustained treatment with paroxetine and clonazepam.¹⁵

There is a lack of high-quality data on combining cognitive-behavioral therapy (CBT) and benzodiazepines for panic disorder, although a Cochrane Review found that adding a benzodiazepine to CBT did not lead to a significant difference in response compared with psychotherapy alone.¹⁶ A recent randomized controlled trial demonstrated that tapering benzodiazepines combined with CBT was associated with successful discontinuation of the drug and prevented return of panic symptoms.¹⁷

Social anxiety. A meta-analysis found that for treating social anxiety, benzodiazepines have better efficacy than SSRIs, monoamine oxidase inhibitors, and anticonvulsants.¹⁸ Longer-acting benzodiazepines may be more effective than shorter-acting agents. One study of patients with social anxiety showed a 38% response rate for alprazolam vs 20% for placebo over 12 weeks, and a similar 10-week study demonstrated a 73% recovery rate with clonazepam vs 22% for placebo.¹⁹ In addition, studies have observed that patients can be maintained on clonazepam for up to 2 years without symptom relapse and will tolerate slow-taper discontinuation.^18,20 Sedation and drowsiness can be lessened by limiting clonazepam doses to 2 to 3 mg/d.

Akathisia and tremor. Akathisia, a syndrome of motor restlessness and inner turmoil, is associated with antipsychotics but can occur with SSRIs. Reducing the dosage or switching to another, usually less potent agent often can relieve akathisia. When these remedies are not tenable, consider benzodiazepines along with other medications—including beta blockers and anticholinergic agents—with demonstrated efficacy in reducing akathisia symptoms. Lorazepam, diazepam, and clonazepam have demonstrated efficacy for relieving akathisia in comparison studies with placebo, propranolol, and diphenhydramine.^21,22

Drug-induced postural tremor can occur with several psychotropics, including lithium, valproic acid, antidepressants, and antipsychotics. A tremor is considered mild if a patient can drink a glass of water with 1 hand without spilling and severe if holding a glass with 2 hands is difficult. Propranolol is most commonly prescribed for these tremors, but alprazolam and clonazepam have demonstrated efficacy, either as monotherapy or coadministered with a beta blocker.²³

Acute agitation. Agitated patients often have acute psychosis and/or mania or dyscontrol secondary to axis II disorders.²⁴ Patients may be paranoid, hostile, disruptive, and combative. Rapidly initiating medication can prevent the need for more restrictive measures, such as seclusion or restraint. Antipsychotics—especially high-potency agents such as haloperidol—and benzodiazepines, as monotherapy or in combination, are a mainstay treatment. Although treatment protocols favor atypical antipsychotics over typical antipsychotics, benzodiazepines are a viable option because of their anxiolytic and sedative effects. Advantages of benzodiazepine monotherapy include decreased extrapyramidal symptoms, greater patient acceptance/preference, and increased sedation compared with antipsychotics. Lorazepam, 1 to 2 mg intramuscularly (IM) or orally, is well tolerated because of its favorable drug-drug interaction profile and lack of significant cardiac side effects. Benzodiazepines can cause respiratory depression in patients with chronic lung disease and additive sedation secondary to opiates, other sedatives/hypnotics, or alcohol. Behavioral disinhibition is rare and is associated with preexisting CNS pathology or mental retardation.²⁵ The IM olanzapine package insert warns against coadministering IM lorazepam because of additive cardiorespiratory depressive effects and excessive somnolence.²⁶

Catatonia. The characteristic symptoms of catatonia are immobility, negativism, muteness, and failure to eat or drink. Benzodiazepines improve these symptoms in approximately 70% to 80% of catatonic patients with affective disorders. Response rates are lower in catatonia in patients with schizophrenia.²⁷ If catatonia in a patient with psychosis is missed, giving antipsychotics before benzodiazepines may worsen catatonic symptoms or precipitate neuroleptic malignant syndrome in some cases. When you suspect a patient has catatonia, start with lorazepam, 1 to 2 mg IV or IM, and examine the patient for diminishing catatonic signs within 1 to 2 hours. If catatonia signs lessen, begin regularly scheduled lorazepam, with dosing varying by age—be more cautious in geriatric patients—and symptom severity. Titrate benzodiazepines for stuporous patients more slowly (eg, 1 mg 3 times a day as a starting dose) than for excited catatonic patients. Lorazepam can be increased gradually as tolerated; it is not unusual for patients to require up to 8 to 12 mg/d. Electroconvulsive therapy (ECT) is the treatment of choice when catatonic patients respond poorly or partially to high-dose benzodiazepines.^28,29

Benzodiazepine reversal for ECT

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of ECT.³⁰ A multi-center study demonstrated that lorazepam (up to 4 mg/d as needed) in the 48 hours before the first ECT session was not associated with effects on seizure threshold or duration; however, larger lorazepam dosages were associated with briefer EEG seizure duration.³¹ Some patients may not tolerate withholding or tapering benzodiazepines in preparation for ECT. Studies investigating flumazenil for pre-ECT benzodiazepine reversal are lacking. One retrospective analysis showed that flumazenil administration immediately before and after ECT resulted in adequate seizures with no difference in clinical outcome compared with patients who were not receiving benzodiazepines or flumazenil.³²

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.³³Table 2 lists recommended durations for tapering benzodiazepines.^33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.³⁴

Table 2

Recommendations for tapering benzodiazepines

Risks of benzodiazepine use

For most indications, benzodiazepine therapy should be short-term.³⁵ Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.³⁶

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.³⁷ Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.³⁴ Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).³⁸

Box 2

Related Resources

• Substance Abuse and Mental Health Services Administration. www.samhsa.gov.
• National Institute on Drug Abuse resources for medical and health professionals. www.drugabuse.gov/medical-health-professionals.
• American Academy of Sleep Medicine. www.aasmnet.org.

Drug Brand Names

• Alprazolam • Xanax
• Chlordiazepoxide • Librium, Limbitrol
• Clonazepam • Klonopin
• Clorazepate • Tranxene
• Diazepam • Valium
• Diphenhydramine • Benadryl, others
• Estazolam • ProSom
• Flumazenil • Romazicon
• Flurazepam • Dalmane
• Haloperidol • Haldol
• Lithium • Lithobid
• Lorazepam • Ativan
• Olanzapine • Zyprexa
• Oxazepam • Serax
• Paroxetine • Paxil
• Pregabalin • Lyrica
• Propranolol • Inderal, InnoPran XL, others
• Quazepam • Doral
• Ramelteon • Rozerem
• Sertraline • Zoloft
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Bedside visit comes too late

A 22-YEAR-OLD MAN underwent a liver biopsy after being admitted to the hospital a week earlier with fever, chills, diarrhea, and general malaise. A number of specialists had seen him in the hospital because of abnormal laboratory studies, increasing fever, and a maculopapular rash over his trunk and face.

After the biopsy, the patient was dizzy and diaphoretic. His attending physician ordered hemoglobin and hematocrit levels, which were lower than earlier that day. Repeat testing showed a further decrease, prompting the physician to order 2 units of red blood cells.

Typing and cross-matching delayed the transfusion for several hours. Before it could be started, the patient was found unresponsive. When the attending physician came to the bedside, the patient had no palpable pulse. A code was called, but resuscitation efforts failed.

An autopsy found a small hole in the liver and 3500 mL of blood in the peritoneal cavity, as well as hepatitis with zonal and submassive necrosis, hemoperitoneum, and hypertrophy of the heart. An HIV test performed before the biopsy eventually came back positive.

PLAINTIFF’S CLAIM The attending physician and nurses were negligent in failing to respond to signs and symptoms of internal bleeding, including falling hematocrit and hemoglobin levels. The attending physician, who was at the hospital when the patient’s condition deteriorated, should have gone to the bedside and taken steps to prevent his death.

THE DEFENSE The patient had been stable overnight; a bedside exam was unnecessary.

VERDICT $1,815,658 Texas verdict.

COMMENT Considering the many demands on clinicians’ time, it’s easy to postpone a face-to-face evaluation of a patient after a procedure. In this case, such a delay cost more than $1.8 million. A laboratory test or nurses’ notes are sometimes inadequate substitutes for a physician’s evaluation.

Failure to investigate suspicious symptoms ends badly

A MAN WITH SIGNS AND SYMPTOMS SUGGESTIVE OF AORTIC ANEURYSM/DISSECTION—including chest pain, pericardial effusion, aortic regurgitation, and aortic dilatation—saw his physician, but the doctor didn’t order any tests, such as computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or transesophageal echocardiogram (TEE).

Two weeks later, the 43-year-old patient returned to the physician, who noted left ventricular hypertrophy with pericardial effusion and mild aortic loop dilatation. Once again, the doctor didn’t order tests to rule out aneurysm/dissection.

Three weeks after the second office visit, the patient collapsed and was taken by ambulance to a hospital, where he was pronounced dead. An autopsy indicated that the cause of death was cardiac tamponade resulting from an undiagnosed aortic dissection.

PLAINTIFF’S CLAIM The physician should have ordered a CT scan with contrast, an MRI, or a TEE, any of which would have confirmed an aortic aneurysm/dissection, mandating immediate admission to a hospital for surgery.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Maryland settlement.

COMMENT Although many common conditions will resolve spontaneously, it’s hard to imagine temporizing in a patient with chest pain and presumed aortic dissection.

Unrecognized spinal infection leads to paralysis

A 355-LB MAN WITH DIABETES AND SPINAL DISC DISEASE experienced a sharp pain between his shoulder blades after playing golf, followed by constant back pain radiating to his chest. He went to the emergency department (ED) the next day and was admitted to the hospital to rule out a heart attack.

During a week in the hospital, the patient was seen by several doctors and diagnosed with pneumonia and excessive myoglobin levels. A computed tomography (CT) scan of the thorax and abdomen showing fluid buildup in the lining around the lungs led to the pneumonia diagnosis. No definitive spinal view was available, however, because of a mixup between a secretary and a radiology technician.

When the patient saw the hospital attending physician (at the family practice group where she was a partner) after discharge from the hospital, he complained of shooting pain down his spine. The doctor prescribed muscle relaxants. Soon afterward, the patient developed difficulty walking and reported no bowel movements for 13 days.

Almost 2 weeks after discharge from the hospital, the patient broke his ankle. He told the paramedics who responded that he felt numb from his nipples to his feet. He was taken to a community hospital, where a doctor ordered another CT scan. The radiologist who read the scan failed to identify the serious spinal infection it indicated.

The patient was transferred back to the original hospital. No doctor saw him for 8 hours after transfer, by which time he was paralyzed from the chest down.

PLAINTIFF’S CLAIM The fluid buildup on the first CT scan was caused not by pneumonia but by an infection in the spinal discs that had spread to the vertebrae and surrounding tissue.

THE DEFENSE The attending physician denied at trial that the patient had told her about the shooting pains down his spine during the posthospitalization visit.

VERDICT $4.75 million Illinois verdict, preceded by more than $2.7 million in settlements with some of the doctors involved and the community hospital.

COMMENT Careful follow-up of ED visits and coordinated care are essential to avoid large verdicts such as this one.

