Applied Evidence

When a patient presents with unilateral hearing loss—especially with a report of gradual onset— that is accompanied by tinnitus, consider an acoustic neuroma (AN). Also known as vestibular schwannoma, ANs represent just 9% of all intracranial tumors. But its relatively slow growth rate can insidiously lead to impaired quality of life and even complete hearing loss.¹ Vestibular symptoms, such as vertigo, may be present. And in some instances, tinnitus may be absent. Even without hearing loss or other symptoms, ANs may be detected incidentally on magnetic resonance imaging (MRI) performed for other reasons. In this article, I describe the diagnostic work-up for AN and 3 options for treatment.

How acoustic neuroma arises

ANs evolve from the abnormal growth and proliferation of Schwann cells, or neurolemmocytes, at their junction with glial cells surrounding the vestibular nerve. ANs represent 80% of all cerebellopontine angle tumors.¹ The incidence in the general population is about 1 in 100,000 people per year, with equal distribution between men and women.¹ Among adults with sensorineural hearing loss, about 1% have ANs.² Tumor growth within the internal auditory canal and resultant compression of cranial nerves VII and VIII causes associated symptoms. Unabated growth can lead to prolapse into the cerebellopontine angle with compression of the brainstem and cerebellum.¹

There are 2 major types of AN. The sporadic type, which will be the focus of this discussion, occurs in 95% of all cases, is unilateral, and usually affects individuals 40 to 60 years old. AN associated with neurofibromatosis type 2 is typically bilateral, autosomal dominant, and usually affects teens and young adults.¹

The only known possible risk factor for the development of AN is the use of cell phones, but data are conflicting. Although 2 meta-analyses did find a correlation between AN and ipsilateral cell phone use >10 years, these studies were limited by possible recall bias and misclassification.^3,4

How acoustic neuroma can present

Slowly progressive, high-frequency, sensori-neural hearing loss is typical for AN. In most cases, hearing loss is unilateral. Nerve compression and stretching from the growing neuroma cause hearing loss of gradual onset.¹ However, up to 25% of patients may present with sudden onset hearing loss due to total occlusion of the internal auditory canal and the artery supplying the cochlea.¹ Tinnitus is reported in up to 70% of patients with AN.¹ The mechanism of injury is the same as for hearing loss.

A feeling of imbalance or unsteadiness occurs in more than 50% of patients with AN.¹ One research group found that vertigo was the more common symptom in patients with smaller tumors, whereas patients with larger tumors complained more of dysequilibrium.¹

Other physical findings can include trigeminal nerve dysfunction (found in 50% of patients with AN, but patients rarely note the absent corneal reflex), facial nerve motor dysfunction (2%), increased intracranial pressure (rare in tumors <3 cm), and brainstem and cerebellar symptoms (rare).¹

Asymptomatic AN. Small tumors may be detected by MRI incidentally before the onset of hearing loss. Such a finding accounts for about 12% of all patients diagnosed with AN.⁵ A 2005 study by Lin et al found the prevalence of incidental AN to be about 2 per 10,000 people.⁶ This is higher than the 1 in 100,000 suggested by epidemiologic studies,⁶ but Lin’s study was performed at a large tertiary center.

Diagnostic evaluation

Contrast MRI is the gold standard for diagnosing AN.² One study did find that a heavily T2-weighted noncontrast scan in the hands of an experienced radiologist reduced the procedural cost and was as effective as contrast MRI in evaluating the VII and VIII cranial nerves within the cerebellopontine angle and internal auditory canal.⁷

Although not as sensitive for small tumors, the auditory brainstem response can be used in certain circumstances. During the initial evaluation, other diagnoses to consider are facial neuroma and jugular foramen tumors.¹

Three options for treatment

The goal of treatment is to slow or eliminate both tumor growth and deterioration in hearing and neurological function. Lin’s study found that 43% of patients with incidental AN had abnormal audiometry findings.⁶ A hearing evaluation may therefore be helpful in guiding patients through a meaningful discussion about prognosis, further testing and consultations, and the 3 therapeutic options—watchful waiting, microsurgery, and stereotactic radiosurgery.⁸