Bedside visit comes too late

A 22-YEAR-OLD MAN underwent a liver biopsy after being admitted to the hospital a week earlier with fever, chills, diarrhea, and general malaise. A number of specialists had seen him in the hospital because of abnormal laboratory studies, increasing fever, and a maculopapular rash over his trunk and face.

After the biopsy, the patient was dizzy and diaphoretic. His attending physician ordered hemoglobin and hematocrit levels, which were lower than earlier that day. Repeat testing showed a further decrease, prompting the physician to order 2 units of red blood cells.

Typing and cross-matching delayed the transfusion for several hours. Before it could be started, the patient was found unresponsive. When the attending physician came to the bedside, the patient had no palpable pulse. A code was called, but resuscitation efforts failed.

An autopsy found a small hole in the liver and 3500 mL of blood in the peritoneal cavity, as well as hepatitis with zonal and submassive necrosis, hemoperitoneum, and hypertrophy of the heart. An HIV test performed before the biopsy eventually came back positive.

PLAINTIFF’S CLAIM The attending physician and nurses were negligent in failing to respond to signs and symptoms of internal bleeding, including falling hematocrit and hemoglobin levels. The attending physician, who was at the hospital when the patient’s condition deteriorated, should have gone to the bedside and taken steps to prevent his death.

THE DEFENSE The patient had been stable overnight; a bedside exam was unnecessary.

VERDICT $1,815,658 Texas verdict.

COMMENT Considering the many demands on clinicians’ time, it’s easy to postpone a face-to-face evaluation of a patient after a procedure. In this case, such a delay cost more than $1.8 million. A laboratory test or nurses’ notes are sometimes inadequate substitutes for a physician’s evaluation.

Failure to investigate suspicious symptoms ends badly

A MAN WITH SIGNS AND SYMPTOMS SUGGESTIVE OF AORTIC ANEURYSM/DISSECTION—including chest pain, pericardial effusion, aortic regurgitation, and aortic dilatation—saw his physician, but the doctor didn’t order any tests, such as computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or transesophageal echocardiogram (TEE).

Two weeks later, the 43-year-old patient returned to the physician, who noted left ventricular hypertrophy with pericardial effusion and mild aortic loop dilatation. Once again, the doctor didn’t order tests to rule out aneurysm/dissection.

Three weeks after the second office visit, the patient collapsed and was taken by ambulance to a hospital, where he was pronounced dead. An autopsy indicated that the cause of death was cardiac tamponade resulting from an undiagnosed aortic dissection.

PLAINTIFF’S CLAIM The physician should have ordered a CT scan with contrast, an MRI, or a TEE, any of which would have confirmed an aortic aneurysm/dissection, mandating immediate admission to a hospital for surgery.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Maryland settlement.

COMMENT Although many common conditions will resolve spontaneously, it’s hard to imagine temporizing in a patient with chest pain and presumed aortic dissection.

Unrecognized spinal infection leads to paralysis

A 355-LB MAN WITH DIABETES AND SPINAL DISC DISEASE experienced a sharp pain between his shoulder blades after playing golf, followed by constant back pain radiating to his chest. He went to the emergency department (ED) the next day and was admitted to the hospital to rule out a heart attack.

During a week in the hospital, the patient was seen by several doctors and diagnosed with pneumonia and excessive myoglobin levels. A computed tomography (CT) scan of the thorax and abdomen showing fluid buildup in the lining around the lungs led to the pneumonia diagnosis. No definitive spinal view was available, however, because of a mixup between a secretary and a radiology technician.

When the patient saw the hospital attending physician (at the family practice group where she was a partner) after discharge from the hospital, he complained of shooting pain down his spine. The doctor prescribed muscle relaxants. Soon afterward, the patient developed difficulty walking and reported no bowel movements for 13 days.

Almost 2 weeks after discharge from the hospital, the patient broke his ankle. He told the paramedics who responded that he felt numb from his nipples to his feet. He was taken to a community hospital, where a doctor ordered another CT scan. The radiologist who read the scan failed to identify the serious spinal infection it indicated.

The patient was transferred back to the original hospital. No doctor saw him for 8 hours after transfer, by which time he was paralyzed from the chest down.

PLAINTIFF’S CLAIM The fluid buildup on the first CT scan was caused not by pneumonia but by an infection in the spinal discs that had spread to the vertebrae and surrounding tissue.

THE DEFENSE The attending physician denied at trial that the patient had told her about the shooting pains down his spine during the posthospitalization visit.

VERDICT $4.75 million Illinois verdict, preceded by more than $2.7 million in settlements with some of the doctors involved and the community hospital.

COMMENT Careful follow-up of ED visits and coordinated care are essential to avoid large verdicts such as this one.

Bedside visit comes too late

A 22-YEAR-OLD MAN underwent a liver biopsy after being admitted to the hospital a week earlier with fever, chills, diarrhea, and general malaise. A number of specialists had seen him in the hospital because of abnormal laboratory studies, increasing fever, and a maculopapular rash over his trunk and face.

After the biopsy, the patient was dizzy and diaphoretic. His attending physician ordered hemoglobin and hematocrit levels, which were lower than earlier that day. Repeat testing showed a further decrease, prompting the physician to order 2 units of red blood cells.

Typing and cross-matching delayed the transfusion for several hours. Before it could be started, the patient was found unresponsive. When the attending physician came to the bedside, the patient had no palpable pulse. A code was called, but resuscitation efforts failed.

An autopsy found a small hole in the liver and 3500 mL of blood in the peritoneal cavity, as well as hepatitis with zonal and submassive necrosis, hemoperitoneum, and hypertrophy of the heart. An HIV test performed before the biopsy eventually came back positive.

PLAINTIFF’S CLAIM The attending physician and nurses were negligent in failing to respond to signs and symptoms of internal bleeding, including falling hematocrit and hemoglobin levels. The attending physician, who was at the hospital when the patient’s condition deteriorated, should have gone to the bedside and taken steps to prevent his death.

THE DEFENSE The patient had been stable overnight; a bedside exam was unnecessary.

VERDICT $1,815,658 Texas verdict.

COMMENT Considering the many demands on clinicians’ time, it’s easy to postpone a face-to-face evaluation of a patient after a procedure. In this case, such a delay cost more than $1.8 million. A laboratory test or nurses’ notes are sometimes inadequate substitutes for a physician’s evaluation.

Failure to investigate suspicious symptoms ends badly

A MAN WITH SIGNS AND SYMPTOMS SUGGESTIVE OF AORTIC ANEURYSM/DISSECTION—including chest pain, pericardial effusion, aortic regurgitation, and aortic dilatation—saw his physician, but the doctor didn’t order any tests, such as computed tomography (CT) with contrast, magnetic resonance imaging (MRI), or transesophageal echocardiogram (TEE).

Two weeks later, the 43-year-old patient returned to the physician, who noted left ventricular hypertrophy with pericardial effusion and mild aortic loop dilatation. Once again, the doctor didn’t order tests to rule out aneurysm/dissection.

Three weeks after the second office visit, the patient collapsed and was taken by ambulance to a hospital, where he was pronounced dead. An autopsy indicated that the cause of death was cardiac tamponade resulting from an undiagnosed aortic dissection.

PLAINTIFF’S CLAIM The physician should have ordered a CT scan with contrast, an MRI, or a TEE, any of which would have confirmed an aortic aneurysm/dissection, mandating immediate admission to a hospital for surgery.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Maryland settlement.

COMMENT Although many common conditions will resolve spontaneously, it’s hard to imagine temporizing in a patient with chest pain and presumed aortic dissection.

Unrecognized spinal infection leads to paralysis

A 355-LB MAN WITH DIABETES AND SPINAL DISC DISEASE experienced a sharp pain between his shoulder blades after playing golf, followed by constant back pain radiating to his chest. He went to the emergency department (ED) the next day and was admitted to the hospital to rule out a heart attack.

During a week in the hospital, the patient was seen by several doctors and diagnosed with pneumonia and excessive myoglobin levels. A computed tomography (CT) scan of the thorax and abdomen showing fluid buildup in the lining around the lungs led to the pneumonia diagnosis. No definitive spinal view was available, however, because of a mixup between a secretary and a radiology technician.

When the patient saw the hospital attending physician (at the family practice group where she was a partner) after discharge from the hospital, he complained of shooting pain down his spine. The doctor prescribed muscle relaxants. Soon afterward, the patient developed difficulty walking and reported no bowel movements for 13 days.

Almost 2 weeks after discharge from the hospital, the patient broke his ankle. He told the paramedics who responded that he felt numb from his nipples to his feet. He was taken to a community hospital, where a doctor ordered another CT scan. The radiologist who read the scan failed to identify the serious spinal infection it indicated.

The patient was transferred back to the original hospital. No doctor saw him for 8 hours after transfer, by which time he was paralyzed from the chest down.

PLAINTIFF’S CLAIM The fluid buildup on the first CT scan was caused not by pneumonia but by an infection in the spinal discs that had spread to the vertebrae and surrounding tissue.

THE DEFENSE The attending physician denied at trial that the patient had told her about the shooting pains down his spine during the posthospitalization visit.

VERDICT $4.75 million Illinois verdict, preceded by more than $2.7 million in settlements with some of the doctors involved and the community hospital.

COMMENT Careful follow-up of ED visits and coordinated care are essential to avoid large verdicts such as this one.

ILLUSTRATIVE CASE

A 25-year-old woman who has been your patient for several years has intermittent bouts of abdominal pain, constipation, gas, and bloating. You believe she can benefit from treatment for IBS. What should you recommend?

IBS is the most common functional disorder of the gastrointestinal (GI) tract, affecting approximately 15% of the US population² and accounting for annual health care costs of roughly $30 billion.³ The primary symptoms are bloating, gas, and abdominal pain that often improves immediately after a bowel movement. Patients may have intermittent diarrhea and constipation, as well.

IBS may be related to “brain-gut dysfunction”
The etiology of IBS is unclear, but many agree that a combination of abnormal GI motility, visceral hypersensitivity, and “brain-gut dysfunction”—the inability of the brain to send signals that turn down pain produced in the GI tract—are contributing factors. Although IBS is not life threatening, it has a significant personal, social, and psychological impact. Despite its high prevalence and impact, only a limited number of large studies have assessed the effectiveness of various treatments.

STUDY SUMMARY: Antispasmodics, antidepressants offer relief—fiber does not

The Cochrane review included 56 randomized controlled trials (RCTs) comparing the efficacy of bulking agents (fiber supplements), anti-spasmodics, or antidepressants with placebo for the treatment of IBS. Twelve RCTs (n=621) focused on bulking agents, 29 (n=2333) on antispasmodics, and 15 (n=922) on antidepressants. Inclusion criteria included age (>12 years) and an IBS diagnosis. The outcomes analyzed were improvement in abdominal pain, global health assessments, and IBS symptom scores. Adverse effects were not evaluated.

Bulking agents. In studies ranging from 4 to 16 weeks, bulking agents were found to have no significant effect on abdominal pain (4 studies; standardized mean difference [SMD], 0.03; 95% confidence interval [CI], -0.34 to 0.40; P=.87) or global functioning (11 studies; risk ratio [RR]=1.11; 95% CI, 0.91-1.35; P=.32). Nor was there an improvement in IBS symptom score (3 studies; SMD=0.00; 95% CI, -0.43 to 0.43; P=1.00).