Watchful waiting has been recommended for the elderly and for infirm patients with tumors <1 cm who would be poor candidates for surgery or radiation. In up to 57% of AN cases, no further tumor growth occurs after diagnosis; in about 8% of these cases, tumor regression is noted.⁹ A little more than half of patients will experience further hearing loss.⁹

Unfortunately, there are no prediction rules for determining who is most at risk for tumor growth and hearing loss. A recent study found that conservative management was a cost-effective approach for tumors <1.5 cm in any age group,¹⁰ provided there was no increase in complications from continued tumor growth. This, then, is a third group of patients for whom watchful waiting might be an option.¹⁰ Follow-up MRI can be used as a surveillance tool.^8,9,11

Microsurgery. This option is the oldest and best-studied treatment for AN. Micro-surgery appears to provide the best tumor control, although morbidity and mortality remain risks. A systematic review by Yamakami in 2003 showed that microsurgery completely removed 96% of ANs, with tumor recurrence, mortality, and major disability rates of 1.8%, 0.63%, and 2.9%, respectively.¹² More recent reviews have shown mortality rates of approximately 0.1%.¹³ Surgery usually involves removal of cranial nerve VIII, with the risk of damage to cranial nerve VII. Nerve-sparing procedures are available. Cerebral spinal fluid leaks and meningitis are occasional adverse events. The experience of the surgical team can affect outcome, including complications and cost.¹⁴

Stereotactic radiosurgery. Through the use of sophisticated imaging devices and 3-dimensional treatment-planning computers, stereotactic irradiation allows much more specific targeting of the AN, with significantly less radiation delivered to surrounding healthy tissues.¹⁵ Dynamic beam shaping and intensity modulation provide flexibility and enable delivery of much higher radiation doses to the tumor, resulting in greater control rates and decreased complications. There are 3 delivery technologies: Gamma Knife, proton beam, and specially modified linear accelerators.

Whereas older studies did not provide sufficient evidence to support the use of low-dose over high-dose radiation for long-term control of ANs,¹⁶ a more recent systematic analysis by Yang et al seems to indicate that patients treated with the lower dose (12.5 Gy) did equally as well with better preservation of hearing.¹⁷

Applying the evidence in practice
A large randomized controlled trial comparing these treatment options has yet to be done and, indeed, would be difficult to conduct due to the small number of AN cases, varying surgical expertise among centers, the different treatment goals inherent in the 3 therapies, and the risk involved in each. Evidence to date generally indicates that observation is appropriate for small intracanalicular tumors (<1 cm) in the elderly, medically infirm, or asymptomatic patients who understand and opt for this management approach. For tumors ≥3 cm, evidence supports microsurgery as optimal management.^13,18 Tumors falling between these extremes pose the real challenge.

Over the last 10 years, numerous studies have demonstrated good tumor control with either microsurgery or radiosurgery, but with varying degrees of hearing preservation and permanent nerve injury to the facial and trigeminal nerve. There is also a concern for malignant transformation of AN after radiosurgery, with 8 cases reported in the literature.^8,13,19

Three evidence-based studies in the last 6 years have compared the 2 interventions. In 2002, Nikolopoulos et al reviewed 111 studies and concluded there was insufficient evidence to support one approach over the other.¹⁸ Pollock conducted a prospective cohort study in 2008 that showed superior outcomes in facial movement, hearing preservation, and Health Status Questionnaire subscales for patients undergoing stereotactic radiosurgery.¹³ This study was limited to nonfractionated radiosurgery, and follow-up varied from 12 to 62 months.