Antispasmodics. Assessed in RCTs ranging from one week to 6 months, antispasmodics significantly improved abdominal pain (RR=1.3; 95% CI, 1.1-1.55; P<.001; number needed to treat [NNT]=7); global functioning (RR=1.5; 95% CI, 1.2-1.8; P<.0001; NNT=5), and IBS symptom score (RR=1.9; 95% CI, 1.3-2.8; P<.01; NNT=3). Ten different antispasmodic agents were studied; in subgroup analyses, 5 of them— cimetropium/dicyclomine, peppermint oil, pinaverium, and trimebutine—were found to have statistically significant benefits.

Antidepressants. In studies of both tricyclics and selective serotonin reuptake inhibitors (SSRIs), antidepressants were found to have a significant effect on improving abdominal pain (RR=1.5; 95% CI, 1.0-2.1; P<.03; NNT=5), global functioning (RR=1.6; 95% CI, 1.2-2; P<.001; NNT=4), and IBS symptom score (RR=2.0; 95% CI, 1.3-3.0; P<.001; NNT=4). Subgroup analyses found statistically significant benefits in global functioning for SSRIs, and in abdominal pain and symptom scores for tricyclics.

WHAT’S NEW: More evidence against fiber for IBS symptoms

This Cochrane review confirms earlier findings—that both antispasmodics and antidepressants are effective treatments for IBS, but bulking agents are not. This is an important finding because dietary fiber adjustment is still among the first recommendations made by leading organizations like the American Gastroenterological Association and the World Gastroenterology Organisation.^4,5

CAVEATS: Limitations of studies included in the meta-analysis

Adverse effects of antispasmodics and antidepressants, which may limit compliance and treatment efficacy, were not addressed by the Cochrane reviewers. The total number of participants in trials of bulking agents was much smaller than that of the other treatments, so it is possible that clinically meaningful improvements were missed due to inadequate statistical power. In addition, the duration of interventions was highly variable, ranging from one to 4 months for bulking agents and antidepressants and from one week to 6 months for antispasmodics.

It is also important to note that 8 of the 12 studies of bulking agents were conducted in GI clinics. (The settings in which the other 4 studies were conducted is unclear.) Given the possibility that patients referred to GI clinics have already tried and failed to respond to fiber (and thus, that those who do respond to fiber are not given referrals), it may be reasonable for family physicians to recommend a trial of bulking agents for patients with IBS and to monitor them for symptom improvement.

CHALLENGES TO IMPLEMENTATION: Patients may favor fiber

Patients with IBS may be reluctant to take antidepressants or antispasmodics, due to concern about adverse effects (eg, headache, insomnia, nervousness, dry mouth, and constipation) or because of a preference for what they see as a more “natural” remedy. It may be helpful to explain that while fiber may have some health benefits, such as lowering cholesterol,⁶ antispasmodics and antidepressants have been found to improve IBS symptoms but thus far, fiber has not.

Acknowledgement

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

ILLUSTRATIVE CASE

A 25-year-old woman who has been your patient for several years has intermittent bouts of abdominal pain, constipation, gas, and bloating. You believe she can benefit from treatment for IBS. What should you recommend?

IBS is the most common functional disorder of the gastrointestinal (GI) tract, affecting approximately 15% of the US population² and accounting for annual health care costs of roughly $30 billion.³ The primary symptoms are bloating, gas, and abdominal pain that often improves immediately after a bowel movement. Patients may have intermittent diarrhea and constipation, as well.

IBS may be related to “brain-gut dysfunction”
The etiology of IBS is unclear, but many agree that a combination of abnormal GI motility, visceral hypersensitivity, and “brain-gut dysfunction”—the inability of the brain to send signals that turn down pain produced in the GI tract—are contributing factors. Although IBS is not life threatening, it has a significant personal, social, and psychological impact. Despite its high prevalence and impact, only a limited number of large studies have assessed the effectiveness of various treatments.

STUDY SUMMARY: Antispasmodics, antidepressants offer relief—fiber does not

The Cochrane review included 56 randomized controlled trials (RCTs) comparing the efficacy of bulking agents (fiber supplements), anti-spasmodics, or antidepressants with placebo for the treatment of IBS. Twelve RCTs (n=621) focused on bulking agents, 29 (n=2333) on antispasmodics, and 15 (n=922) on antidepressants. Inclusion criteria included age (>12 years) and an IBS diagnosis. The outcomes analyzed were improvement in abdominal pain, global health assessments, and IBS symptom scores. Adverse effects were not evaluated.

Bulking agents. In studies ranging from 4 to 16 weeks, bulking agents were found to have no significant effect on abdominal pain (4 studies; standardized mean difference [SMD], 0.03; 95% confidence interval [CI], -0.34 to 0.40; P=.87) or global functioning (11 studies; risk ratio [RR]=1.11; 95% CI, 0.91-1.35; P=.32). Nor was there an improvement in IBS symptom score (3 studies; SMD=0.00; 95% CI, -0.43 to 0.43; P=1.00).

Antispasmodics. Assessed in RCTs ranging from one week to 6 months, antispasmodics significantly improved abdominal pain (RR=1.3; 95% CI, 1.1-1.55; P<.001; number needed to treat [NNT]=7); global functioning (RR=1.5; 95% CI, 1.2-1.8; P<.0001; NNT=5), and IBS symptom score (RR=1.9; 95% CI, 1.3-2.8; P<.01; NNT=3). Ten different antispasmodic agents were studied; in subgroup analyses, 5 of them— cimetropium/dicyclomine, peppermint oil, pinaverium, and trimebutine—were found to have statistically significant benefits.

Antidepressants. In studies of both tricyclics and selective serotonin reuptake inhibitors (SSRIs), antidepressants were found to have a significant effect on improving abdominal pain (RR=1.5; 95% CI, 1.0-2.1; P<.03; NNT=5), global functioning (RR=1.6; 95% CI, 1.2-2; P<.001; NNT=4), and IBS symptom score (RR=2.0; 95% CI, 1.3-3.0; P<.001; NNT=4). Subgroup analyses found statistically significant benefits in global functioning for SSRIs, and in abdominal pain and symptom scores for tricyclics.

WHAT’S NEW: More evidence against fiber for IBS symptoms

This Cochrane review confirms earlier findings—that both antispasmodics and antidepressants are effective treatments for IBS, but bulking agents are not. This is an important finding because dietary fiber adjustment is still among the first recommendations made by leading organizations like the American Gastroenterological Association and the World Gastroenterology Organisation.^4,5

CAVEATS: Limitations of studies included in the meta-analysis

Adverse effects of antispasmodics and antidepressants, which may limit compliance and treatment efficacy, were not addressed by the Cochrane reviewers. The total number of participants in trials of bulking agents was much smaller than that of the other treatments, so it is possible that clinically meaningful improvements were missed due to inadequate statistical power. In addition, the duration of interventions was highly variable, ranging from one to 4 months for bulking agents and antidepressants and from one week to 6 months for antispasmodics.

It is also important to note that 8 of the 12 studies of bulking agents were conducted in GI clinics. (The settings in which the other 4 studies were conducted is unclear.) Given the possibility that patients referred to GI clinics have already tried and failed to respond to fiber (and thus, that those who do respond to fiber are not given referrals), it may be reasonable for family physicians to recommend a trial of bulking agents for patients with IBS and to monitor them for symptom improvement.

CHALLENGES TO IMPLEMENTATION: Patients may favor fiber

Patients with IBS may be reluctant to take antidepressants or antispasmodics, due to concern about adverse effects (eg, headache, insomnia, nervousness, dry mouth, and constipation) or because of a preference for what they see as a more “natural” remedy. It may be helpful to explain that while fiber may have some health benefits, such as lowering cholesterol,⁶ antispasmodics and antidepressants have been found to improve IBS symptoms but thus far, fiber has not.

Acknowledgement

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

ILLUSTRATIVE CASE

A 25-year-old woman who has been your patient for several years has intermittent bouts of abdominal pain, constipation, gas, and bloating. You believe she can benefit from treatment for IBS. What should you recommend?

IBS is the most common functional disorder of the gastrointestinal (GI) tract, affecting approximately 15% of the US population² and accounting for annual health care costs of roughly $30 billion.³ The primary symptoms are bloating, gas, and abdominal pain that often improves immediately after a bowel movement. Patients may have intermittent diarrhea and constipation, as well.

IBS may be related to “brain-gut dysfunction”
The etiology of IBS is unclear, but many agree that a combination of abnormal GI motility, visceral hypersensitivity, and “brain-gut dysfunction”—the inability of the brain to send signals that turn down pain produced in the GI tract—are contributing factors. Although IBS is not life threatening, it has a significant personal, social, and psychological impact. Despite its high prevalence and impact, only a limited number of large studies have assessed the effectiveness of various treatments.

STUDY SUMMARY: Antispasmodics, antidepressants offer relief—fiber does not

The Cochrane review included 56 randomized controlled trials (RCTs) comparing the efficacy of bulking agents (fiber supplements), anti-spasmodics, or antidepressants with placebo for the treatment of IBS. Twelve RCTs (n=621) focused on bulking agents, 29 (n=2333) on antispasmodics, and 15 (n=922) on antidepressants. Inclusion criteria included age (>12 years) and an IBS diagnosis. The outcomes analyzed were improvement in abdominal pain, global health assessments, and IBS symptom scores. Adverse effects were not evaluated.

Bulking agents. In studies ranging from 4 to 16 weeks, bulking agents were found to have no significant effect on abdominal pain (4 studies; standardized mean difference [SMD], 0.03; 95% confidence interval [CI], -0.34 to 0.40; P=.87) or global functioning (11 studies; risk ratio [RR]=1.11; 95% CI, 0.91-1.35; P=.32). Nor was there an improvement in IBS symptom score (3 studies; SMD=0.00; 95% CI, -0.43 to 0.43; P=1.00).

Antispasmodics. Assessed in RCTs ranging from one week to 6 months, antispasmodics significantly improved abdominal pain (RR=1.3; 95% CI, 1.1-1.55; P<.001; number needed to treat [NNT]=7); global functioning (RR=1.5; 95% CI, 1.2-1.8; P<.0001; NNT=5), and IBS symptom score (RR=1.9; 95% CI, 1.3-2.8; P<.01; NNT=3). Ten different antispasmodic agents were studied; in subgroup analyses, 5 of them— cimetropium/dicyclomine, peppermint oil, pinaverium, and trimebutine—were found to have statistically significant benefits.

Antidepressants. In studies of both tricyclics and selective serotonin reuptake inhibitors (SSRIs), antidepressants were found to have a significant effect on improving abdominal pain (RR=1.5; 95% CI, 1.0-2.1; P<.03; NNT=5), global functioning (RR=1.6; 95% CI, 1.2-2; P<.001; NNT=4), and IBS symptom score (RR=2.0; 95% CI, 1.3-3.0; P<.001; NNT=4). Subgroup analyses found statistically significant benefits in global functioning for SSRIs, and in abdominal pain and symptom scores for tricyclics.

WHAT’S NEW: More evidence against fiber for IBS symptoms

This Cochrane review confirms earlier findings—that both antispasmodics and antidepressants are effective treatments for IBS, but bulking agents are not. This is an important finding because dietary fiber adjustment is still among the first recommendations made by leading organizations like the American Gastroenterological Association and the World Gastroenterology Organisation.^4,5

CAVEATS: Limitations of studies included in the meta-analysis

Adverse effects of antispasmodics and antidepressants, which may limit compliance and treatment efficacy, were not addressed by the Cochrane reviewers. The total number of participants in trials of bulking agents was much smaller than that of the other treatments, so it is possible that clinically meaningful improvements were missed due to inadequate statistical power. In addition, the duration of interventions was highly variable, ranging from one to 4 months for bulking agents and antidepressants and from one week to 6 months for antispasmodics.

It is also important to note that 8 of the 12 studies of bulking agents were conducted in GI clinics. (The settings in which the other 4 studies were conducted is unclear.) Given the possibility that patients referred to GI clinics have already tried and failed to respond to fiber (and thus, that those who do respond to fiber are not given referrals), it may be reasonable for family physicians to recommend a trial of bulking agents for patients with IBS and to monitor them for symptom improvement.

CHALLENGES TO IMPLEMENTATION: Patients may favor fiber

Patients with IBS may be reluctant to take antidepressants or antispasmodics, due to concern about adverse effects (eg, headache, insomnia, nervousness, dry mouth, and constipation) or because of a preference for what they see as a more “natural” remedy. It may be helpful to explain that while fiber may have some health benefits, such as lowering cholesterol,⁶ antispasmodics and antidepressants have been found to improve IBS symptoms but thus far, fiber has not.

Acknowledgement

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

A 31-year-old construction worker with a history of intermittent cocaine use was brought to the emergency department (ED) by the police. He was handcuffed and appeared confused and frightened. The patient’s wife had phoned the police after he began running through a field in pursuit of perceived invaders of their home. The wife reported that a few hours earlier, the patient had begun to hallucinate and had become very fearful after getting high.

His heart rate was 126, blood pressure 136/96 mm Hg, and temperature 99.6°F. During the initial exam, the patient became agitated, attempted to assault a nurse, and tried to leave the ED before being subdued. A urine screen for drugs was negative for cocaine. His creatine phosphokinase was 850 U/L, creatinine 2.32 mg/dL, and blood urea nitrogen 27 mg/dL.

The health care team learned that the drug he’d been snorting earlier that day—and the day before—was “bath salts.”

This patient was one of the 30 that we’ve seen at our university hospital over the past year.

Since early 2010, EDs, psychiatric facilities, and poison control centers have seen a surge in the number of patients abusing novel synthetic stimulants—cathinones—that had once been sold in convenience stores and tobacco shops and often labeled innocuously as “bath salts” or “plant food.” Sales have largely gone underground, sold by those trafficking in methamphetamine and cocaine. These products are also available for online purchase and may be sold under such provocative names as “Cloud Nine” or “Rave.”¹ In 2010, poison control centers received 304 calls related to the use of these substances; in 2011, the number was 6138.²

Cathinone: An emerging recreational drug

For centuries the peoples of East Africa and the Arabian Peninsula have used the leaves of the indigenous khat plant (Catha edulis) for its amphetamine-like properties.³ Its active ingredient, cathinone, is a central nervous system stimulant that inhibits dopamine reuptake.⁴ In 2005, extracts from the plant were imported to Israel as “Hagigat” and promoted as a stimulant or aphrodisiac. These products were banned by the Israeli government in 2008 following documented cases of cardiovascular and neurologic sequelae.⁵

The growing problem of synthetic cathinone analogs in the United States. In 2008, synthetic analogs of cathinone were first identified in an analysis of drugs seized in the United States from individuals suffering psychological reactions to their use.¹ Two such substances, 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV), have since circulated worldwide, publicized by information on the Internet. Although the packets sold as “bath salts” clearly state that the contents are not for human consumption, Web sites promote the chemicals as “legal highs.”⁶

While these substances were being banned in many Western European countries, their use rapidly increased throughout the United States and elsewhere, often as an alternative to cocaine. Increases in the number of reports to poison control centers throughout the United States provide evidence of the increasing use of these drugs, despite legislation outlawing possession and sale in many states.⁷ In September 2011, the US Drug Enforcement Agency, using its emergency scheduling authority, made possession and sale of MDPV and mephedrone illegal throughout the United States.⁸

Who’s using bath salts? A review of calls to 2 poison control centers involving 236 patients over a 7-month period ending in February 2011 suggests that users of cathinones are primarily male (78%) and young (modal age 26).⁷ Many users of cathinones do not regularly use other drugs recreationally, and they believe the open sale of these substances implies low risk.⁷ However, one reported series from a hospital in Michigan indicated that 69% of users presenting to the ED had acknowledged past use of illicit drugs.⁹

What the drugs look like. Mephedrone and MDPV are supplied as white powders packaged in small packets of 500 mg and sell for about $25. Most users take the drug by nasal insufflation, although there is an alarming trend toward intravenous use.⁷ The intended effects in using these stimulants are improved attention and energy, as well as euphoria. Doses of about 25 mg produce these effects in most individuals and last for 2 to 3 hours, leading some users to compulsively re-dose to maintain the effects.

Use of bath salts leads to paranoid delusions, violent behavior

Both mephedrone and MDPV are strong inhibitors of dopamine reuptake in areas of the brain regulating reward and motivation.^10,11 With prolonged exposure, the resultant stimulant effect of dopamine in reward centers of the brain moves a user from recreational pleasure seeking to addictive use just to maintain normal function.¹² This transition occurs in a matter of days or weeks in some individuals, and we have seen multiple readmissions for paranoid psychotic reactions shortly after discharge from hospitalization.

Multiple serious complications of use have been described. The mainstream media have reported bizarre suicides and some homicides.^13,14 Our clinic has reported on a unique hallucinatory delirium after use of MDPV, resulting in paranoid delusions and violent behavior in response to vivid hallucinations.¹⁵ Other patients suffer prolonged anxiety and panic reactions or depressive symptoms with suicidal ideation.¹⁶

Cardiovascular and other sequelae
About half of patients presenting to hospital EDs have cardiovascular complications such as tachycardia, chest pain, and hypertension from the sympathomimetic effects of these agents.^9,16 There have also been reports of rhabdomyolysis and renal failure requiring intensive medical treatment.^7,9,16

Taken together, mental status changes and physiologic reactions are similar to the “excited delirium” attributed to cocaine, methamphetamine, phencyclidine (PCP), and methylenedioxymethamphetamine (Ecstasy), all drugs that act on central monoamines.^17–20 There have also been reports of death after the use of these drugs.²¹

Cathinones do not show up on routine drug screens
A routine urine screen for synthetic cathinones is not available, although a specific test arranged through commercial laboratories is available for cases when use is suspected. According to a written communication from A. Macher, MD, in 2011 (manuscript in preparation), urine drug screens for PCP using the immunoassay method may yield a false-positive result in the presence of MDPV. Simply asking patients whether they’ve been using these products often elicits an honest answer.

Treatment is largely supportive

Management guidance based on clinical trials is lacking. Cardiovascular complications require usual treatment.^9,16 Serious psychiatric reactions may necessitate hospitalization to assure patient safety, particularly with evidence suggesting the potential to act on paranoid delusions or suicidal ideation. Benzodiazepines may be needed to control agitation, and low-dose antipsychotics, such as risperidone 1 mg, can aid in treating hallucinations.^9,15

The hallucinatory psychosis seen with these substances is best characterized as a toxic delirium.¹⁵ Aggressive use of antipsychotic agents is not advised, given the risk of treatment-related morbidity in patients with a history of repeated stimulant use.²² Many patients presenting with acute delirium may require restraints. These procedures should be used with caution to minimize muscle tissue damage; patients should be monitored frequently for hyperthermia, dehydration, and rhabdomyolysis.¹⁶

Nothing is known about the long-term effects of these drugs, although substances with similar actions are associated with long-term cognitive and memory deficits after repeated use.⁴

CORRESPONDENCE Thomas M. Penders, MD, LFAPA, Department of Psychiatry, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

A 31-year-old construction worker with a history of intermittent cocaine use was brought to the emergency department (ED) by the police. He was handcuffed and appeared confused and frightened. The patient’s wife had phoned the police after he began running through a field in pursuit of perceived invaders of their home. The wife reported that a few hours earlier, the patient had begun to hallucinate and had become very fearful after getting high.

His heart rate was 126, blood pressure 136/96 mm Hg, and temperature 99.6°F. During the initial exam, the patient became agitated, attempted to assault a nurse, and tried to leave the ED before being subdued. A urine screen for drugs was negative for cocaine. His creatine phosphokinase was 850 U/L, creatinine 2.32 mg/dL, and blood urea nitrogen 27 mg/dL.

The health care team learned that the drug he’d been snorting earlier that day—and the day before—was “bath salts.”

This patient was one of the 30 that we’ve seen at our university hospital over the past year.

Since early 2010, EDs, psychiatric facilities, and poison control centers have seen a surge in the number of patients abusing novel synthetic stimulants—cathinones—that had once been sold in convenience stores and tobacco shops and often labeled innocuously as “bath salts” or “plant food.” Sales have largely gone underground, sold by those trafficking in methamphetamine and cocaine. These products are also available for online purchase and may be sold under such provocative names as “Cloud Nine” or “Rave.”¹ In 2010, poison control centers received 304 calls related to the use of these substances; in 2011, the number was 6138.²

Cathinone: An emerging recreational drug

For centuries the peoples of East Africa and the Arabian Peninsula have used the leaves of the indigenous khat plant (Catha edulis) for its amphetamine-like properties.³ Its active ingredient, cathinone, is a central nervous system stimulant that inhibits dopamine reuptake.⁴ In 2005, extracts from the plant were imported to Israel as “Hagigat” and promoted as a stimulant or aphrodisiac. These products were banned by the Israeli government in 2008 following documented cases of cardiovascular and neurologic sequelae.⁵

The growing problem of synthetic cathinone analogs in the United States. In 2008, synthetic analogs of cathinone were first identified in an analysis of drugs seized in the United States from individuals suffering psychological reactions to their use.¹ Two such substances, 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV), have since circulated worldwide, publicized by information on the Internet. Although the packets sold as “bath salts” clearly state that the contents are not for human consumption, Web sites promote the chemicals as “legal highs.”⁶

While these substances were being banned in many Western European countries, their use rapidly increased throughout the United States and elsewhere, often as an alternative to cocaine. Increases in the number of reports to poison control centers throughout the United States provide evidence of the increasing use of these drugs, despite legislation outlawing possession and sale in many states.⁷ In September 2011, the US Drug Enforcement Agency, using its emergency scheduling authority, made possession and sale of MDPV and mephedrone illegal throughout the United States.⁸

Who’s using bath salts? A review of calls to 2 poison control centers involving 236 patients over a 7-month period ending in February 2011 suggests that users of cathinones are primarily male (78%) and young (modal age 26).⁷ Many users of cathinones do not regularly use other drugs recreationally, and they believe the open sale of these substances implies low risk.⁷ However, one reported series from a hospital in Michigan indicated that 69% of users presenting to the ED had acknowledged past use of illicit drugs.⁹

What the drugs look like. Mephedrone and MDPV are supplied as white powders packaged in small packets of 500 mg and sell for about $25. Most users take the drug by nasal insufflation, although there is an alarming trend toward intravenous use.⁷ The intended effects in using these stimulants are improved attention and energy, as well as euphoria. Doses of about 25 mg produce these effects in most individuals and last for 2 to 3 hours, leading some users to compulsively re-dose to maintain the effects.