In 2009, a Norwegian prospective study of 91 patients reported better facial nerve and hearing outcomes from radiosurgery for medium and small tumors. This study was well performed, but it looked at only a small, non-randomized population.²⁰ The same author in 2005 had found that, from the patient perspective, cranial nerve function and overall outcomes were better in the radiosurgery group.²¹

Stereotactic radiosurgery does confer lower risks for acute treatment complications than microsurgery, and therefore can be advantageous for patients who are older, infirm, require anticoagulant therapy, are otherwise poor candidates for surgery or anesthesia, or have serviceable hearing and opt for a more conservative approach. Other advantages of stereotactic radiosurgery over microsurgery are its lower cost and its preferred use in patients with permanent hearing loss in the unaffected ear. These advantages of stereotactic radiosurgery may, however, be offset in the long term by cranial neuropathy and eventual hearing loss, which can be comparable to the experiences of patients after microsurgery.⁸

Based on these limited studies, patient-oriented outcomes can be comparable between stereotactic radiosurgery and micro-surgery in medium-sized tumors (1-2.9 cm), depending on the patient’s clinical presentation. Hearing and preservation of nerve VII are more likely with radiosurgery than with microsurgery. But several real and potentially large confounding factors limit this interpretation. How does one define tumor control in light of AN’s inherently slow growth? What about reports of less than optimal microsurgery outcomes if previous radiosurgery has failed? And, although it is small, a definite risk of malignant transformation exists after irradiation.^8,13

For patients to make good decisions, family physicians need to be aware of these issues when discussing treatment options. To aid in patient education and decision making, there is a helpful algorithm from the International RadioSurgery Association in Stereotactic radiosurgery for patients with vestibular schwannomas (available online at http://www.irsa.org/ANGuideline.pdf).¹⁵

Follow-up

Follow-up depends on the treatment modality, but usually relies on MRI to document tumor behavior. MRI studies are typically performed at predetermined intervals such as 6 months and 1, 2, and 4 years. For patients with preserved serviceable hearing, audiograms are recommended at intervals coinciding with clinical and neuroimaging re-evaluations. Tumors proven to be stable over 4 to 5 years can subsequently be reassessed at 2- to 4-year intervals.¹⁵

Enabling recovery. One of the most important educational opportunities involves early vestibular rehabilitation to facilitate recovery of postural control after treatment. Research has shown benefit from customized vestibular rehabilitation in addition to instructions that stress the need to engage in some type of activity, such as walking or other modes of exercise.²²

CORRESPONDENCE
Robert McDonald, MD, Spartanburg Family Medicine Residency Program, 853 N. Church Street, Suite 510, Spartanburg, SC 29303; rmcdonald@srhs.com

When a patient presents with unilateral hearing loss—especially with a report of gradual onset— that is accompanied by tinnitus, consider an acoustic neuroma (AN). Also known as vestibular schwannoma, ANs represent just 9% of all intracranial tumors. But its relatively slow growth rate can insidiously lead to impaired quality of life and even complete hearing loss.¹ Vestibular symptoms, such as vertigo, may be present. And in some instances, tinnitus may be absent. Even without hearing loss or other symptoms, ANs may be detected incidentally on magnetic resonance imaging (MRI) performed for other reasons. In this article, I describe the diagnostic work-up for AN and 3 options for treatment.

How acoustic neuroma arises

ANs evolve from the abnormal growth and proliferation of Schwann cells, or neurolemmocytes, at their junction with glial cells surrounding the vestibular nerve. ANs represent 80% of all cerebellopontine angle tumors.¹ The incidence in the general population is about 1 in 100,000 people per year, with equal distribution between men and women.¹ Among adults with sensorineural hearing loss, about 1% have ANs.² Tumor growth within the internal auditory canal and resultant compression of cranial nerves VII and VIII causes associated symptoms. Unabated growth can lead to prolapse into the cerebellopontine angle with compression of the brainstem and cerebellum.¹

There are 2 major types of AN. The sporadic type, which will be the focus of this discussion, occurs in 95% of all cases, is unilateral, and usually affects individuals 40 to 60 years old. AN associated with neurofibromatosis type 2 is typically bilateral, autosomal dominant, and usually affects teens and young adults.¹

The only known possible risk factor for the development of AN is the use of cell phones, but data are conflicting. Although 2 meta-analyses did find a correlation between AN and ipsilateral cell phone use >10 years, these studies were limited by possible recall bias and misclassification.^3,4

How acoustic neuroma can present

Slowly progressive, high-frequency, sensori-neural hearing loss is typical for AN. In most cases, hearing loss is unilateral. Nerve compression and stretching from the growing neuroma cause hearing loss of gradual onset.¹ However, up to 25% of patients may present with sudden onset hearing loss due to total occlusion of the internal auditory canal and the artery supplying the cochlea.¹ Tinnitus is reported in up to 70% of patients with AN.¹ The mechanism of injury is the same as for hearing loss.

A feeling of imbalance or unsteadiness occurs in more than 50% of patients with AN.¹ One research group found that vertigo was the more common symptom in patients with smaller tumors, whereas patients with larger tumors complained more of dysequilibrium.¹

Other physical findings can include trigeminal nerve dysfunction (found in 50% of patients with AN, but patients rarely note the absent corneal reflex), facial nerve motor dysfunction (2%), increased intracranial pressure (rare in tumors <3 cm), and brainstem and cerebellar symptoms (rare).¹

Asymptomatic AN. Small tumors may be detected by MRI incidentally before the onset of hearing loss. Such a finding accounts for about 12% of all patients diagnosed with AN.⁵ A 2005 study by Lin et al found the prevalence of incidental AN to be about 2 per 10,000 people.⁶ This is higher than the 1 in 100,000 suggested by epidemiologic studies,⁶ but Lin’s study was performed at a large tertiary center.

Diagnostic evaluation

Contrast MRI is the gold standard for diagnosing AN.² One study did find that a heavily T2-weighted noncontrast scan in the hands of an experienced radiologist reduced the procedural cost and was as effective as contrast MRI in evaluating the VII and VIII cranial nerves within the cerebellopontine angle and internal auditory canal.⁷

Although not as sensitive for small tumors, the auditory brainstem response can be used in certain circumstances. During the initial evaluation, other diagnoses to consider are facial neuroma and jugular foramen tumors.¹

Three options for treatment

The goal of treatment is to slow or eliminate both tumor growth and deterioration in hearing and neurological function. Lin’s study found that 43% of patients with incidental AN had abnormal audiometry findings.⁶ A hearing evaluation may therefore be helpful in guiding patients through a meaningful discussion about prognosis, further testing and consultations, and the 3 therapeutic options—watchful waiting, microsurgery, and stereotactic radiosurgery.⁸

Watchful waiting has been recommended for the elderly and for infirm patients with tumors <1 cm who would be poor candidates for surgery or radiation. In up to 57% of AN cases, no further tumor growth occurs after diagnosis; in about 8% of these cases, tumor regression is noted.⁹ A little more than half of patients will experience further hearing loss.⁹

Unfortunately, there are no prediction rules for determining who is most at risk for tumor growth and hearing loss. A recent study found that conservative management was a cost-effective approach for tumors <1.5 cm in any age group,¹⁰ provided there was no increase in complications from continued tumor growth. This, then, is a third group of patients for whom watchful waiting might be an option.¹⁰ Follow-up MRI can be used as a surveillance tool.^8,9,11

Microsurgery. This option is the oldest and best-studied treatment for AN. Micro-surgery appears to provide the best tumor control, although morbidity and mortality remain risks. A systematic review by Yamakami in 2003 showed that microsurgery completely removed 96% of ANs, with tumor recurrence, mortality, and major disability rates of 1.8%, 0.63%, and 2.9%, respectively.¹² More recent reviews have shown mortality rates of approximately 0.1%.¹³ Surgery usually involves removal of cranial nerve VIII, with the risk of damage to cranial nerve VII. Nerve-sparing procedures are available. Cerebral spinal fluid leaks and meningitis are occasional adverse events. The experience of the surgical team can affect outcome, including complications and cost.¹⁴

Stereotactic radiosurgery. Through the use of sophisticated imaging devices and 3-dimensional treatment-planning computers, stereotactic irradiation allows much more specific targeting of the AN, with significantly less radiation delivered to surrounding healthy tissues.¹⁵ Dynamic beam shaping and intensity modulation provide flexibility and enable delivery of much higher radiation doses to the tumor, resulting in greater control rates and decreased complications. There are 3 delivery technologies: Gamma Knife, proton beam, and specially modified linear accelerators.