Use of bath salts leads to paranoid delusions, violent behavior

Both mephedrone and MDPV are strong inhibitors of dopamine reuptake in areas of the brain regulating reward and motivation.^10,11 With prolonged exposure, the resultant stimulant effect of dopamine in reward centers of the brain moves a user from recreational pleasure seeking to addictive use just to maintain normal function.¹² This transition occurs in a matter of days or weeks in some individuals, and we have seen multiple readmissions for paranoid psychotic reactions shortly after discharge from hospitalization.

Multiple serious complications of use have been described. The mainstream media have reported bizarre suicides and some homicides.^13,14 Our clinic has reported on a unique hallucinatory delirium after use of MDPV, resulting in paranoid delusions and violent behavior in response to vivid hallucinations.¹⁵ Other patients suffer prolonged anxiety and panic reactions or depressive symptoms with suicidal ideation.¹⁶

Cardiovascular and other sequelae
About half of patients presenting to hospital EDs have cardiovascular complications such as tachycardia, chest pain, and hypertension from the sympathomimetic effects of these agents.^9,16 There have also been reports of rhabdomyolysis and renal failure requiring intensive medical treatment.^7,9,16

Taken together, mental status changes and physiologic reactions are similar to the “excited delirium” attributed to cocaine, methamphetamine, phencyclidine (PCP), and methylenedioxymethamphetamine (Ecstasy), all drugs that act on central monoamines.^17–20 There have also been reports of death after the use of these drugs.²¹

Cathinones do not show up on routine drug screens
A routine urine screen for synthetic cathinones is not available, although a specific test arranged through commercial laboratories is available for cases when use is suspected. According to a written communication from A. Macher, MD, in 2011 (manuscript in preparation), urine drug screens for PCP using the immunoassay method may yield a false-positive result in the presence of MDPV. Simply asking patients whether they’ve been using these products often elicits an honest answer.

Treatment is largely supportive

Management guidance based on clinical trials is lacking. Cardiovascular complications require usual treatment.^9,16 Serious psychiatric reactions may necessitate hospitalization to assure patient safety, particularly with evidence suggesting the potential to act on paranoid delusions or suicidal ideation. Benzodiazepines may be needed to control agitation, and low-dose antipsychotics, such as risperidone 1 mg, can aid in treating hallucinations.^9,15

The hallucinatory psychosis seen with these substances is best characterized as a toxic delirium.¹⁵ Aggressive use of antipsychotic agents is not advised, given the risk of treatment-related morbidity in patients with a history of repeated stimulant use.²² Many patients presenting with acute delirium may require restraints. These procedures should be used with caution to minimize muscle tissue damage; patients should be monitored frequently for hyperthermia, dehydration, and rhabdomyolysis.¹⁶

Nothing is known about the long-term effects of these drugs, although substances with similar actions are associated with long-term cognitive and memory deficits after repeated use.⁴

CORRESPONDENCE Thomas M. Penders, MD, LFAPA, Department of Psychiatry, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

A 31-year-old construction worker with a history of intermittent cocaine use was brought to the emergency department (ED) by the police. He was handcuffed and appeared confused and frightened. The patient’s wife had phoned the police after he began running through a field in pursuit of perceived invaders of their home. The wife reported that a few hours earlier, the patient had begun to hallucinate and had become very fearful after getting high.

His heart rate was 126, blood pressure 136/96 mm Hg, and temperature 99.6°F. During the initial exam, the patient became agitated, attempted to assault a nurse, and tried to leave the ED before being subdued. A urine screen for drugs was negative for cocaine. His creatine phosphokinase was 850 U/L, creatinine 2.32 mg/dL, and blood urea nitrogen 27 mg/dL.

The health care team learned that the drug he’d been snorting earlier that day—and the day before—was “bath salts.”

This patient was one of the 30 that we’ve seen at our university hospital over the past year.

Since early 2010, EDs, psychiatric facilities, and poison control centers have seen a surge in the number of patients abusing novel synthetic stimulants—cathinones—that had once been sold in convenience stores and tobacco shops and often labeled innocuously as “bath salts” or “plant food.” Sales have largely gone underground, sold by those trafficking in methamphetamine and cocaine. These products are also available for online purchase and may be sold under such provocative names as “Cloud Nine” or “Rave.”¹ In 2010, poison control centers received 304 calls related to the use of these substances; in 2011, the number was 6138.²

Cathinone: An emerging recreational drug

For centuries the peoples of East Africa and the Arabian Peninsula have used the leaves of the indigenous khat plant (Catha edulis) for its amphetamine-like properties.³ Its active ingredient, cathinone, is a central nervous system stimulant that inhibits dopamine reuptake.⁴ In 2005, extracts from the plant were imported to Israel as “Hagigat” and promoted as a stimulant or aphrodisiac. These products were banned by the Israeli government in 2008 following documented cases of cardiovascular and neurologic sequelae.⁵

The growing problem of synthetic cathinone analogs in the United States. In 2008, synthetic analogs of cathinone were first identified in an analysis of drugs seized in the United States from individuals suffering psychological reactions to their use.¹ Two such substances, 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV), have since circulated worldwide, publicized by information on the Internet. Although the packets sold as “bath salts” clearly state that the contents are not for human consumption, Web sites promote the chemicals as “legal highs.”⁶

While these substances were being banned in many Western European countries, their use rapidly increased throughout the United States and elsewhere, often as an alternative to cocaine. Increases in the number of reports to poison control centers throughout the United States provide evidence of the increasing use of these drugs, despite legislation outlawing possession and sale in many states.⁷ In September 2011, the US Drug Enforcement Agency, using its emergency scheduling authority, made possession and sale of MDPV and mephedrone illegal throughout the United States.⁸

Who’s using bath salts? A review of calls to 2 poison control centers involving 236 patients over a 7-month period ending in February 2011 suggests that users of cathinones are primarily male (78%) and young (modal age 26).⁷ Many users of cathinones do not regularly use other drugs recreationally, and they believe the open sale of these substances implies low risk.⁷ However, one reported series from a hospital in Michigan indicated that 69% of users presenting to the ED had acknowledged past use of illicit drugs.⁹

What the drugs look like. Mephedrone and MDPV are supplied as white powders packaged in small packets of 500 mg and sell for about $25. Most users take the drug by nasal insufflation, although there is an alarming trend toward intravenous use.⁷ The intended effects in using these stimulants are improved attention and energy, as well as euphoria. Doses of about 25 mg produce these effects in most individuals and last for 2 to 3 hours, leading some users to compulsively re-dose to maintain the effects.

Use of bath salts leads to paranoid delusions, violent behavior

Both mephedrone and MDPV are strong inhibitors of dopamine reuptake in areas of the brain regulating reward and motivation.^10,11 With prolonged exposure, the resultant stimulant effect of dopamine in reward centers of the brain moves a user from recreational pleasure seeking to addictive use just to maintain normal function.¹² This transition occurs in a matter of days or weeks in some individuals, and we have seen multiple readmissions for paranoid psychotic reactions shortly after discharge from hospitalization.

Multiple serious complications of use have been described. The mainstream media have reported bizarre suicides and some homicides.^13,14 Our clinic has reported on a unique hallucinatory delirium after use of MDPV, resulting in paranoid delusions and violent behavior in response to vivid hallucinations.¹⁵ Other patients suffer prolonged anxiety and panic reactions or depressive symptoms with suicidal ideation.¹⁶

Cardiovascular and other sequelae
About half of patients presenting to hospital EDs have cardiovascular complications such as tachycardia, chest pain, and hypertension from the sympathomimetic effects of these agents.^9,16 There have also been reports of rhabdomyolysis and renal failure requiring intensive medical treatment.^7,9,16

Taken together, mental status changes and physiologic reactions are similar to the “excited delirium” attributed to cocaine, methamphetamine, phencyclidine (PCP), and methylenedioxymethamphetamine (Ecstasy), all drugs that act on central monoamines.^17–20 There have also been reports of death after the use of these drugs.²¹

Cathinones do not show up on routine drug screens
A routine urine screen for synthetic cathinones is not available, although a specific test arranged through commercial laboratories is available for cases when use is suspected. According to a written communication from A. Macher, MD, in 2011 (manuscript in preparation), urine drug screens for PCP using the immunoassay method may yield a false-positive result in the presence of MDPV. Simply asking patients whether they’ve been using these products often elicits an honest answer.

Treatment is largely supportive

Management guidance based on clinical trials is lacking. Cardiovascular complications require usual treatment.^9,16 Serious psychiatric reactions may necessitate hospitalization to assure patient safety, particularly with evidence suggesting the potential to act on paranoid delusions or suicidal ideation. Benzodiazepines may be needed to control agitation, and low-dose antipsychotics, such as risperidone 1 mg, can aid in treating hallucinations.^9,15

The hallucinatory psychosis seen with these substances is best characterized as a toxic delirium.¹⁵ Aggressive use of antipsychotic agents is not advised, given the risk of treatment-related morbidity in patients with a history of repeated stimulant use.²² Many patients presenting with acute delirium may require restraints. These procedures should be used with caution to minimize muscle tissue damage; patients should be monitored frequently for hyperthermia, dehydration, and rhabdomyolysis.¹⁶

Nothing is known about the long-term effects of these drugs, although substances with similar actions are associated with long-term cognitive and memory deficits after repeated use.⁴

CORRESPONDENCE Thomas M. Penders, MD, LFAPA, Department of Psychiatry, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834; [email protected]

Ankle sprain, one of the more common injuries that primary care physicians evaluate, is usually managed with conservative treatment. Not uncommonly, however, lateral ankle sprain is diagnosed without consideration of a broader differential diagnosis.

Contributing to the problem is the fact that the clinical presentation of some fractures and tendon injuries is similar to that of a routine sprain. In some cases, the mechanism of injury—sprains are usually caused by excessive inversion of the ankle on a plantar-flexed foot—is similar, as well. What’s more, radiographs are often omitted or misinterpreted.

In the pages that follow, we highlight 4 commonly misdiagnosed injuries: fifth metatarsal fractures, navicular fractures, talar dome lesions, and peroneal tendon injuries. These injuries should be included in the differential diagnosis of an acute ankle injury—or a subacute foot or ankle injury that fails to respond as expected. Prompt recognition and appropriate treatment result in optimal outcomes. When foot and ankle fractures and tendon injuries are misdiagnosed (or simply missed) and do not receive adequate treatment, long-term morbidity, including frequent reinjury and disability, may result.¹

Are x-rays needed? Turn to the Ottawa rules

Ankle sprains represent a disruption in a ligament supporting a joint, and result in pain, edema, and ecchymosis, and often affect a patient’s ability to bear weight. While uncomplicated sprains generally heal with conservative treatment, other common foot and ankle injuries may require a different approach.

The Ottawa foot and ankle rules are an evidence-based guide to the use of initial radiographs after acute ankle injury (TABLE 1).^2-4 Pain—near the malleoli (for the ankle) or in the midfoot—is the key criterion, but x-rays are recommended only if at least one other specified criterion is also met. With a sensitivity of nearly 100%, the rules have been shown to reliably exclude, and diagnose, ankle and midfoot fractures in children >5 years and adults.^2,5

Table 1
Ottawa ankle and foot rules^2-4

Fifth metatarsal fractures are easily missed

The mechanism of injury for a fifth metatarsal fracture is often similar to that of a lateral ankle sprain. In addition, isolated ankle radiographs may not adequately evaluate the fifth metatarsal, which increases the risk of misdiagnosis.⁶

3 types of fifth metatarsal fractures
Fifth metatarsal fractures involve one of the following:

1. an avulsion fracture, caused by the pull of the plantar aponeurosis and the peroneus brevis tendon at the tuberosity of the bone
2. a Jones fracture, at the base of the fourth and fifth metatarsal (FIGURE 1)
3. a shaft fracture, distal to the fifth metatarsal joint in the proximal diaphysis.^6-8

FIGURE 1
Jones fractures heal slowly

While avulsion fractures are generally the result of an inversion ankle injury, Jones fractures are usually caused by a large adductive force applied to the forefoot on a plantar-flexed ankle.⁶ Shaft fractures, also known as diaphyseal stress fractures, are overuse injuries from chronic overload, usually after a sudden increase in running or walking.⁹

Patients with fifth metatarsal fractures typically have tenderness with palpation over the area of injury, with edema and ecchymosis when the injury is acute. Evidence-based guidelines recommend x-rays of the foot, including anteroposterior (AP), lateral, and oblique views.^2-4 One study supports the use of an additional x-ray—an AP view of the ankle, including the base of the fifth metatarsal—if clinical suspicion is high and initial radiographs are negative or inconclusive.¹⁰

Shaft fractures may not be seen on x-rays in the first 3 weeks, but a periosteal reaction or linear lucency near the symptomatic area may be noticeable on radiographs taken at a later date.¹¹ If this overuse injury seems likely but does not show up on the initial x-rays, however, magnetic resonance imaging (MRI) or a technetium bone scan can reliably identify a stress fracture.⁹

How to treat, when to refer
Treatment of fifth metatarsal fractures range from conservative to surgical, depending on the type (and extent) of injury (TABLE 2).^1,5,6,12-14

TABLE 2

Nondisplaced avulsion fractures can be treated conservatively, with relative immobilization. In one prospective study, the use of a stiff-soled shoe, with weight-bearing as tolerated, was associated with excellent long-term outcomes.¹¹ Orthopedic referral for probable reduction and fixation is indicated for avulsion fractures that are comminuted or >2 mm displaced, or have >30% involvement of the cubometatarsal joint.^15,16

Jones fractures are known for prolonged healing and nonunion, as well as a high rate of complications. If the fracture is nondisplaced, start with conservative treatment, consisting of nonweight-bearing immobilization for 6 to 8 weeks, with additional immobilization dependent on radiographs. One randomized controlled trial of patients with Jones fractures showed a relatively high failure rate (44%) with casting; patients for whom casting was successful still had a median time to bony union of 15 weeks.¹⁷ Specialty consultation may be needed when there is fracture displacement, absence of bony union, or high clinical concern.^6,17

Is your patient an athlete? Surgical fixation is favored for injured athletes with Jones fractures because failure rates are lower and both clinical union and return to play are shorter.^18,19 In a case series involving 23 athletic patients with Jones fractures, the success rate for immediate surgical screw fixation approached 100% within 6 to 8 weeks.¹⁸

Nondisplaced shaft fractures may be treated conservatively, with 6 to 8 weeks of immobilization with a protective orthosis. An orthopedic referral is recommended for patients whose fractures have >3 mm displacement or >10 degree angulation.¹⁵

Navicular fractures are overuse injuries

The navicular is predisposed to stress injury because the central third of the bone is relatively avascular. In addition, the navicular is the area of greatest stress and impingement between the talus and cuneiform bones during repetitive foot strikes.^12,20 Navicular fractures occur predominantly in track and field athletes.¹²

Patients presenting with a navicular stress fracture often report a gradual onset of vague dorsal midfoot pain associated with their workout.¹⁷ Examination typically reveals tenderness on palpation over the dorsal aspect of the navicular; passive eversion and active inversion may be painful, but edema and ecchymosis are usually absent.²¹

When pain is elicited by palpation of the navicular, radiographs are recommended.^2,6 X-rays have a relatively low sensitivity (33%), however, for detecting acute navicular stress fractures. If initial radiographs are negative but there is a high clinical suspicion, advanced studies—with either MRI or a technetium bone scan—are recommended for a definitive diagnosis.^12,22 While both are highly sensitive for navicular stress fractures, MRI provides greater specificity and anatomic detail.²³

Most navicular fractures are nondisplaced
Nondisplaced navicular fractures can be treated conservatively, with nonweight-bearing immobilization for 6 to 8 weeks followed by progressive activity.²⁴ Prospective studies have found that conservative treatment has a high success rate, with athletes usually able to return to play within 6 months.^22,24,25 If tenderness remains after 6 to 8 weeks of immobilization, treatment choices are continued immobilization with no weight-bearing or orthopedic referral.²⁶

Referral is indicated for navicular fractures that are comminuted or displaced, or involve more than one bone cortex.²⁶ Surgical screw fixation may be recommended for navicular stress fractures in selected athletes because of its high success rate—and likelihood of an earlier return to play.²⁷

Talar injuries are characterized by persistent pain

Injuries to the talus commonly occur at the same time as ankle sprains and may cause persistent pain, even after the sprain has healed.²⁸ Evidence suggests that up to 90% of residual pain is related to an underlying cartilage injury.^29,30 Most talar injuries are associated with the disruption of the cartilage overlaying the talar dome, which may lead to osteochondritis dissecans.²⁹ Subtle talus fractures are also a concern after an acute ankle injury.

Osteochondral lesions are associated with a dull ankle pain deep in a location with a prior ankle injury; in some cases, the pain will become chronic.³¹ Physical exam findings typically include ankle joint effusion with localized tenderness around the joint.³¹

Ankle radiographs are insensitive for identifying osteochondral lesions, and MRI is recommended for evaluating suspected lesions.^29,31 Treatment varies, depending on symptoms and severity. Patients with minimal symptoms may be treated conservatively; however, high failure rates have been reported.³² Surgical treatment depends on the size and site of the lesion and the degree of cartilage injury, and surgical consultation is recommended.³¹

Fractures of the talar dome (FIGURE 2) may be either medial or lateral and are often the result of inversion ankle injuries.¹⁴ History and clinical findings vary depending on the type of fracture.

FIGURE 2
Talar dome injuries often result from inversion ankle injuries

As with osteochondral lesions, ankle radiographs may fail to identify talus fractures. Computed tomography (CT) should be used to evaluate acute fractures of the talus, as CT scan is better able to define displacement, size, and intra-articular involvement.³³ Talar fractures may be managed conservatively with immobilization and nonweight-bearing for 4 to 6 weeks, but specialty consultation should be considered.14,33

A tarsal coalition—an incomplete, congenital separation of the bones, occasionally involving the talus and the calcaneus—can also be a cause of persistent pain after a sprain.²⁸ Physical exam typically demonstrates decreased range of motion in the subtalar or transverse tarsal joint. Radiographs may identify the coalition, but MRI or CT scan provides optimal visualization. Immobilization for 6 weeks is the recommended initial treatment, but if that fails, surgical excision or fusion may be necessary.

Peroneal tendon injuries may cause ankle instability

Peroneal tendon injuries, which include strains, subluxation, dislocation, and tears of one or both of the peroneal tendons, are often caused by ankle inversion similar to that of an uncomplicated sprain. Subsequent ankle instability may result from untreated peroneal tendon injuries.³⁴ Peroneal tendon subluxation accounts for a very small number (0.3%-0.5%) of traumatic ankle injuries.³⁵

Peroneal tendon injuries often occur during sports that involve frequent lateral movement or cutting—eg, football, basketball, and soccer—and are often caused by sudden dorsiflexion of the inverted foot, with coincident contraction of the peroneal muscles.^36,37 This mechanism can disrupt the superior peroneal retinaculum, leading to recurrent subluxation or dislocation and subsequent ankle instability.^36,38 Chronic subluxation can also result in longitudinal tears of the peroneal tendons, especially of the peroneus brevis.^36,38,39

Patients with peroneal tendon injuries may report a “pop” at the time of injury. Pain is typically located posterior to the lateral malleolus, and recurrent subluxation is often described as a “snapping” around the lateral ankle during athletic activities.^37,38 Instability is common in patients with subacute or chronic peroneal tendon injuries, especially on uneven surfaces.³⁸

Acute peroneal tendon injuries cause posterolateral ankle pain, swelling, and weakness; exam findings include tenderness along the course of the peroneal tendons with associated edema.³⁷ Subluxation or dislocation of the peroneal brevis tendon may be confirmed by placing the foot in plantar flexion and inversion and asking the patient to forcibly dorsiflex and evert the injured ankle.

Plain radiographs are usually normal in an isolated injury to the peroneal tendons. A fracture of the posterolateral margin of the fibula is a rare finding but indicates disruption of the peroneal retinaculum.³⁶ MRI provides the best imaging for peroneal tendons and the stabilizing retinaculum, although a CT scan can provide detailed bony anatomy when subtle fractures are suspected or additional evaluation is needed.

Subluxation or dislocation indicate a need for surgery
Conservative management is recommended for peroneal tendon strains, but surgical treatment is increasingly recommended for subluxation or dislocation, especially if the problem is recurrent.^36,37 Conservative treatment consists of short-term immobilization with a walking boot or brace, followed by physical therapy to improve strength and motion. Surgical treatment of subluxation and dislocation by stabilizing the peroneal tendons within the peroneal groove has been shown to provide lasting stability and improvement.^37,38,40,41

CORRESPONDENCE Scott Hall, MD, University of Nevada-Reno, Brigham Building 316, Reno, NV 89557; [email protected]

Ankle sprain, one of the more common injuries that primary care physicians evaluate, is usually managed with conservative treatment. Not uncommonly, however, lateral ankle sprain is diagnosed without consideration of a broader differential diagnosis.

Contributing to the problem is the fact that the clinical presentation of some fractures and tendon injuries is similar to that of a routine sprain. In some cases, the mechanism of injury—sprains are usually caused by excessive inversion of the ankle on a plantar-flexed foot—is similar, as well. What’s more, radiographs are often omitted or misinterpreted.

In the pages that follow, we highlight 4 commonly misdiagnosed injuries: fifth metatarsal fractures, navicular fractures, talar dome lesions, and peroneal tendon injuries. These injuries should be included in the differential diagnosis of an acute ankle injury—or a subacute foot or ankle injury that fails to respond as expected. Prompt recognition and appropriate treatment result in optimal outcomes. When foot and ankle fractures and tendon injuries are misdiagnosed (or simply missed) and do not receive adequate treatment, long-term morbidity, including frequent reinjury and disability, may result.¹

Are x-rays needed? Turn to the Ottawa rules

Ankle sprains represent a disruption in a ligament supporting a joint, and result in pain, edema, and ecchymosis, and often affect a patient’s ability to bear weight. While uncomplicated sprains generally heal with conservative treatment, other common foot and ankle injuries may require a different approach.

The Ottawa foot and ankle rules are an evidence-based guide to the use of initial radiographs after acute ankle injury (TABLE 1).^2-4 Pain—near the malleoli (for the ankle) or in the midfoot—is the key criterion, but x-rays are recommended only if at least one other specified criterion is also met. With a sensitivity of nearly 100%, the rules have been shown to reliably exclude, and diagnose, ankle and midfoot fractures in children >5 years and adults.^2,5

Table 1
Ottawa ankle and foot rules^2-4

Fifth metatarsal fractures are easily missed

The mechanism of injury for a fifth metatarsal fracture is often similar to that of a lateral ankle sprain. In addition, isolated ankle radiographs may not adequately evaluate the fifth metatarsal, which increases the risk of misdiagnosis.⁶

3 types of fifth metatarsal fractures
Fifth metatarsal fractures involve one of the following:

1. an avulsion fracture, caused by the pull of the plantar aponeurosis and the peroneus brevis tendon at the tuberosity of the bone
2. a Jones fracture, at the base of the fourth and fifth metatarsal (FIGURE 1)
3. a shaft fracture, distal to the fifth metatarsal joint in the proximal diaphysis.^6-8

FIGURE 1
Jones fractures heal slowly

While avulsion fractures are generally the result of an inversion ankle injury, Jones fractures are usually caused by a large adductive force applied to the forefoot on a plantar-flexed ankle.⁶ Shaft fractures, also known as diaphyseal stress fractures, are overuse injuries from chronic overload, usually after a sudden increase in running or walking.⁹

Patients with fifth metatarsal fractures typically have tenderness with palpation over the area of injury, with edema and ecchymosis when the injury is acute. Evidence-based guidelines recommend x-rays of the foot, including anteroposterior (AP), lateral, and oblique views.^2-4 One study supports the use of an additional x-ray—an AP view of the ankle, including the base of the fifth metatarsal—if clinical suspicion is high and initial radiographs are negative or inconclusive.¹⁰

Shaft fractures may not be seen on x-rays in the first 3 weeks, but a periosteal reaction or linear lucency near the symptomatic area may be noticeable on radiographs taken at a later date.¹¹ If this overuse injury seems likely but does not show up on the initial x-rays, however, magnetic resonance imaging (MRI) or a technetium bone scan can reliably identify a stress fracture.⁹

How to treat, when to refer
Treatment of fifth metatarsal fractures range from conservative to surgical, depending on the type (and extent) of injury (TABLE 2).^1,5,6,12-14

TABLE 2

Nondisplaced avulsion fractures can be treated conservatively, with relative immobilization. In one prospective study, the use of a stiff-soled shoe, with weight-bearing as tolerated, was associated with excellent long-term outcomes.¹¹ Orthopedic referral for probable reduction and fixation is indicated for avulsion fractures that are comminuted or >2 mm displaced, or have >30% involvement of the cubometatarsal joint.^15,16

Jones fractures are known for prolonged healing and nonunion, as well as a high rate of complications. If the fracture is nondisplaced, start with conservative treatment, consisting of nonweight-bearing immobilization for 6 to 8 weeks, with additional immobilization dependent on radiographs. One randomized controlled trial of patients with Jones fractures showed a relatively high failure rate (44%) with casting; patients for whom casting was successful still had a median time to bony union of 15 weeks.¹⁷ Specialty consultation may be needed when there is fracture displacement, absence of bony union, or high clinical concern.^6,17

Is your patient an athlete? Surgical fixation is favored for injured athletes with Jones fractures because failure rates are lower and both clinical union and return to play are shorter.^18,19 In a case series involving 23 athletic patients with Jones fractures, the success rate for immediate surgical screw fixation approached 100% within 6 to 8 weeks.¹⁸

Nondisplaced shaft fractures may be treated conservatively, with 6 to 8 weeks of immobilization with a protective orthosis. An orthopedic referral is recommended for patients whose fractures have >3 mm displacement or >10 degree angulation.¹⁵

Navicular fractures are overuse injuries

The navicular is predisposed to stress injury because the central third of the bone is relatively avascular. In addition, the navicular is the area of greatest stress and impingement between the talus and cuneiform bones during repetitive foot strikes.^12,20 Navicular fractures occur predominantly in track and field athletes.¹²

Patients presenting with a navicular stress fracture often report a gradual onset of vague dorsal midfoot pain associated with their workout.¹⁷ Examination typically reveals tenderness on palpation over the dorsal aspect of the navicular; passive eversion and active inversion may be painful, but edema and ecchymosis are usually absent.²¹

When pain is elicited by palpation of the navicular, radiographs are recommended.^2,6 X-rays have a relatively low sensitivity (33%), however, for detecting acute navicular stress fractures. If initial radiographs are negative but there is a high clinical suspicion, advanced studies—with either MRI or a technetium bone scan—are recommended for a definitive diagnosis.^12,22 While both are highly sensitive for navicular stress fractures, MRI provides greater specificity and anatomic detail.²³

Most navicular fractures are nondisplaced
Nondisplaced navicular fractures can be treated conservatively, with nonweight-bearing immobilization for 6 to 8 weeks followed by progressive activity.²⁴ Prospective studies have found that conservative treatment has a high success rate, with athletes usually able to return to play within 6 months.^22,24,25 If tenderness remains after 6 to 8 weeks of immobilization, treatment choices are continued immobilization with no weight-bearing or orthopedic referral.²⁶

Referral is indicated for navicular fractures that are comminuted or displaced, or involve more than one bone cortex.²⁶ Surgical screw fixation may be recommended for navicular stress fractures in selected athletes because of its high success rate—and likelihood of an earlier return to play.²⁷

Talar injuries are characterized by persistent pain

Injuries to the talus commonly occur at the same time as ankle sprains and may cause persistent pain, even after the sprain has healed.²⁸ Evidence suggests that up to 90% of residual pain is related to an underlying cartilage injury.^29,30 Most talar injuries are associated with the disruption of the cartilage overlaying the talar dome, which may lead to osteochondritis dissecans.²⁹ Subtle talus fractures are also a concern after an acute ankle injury.

Osteochondral lesions are associated with a dull ankle pain deep in a location with a prior ankle injury; in some cases, the pain will become chronic.³¹ Physical exam findings typically include ankle joint effusion with localized tenderness around the joint.³¹

Ankle radiographs are insensitive for identifying osteochondral lesions, and MRI is recommended for evaluating suspected lesions.^29,31 Treatment varies, depending on symptoms and severity. Patients with minimal symptoms may be treated conservatively; however, high failure rates have been reported.³² Surgical treatment depends on the size and site of the lesion and the degree of cartilage injury, and surgical consultation is recommended.³¹

Fractures of the talar dome (FIGURE 2) may be either medial or lateral and are often the result of inversion ankle injuries.¹⁴ History and clinical findings vary depending on the type of fracture.

FIGURE 2
Talar dome injuries often result from inversion ankle injuries

As with osteochondral lesions, ankle radiographs may fail to identify talus fractures. Computed tomography (CT) should be used to evaluate acute fractures of the talus, as CT scan is better able to define displacement, size, and intra-articular involvement.³³ Talar fractures may be managed conservatively with immobilization and nonweight-bearing for 4 to 6 weeks, but specialty consultation should be considered.14,33

A tarsal coalition—an incomplete, congenital separation of the bones, occasionally involving the talus and the calcaneus—can also be a cause of persistent pain after a sprain.²⁸ Physical exam typically demonstrates decreased range of motion in the subtalar or transverse tarsal joint. Radiographs may identify the coalition, but MRI or CT scan provides optimal visualization. Immobilization for 6 weeks is the recommended initial treatment, but if that fails, surgical excision or fusion may be necessary.

Peroneal tendon injuries may cause ankle instability

Peroneal tendon injuries, which include strains, subluxation, dislocation, and tears of one or both of the peroneal tendons, are often caused by ankle inversion similar to that of an uncomplicated sprain. Subsequent ankle instability may result from untreated peroneal tendon injuries.³⁴ Peroneal tendon subluxation accounts for a very small number (0.3%-0.5%) of traumatic ankle injuries.³⁵

Peroneal tendon injuries often occur during sports that involve frequent lateral movement or cutting—eg, football, basketball, and soccer—and are often caused by sudden dorsiflexion of the inverted foot, with coincident contraction of the peroneal muscles.^36,37 This mechanism can disrupt the superior peroneal retinaculum, leading to recurrent subluxation or dislocation and subsequent ankle instability.^36,38 Chronic subluxation can also result in longitudinal tears of the peroneal tendons, especially of the peroneus brevis.^36,38,39

Patients with peroneal tendon injuries may report a “pop” at the time of injury. Pain is typically located posterior to the lateral malleolus, and recurrent subluxation is often described as a “snapping” around the lateral ankle during athletic activities.^37,38 Instability is common in patients with subacute or chronic peroneal tendon injuries, especially on uneven surfaces.³⁸

Acute peroneal tendon injuries cause posterolateral ankle pain, swelling, and weakness; exam findings include tenderness along the course of the peroneal tendons with associated edema.³⁷ Subluxation or dislocation of the peroneal brevis tendon may be confirmed by placing the foot in plantar flexion and inversion and asking the patient to forcibly dorsiflex and evert the injured ankle.

Plain radiographs are usually normal in an isolated injury to the peroneal tendons. A fracture of the posterolateral margin of the fibula is a rare finding but indicates disruption of the peroneal retinaculum.³⁶ MRI provides the best imaging for peroneal tendons and the stabilizing retinaculum, although a CT scan can provide detailed bony anatomy when subtle fractures are suspected or additional evaluation is needed.

Subluxation or dislocation indicate a need for surgery
Conservative management is recommended for peroneal tendon strains, but surgical treatment is increasingly recommended for subluxation or dislocation, especially if the problem is recurrent.^36,37 Conservative treatment consists of short-term immobilization with a walking boot or brace, followed by physical therapy to improve strength and motion. Surgical treatment of subluxation and dislocation by stabilizing the peroneal tendons within the peroneal groove has been shown to provide lasting stability and improvement.^37,38,40,41

CORRESPONDENCE Scott Hall, MD, University of Nevada-Reno, Brigham Building 316, Reno, NV 89557; [email protected]

Ankle sprain, one of the more common injuries that primary care physicians evaluate, is usually managed with conservative treatment. Not uncommonly, however, lateral ankle sprain is diagnosed without consideration of a broader differential diagnosis.

Contributing to the problem is the fact that the clinical presentation of some fractures and tendon injuries is similar to that of a routine sprain. In some cases, the mechanism of injury—sprains are usually caused by excessive inversion of the ankle on a plantar-flexed foot—is similar, as well. What’s more, radiographs are often omitted or misinterpreted.

In the pages that follow, we highlight 4 commonly misdiagnosed injuries: fifth metatarsal fractures, navicular fractures, talar dome lesions, and peroneal tendon injuries. These injuries should be included in the differential diagnosis of an acute ankle injury—or a subacute foot or ankle injury that fails to respond as expected. Prompt recognition and appropriate treatment result in optimal outcomes. When foot and ankle fractures and tendon injuries are misdiagnosed (or simply missed) and do not receive adequate treatment, long-term morbidity, including frequent reinjury and disability, may result.¹

Are x-rays needed? Turn to the Ottawa rules

Ankle sprains represent a disruption in a ligament supporting a joint, and result in pain, edema, and ecchymosis, and often affect a patient’s ability to bear weight. While uncomplicated sprains generally heal with conservative treatment, other common foot and ankle injuries may require a different approach.

The Ottawa foot and ankle rules are an evidence-based guide to the use of initial radiographs after acute ankle injury (TABLE 1).^2-4 Pain—near the malleoli (for the ankle) or in the midfoot—is the key criterion, but x-rays are recommended only if at least one other specified criterion is also met. With a sensitivity of nearly 100%, the rules have been shown to reliably exclude, and diagnose, ankle and midfoot fractures in children >5 years and adults.^2,5

Table 1
Ottawa ankle and foot rules^2-4

Fifth metatarsal fractures are easily missed

The mechanism of injury for a fifth metatarsal fracture is often similar to that of a lateral ankle sprain. In addition, isolated ankle radiographs may not adequately evaluate the fifth metatarsal, which increases the risk of misdiagnosis.⁶

3 types of fifth metatarsal fractures
Fifth metatarsal fractures involve one of the following:

1. an avulsion fracture, caused by the pull of the plantar aponeurosis and the peroneus brevis tendon at the tuberosity of the bone
2. a Jones fracture, at the base of the fourth and fifth metatarsal (FIGURE 1)
3. a shaft fracture, distal to the fifth metatarsal joint in the proximal diaphysis.^6-8

FIGURE 1
Jones fractures heal slowly

While avulsion fractures are generally the result of an inversion ankle injury, Jones fractures are usually caused by a large adductive force applied to the forefoot on a plantar-flexed ankle.⁶ Shaft fractures, also known as diaphyseal stress fractures, are overuse injuries from chronic overload, usually after a sudden increase in running or walking.⁹

Patients with fifth metatarsal fractures typically have tenderness with palpation over the area of injury, with edema and ecchymosis when the injury is acute. Evidence-based guidelines recommend x-rays of the foot, including anteroposterior (AP), lateral, and oblique views.^2-4 One study supports the use of an additional x-ray—an AP view of the ankle, including the base of the fifth metatarsal—if clinical suspicion is high and initial radiographs are negative or inconclusive.¹⁰

Shaft fractures may not be seen on x-rays in the first 3 weeks, but a periosteal reaction or linear lucency near the symptomatic area may be noticeable on radiographs taken at a later date.¹¹ If this overuse injury seems likely but does not show up on the initial x-rays, however, magnetic resonance imaging (MRI) or a technetium bone scan can reliably identify a stress fracture.⁹

How to treat, when to refer
Treatment of fifth metatarsal fractures range from conservative to surgical, depending on the type (and extent) of injury (TABLE 2).^1,5,6,12-14

TABLE 2

Nondisplaced avulsion fractures can be treated conservatively, with relative immobilization. In one prospective study, the use of a stiff-soled shoe, with weight-bearing as tolerated, was associated with excellent long-term outcomes.¹¹ Orthopedic referral for probable reduction and fixation is indicated for avulsion fractures that are comminuted or >2 mm displaced, or have >30% involvement of the cubometatarsal joint.^15,16

Jones fractures are known for prolonged healing and nonunion, as well as a high rate of complications. If the fracture is nondisplaced, start with conservative treatment, consisting of nonweight-bearing immobilization for 6 to 8 weeks, with additional immobilization dependent on radiographs. One randomized controlled trial of patients with Jones fractures showed a relatively high failure rate (44%) with casting; patients for whom casting was successful still had a median time to bony union of 15 weeks.¹⁷ Specialty consultation may be needed when there is fracture displacement, absence of bony union, or high clinical concern.^6,17

Is your patient an athlete? Surgical fixation is favored for injured athletes with Jones fractures because failure rates are lower and both clinical union and return to play are shorter.^18,19 In a case series involving 23 athletic patients with Jones fractures, the success rate for immediate surgical screw fixation approached 100% within 6 to 8 weeks.¹⁸

Nondisplaced shaft fractures may be treated conservatively, with 6 to 8 weeks of immobilization with a protective orthosis. An orthopedic referral is recommended for patients whose fractures have >3 mm displacement or >10 degree angulation.¹⁵

Navicular fractures are overuse injuries

The navicular is predisposed to stress injury because the central third of the bone is relatively avascular. In addition, the navicular is the area of greatest stress and impingement between the talus and cuneiform bones during repetitive foot strikes.^12,20 Navicular fractures occur predominantly in track and field athletes.¹²

Patients presenting with a navicular stress fracture often report a gradual onset of vague dorsal midfoot pain associated with their workout.¹⁷ Examination typically reveals tenderness on palpation over the dorsal aspect of the navicular; passive eversion and active inversion may be painful, but edema and ecchymosis are usually absent.²¹

When pain is elicited by palpation of the navicular, radiographs are recommended.^2,6 X-rays have a relatively low sensitivity (33%), however, for detecting acute navicular stress fractures. If initial radiographs are negative but there is a high clinical suspicion, advanced studies—with either MRI or a technetium bone scan—are recommended for a definitive diagnosis.^12,22 While both are highly sensitive for navicular stress fractures, MRI provides greater specificity and anatomic detail.²³

Most navicular fractures are nondisplaced
Nondisplaced navicular fractures can be treated conservatively, with nonweight-bearing immobilization for 6 to 8 weeks followed by progressive activity.²⁴ Prospective studies have found that conservative treatment has a high success rate, with athletes usually able to return to play within 6 months.^22,24,25 If tenderness remains after 6 to 8 weeks of immobilization, treatment choices are continued immobilization with no weight-bearing or orthopedic referral.²⁶

Referral is indicated for navicular fractures that are comminuted or displaced, or involve more than one bone cortex.²⁶ Surgical screw fixation may be recommended for navicular stress fractures in selected athletes because of its high success rate—and likelihood of an earlier return to play.²⁷

Talar injuries are characterized by persistent pain

Injuries to the talus commonly occur at the same time as ankle sprains and may cause persistent pain, even after the sprain has healed.²⁸ Evidence suggests that up to 90% of residual pain is related to an underlying cartilage injury.^29,30 Most talar injuries are associated with the disruption of the cartilage overlaying the talar dome, which may lead to osteochondritis dissecans.²⁹ Subtle talus fractures are also a concern after an acute ankle injury.

Osteochondral lesions are associated with a dull ankle pain deep in a location with a prior ankle injury; in some cases, the pain will become chronic.³¹ Physical exam findings typically include ankle joint effusion with localized tenderness around the joint.³¹

Ankle radiographs are insensitive for identifying osteochondral lesions, and MRI is recommended for evaluating suspected lesions.^29,31 Treatment varies, depending on symptoms and severity. Patients with minimal symptoms may be treated conservatively; however, high failure rates have been reported.³² Surgical treatment depends on the size and site of the lesion and the degree of cartilage injury, and surgical consultation is recommended.³¹

Fractures of the talar dome (FIGURE 2) may be either medial or lateral and are often the result of inversion ankle injuries.¹⁴ History and clinical findings vary depending on the type of fracture.

FIGURE 2
Talar dome injuries often result from inversion ankle injuries

As with osteochondral lesions, ankle radiographs may fail to identify talus fractures. Computed tomography (CT) should be used to evaluate acute fractures of the talus, as CT scan is better able to define displacement, size, and intra-articular involvement.³³ Talar fractures may be managed conservatively with immobilization and nonweight-bearing for 4 to 6 weeks, but specialty consultation should be considered.14,33

A tarsal coalition—an incomplete, congenital separation of the bones, occasionally involving the talus and the calcaneus—can also be a cause of persistent pain after a sprain.²⁸ Physical exam typically demonstrates decreased range of motion in the subtalar or transverse tarsal joint. Radiographs may identify the coalition, but MRI or CT scan provides optimal visualization. Immobilization for 6 weeks is the recommended initial treatment, but if that fails, surgical excision or fusion may be necessary.

Peroneal tendon injuries may cause ankle instability

Peroneal tendon injuries, which include strains, subluxation, dislocation, and tears of one or both of the peroneal tendons, are often caused by ankle inversion similar to that of an uncomplicated sprain. Subsequent ankle instability may result from untreated peroneal tendon injuries.³⁴ Peroneal tendon subluxation accounts for a very small number (0.3%-0.5%) of traumatic ankle injuries.³⁵

Peroneal tendon injuries often occur during sports that involve frequent lateral movement or cutting—eg, football, basketball, and soccer—and are often caused by sudden dorsiflexion of the inverted foot, with coincident contraction of the peroneal muscles.^36,37 This mechanism can disrupt the superior peroneal retinaculum, leading to recurrent subluxation or dislocation and subsequent ankle instability.^36,38 Chronic subluxation can also result in longitudinal tears of the peroneal tendons, especially of the peroneus brevis.^36,38,39

Patients with peroneal tendon injuries may report a “pop” at the time of injury. Pain is typically located posterior to the lateral malleolus, and recurrent subluxation is often described as a “snapping” around the lateral ankle during athletic activities.^37,38 Instability is common in patients with subacute or chronic peroneal tendon injuries, especially on uneven surfaces.³⁸

Acute peroneal tendon injuries cause posterolateral ankle pain, swelling, and weakness; exam findings include tenderness along the course of the peroneal tendons with associated edema.³⁷ Subluxation or dislocation of the peroneal brevis tendon may be confirmed by placing the foot in plantar flexion and inversion and asking the patient to forcibly dorsiflex and evert the injured ankle.

Plain radiographs are usually normal in an isolated injury to the peroneal tendons. A fracture of the posterolateral margin of the fibula is a rare finding but indicates disruption of the peroneal retinaculum.³⁶ MRI provides the best imaging for peroneal tendons and the stabilizing retinaculum, although a CT scan can provide detailed bony anatomy when subtle fractures are suspected or additional evaluation is needed.

Subluxation or dislocation indicate a need for surgery
Conservative management is recommended for peroneal tendon strains, but surgical treatment is increasingly recommended for subluxation or dislocation, especially if the problem is recurrent.^36,37 Conservative treatment consists of short-term immobilization with a walking boot or brace, followed by physical therapy to improve strength and motion. Surgical treatment of subluxation and dislocation by stabilizing the peroneal tendons within the peroneal groove has been shown to provide lasting stability and improvement.^37,38,40,41

CORRESPONDENCE Scott Hall, MD, University of Nevada-Reno, Brigham Building 316, Reno, NV 89557; [email protected]