Whereas older studies did not provide sufficient evidence to support the use of low-dose over high-dose radiation for long-term control of ANs,¹⁶ a more recent systematic analysis by Yang et al seems to indicate that patients treated with the lower dose (12.5 Gy) did equally as well with better preservation of hearing.¹⁷

Applying the evidence in practice
A large randomized controlled trial comparing these treatment options has yet to be done and, indeed, would be difficult to conduct due to the small number of AN cases, varying surgical expertise among centers, the different treatment goals inherent in the 3 therapies, and the risk involved in each. Evidence to date generally indicates that observation is appropriate for small intracanalicular tumors (<1 cm) in the elderly, medically infirm, or asymptomatic patients who understand and opt for this management approach. For tumors ≥3 cm, evidence supports microsurgery as optimal management.^13,18 Tumors falling between these extremes pose the real challenge.

Over the last 10 years, numerous studies have demonstrated good tumor control with either microsurgery or radiosurgery, but with varying degrees of hearing preservation and permanent nerve injury to the facial and trigeminal nerve. There is also a concern for malignant transformation of AN after radiosurgery, with 8 cases reported in the literature.^8,13,19

Three evidence-based studies in the last 6 years have compared the 2 interventions. In 2002, Nikolopoulos et al reviewed 111 studies and concluded there was insufficient evidence to support one approach over the other.¹⁸ Pollock conducted a prospective cohort study in 2008 that showed superior outcomes in facial movement, hearing preservation, and Health Status Questionnaire subscales for patients undergoing stereotactic radiosurgery.¹³ This study was limited to nonfractionated radiosurgery, and follow-up varied from 12 to 62 months.

In 2009, a Norwegian prospective study of 91 patients reported better facial nerve and hearing outcomes from radiosurgery for medium and small tumors. This study was well performed, but it looked at only a small, non-randomized population.²⁰ The same author in 2005 had found that, from the patient perspective, cranial nerve function and overall outcomes were better in the radiosurgery group.²¹

Stereotactic radiosurgery does confer lower risks for acute treatment complications than microsurgery, and therefore can be advantageous for patients who are older, infirm, require anticoagulant therapy, are otherwise poor candidates for surgery or anesthesia, or have serviceable hearing and opt for a more conservative approach. Other advantages of stereotactic radiosurgery over microsurgery are its lower cost and its preferred use in patients with permanent hearing loss in the unaffected ear. These advantages of stereotactic radiosurgery may, however, be offset in the long term by cranial neuropathy and eventual hearing loss, which can be comparable to the experiences of patients after microsurgery.⁸

Based on these limited studies, patient-oriented outcomes can be comparable between stereotactic radiosurgery and micro-surgery in medium-sized tumors (1-2.9 cm), depending on the patient’s clinical presentation. Hearing and preservation of nerve VII are more likely with radiosurgery than with microsurgery. But several real and potentially large confounding factors limit this interpretation. How does one define tumor control in light of AN’s inherently slow growth? What about reports of less than optimal microsurgery outcomes if previous radiosurgery has failed? And, although it is small, a definite risk of malignant transformation exists after irradiation.^8,13

For patients to make good decisions, family physicians need to be aware of these issues when discussing treatment options. To aid in patient education and decision making, there is a helpful algorithm from the International RadioSurgery Association in Stereotactic radiosurgery for patients with vestibular schwannomas (available online at http://www.irsa.org/ANGuideline.pdf).¹⁵

Follow-up

Follow-up depends on the treatment modality, but usually relies on MRI to document tumor behavior. MRI studies are typically performed at predetermined intervals such as 6 months and 1, 2, and 4 years. For patients with preserved serviceable hearing, audiograms are recommended at intervals coinciding with clinical and neuroimaging re-evaluations. Tumors proven to be stable over 4 to 5 years can subsequently be reassessed at 2- to 4-year intervals.¹⁵

Enabling recovery. One of the most important educational opportunities involves early vestibular rehabilitation to facilitate recovery of postural control after treatment. Research has shown benefit from customized vestibular rehabilitation in addition to instructions that stress the need to engage in some type of activity, such as walking or other modes of exercise.²²

CORRESPONDENCE
Robert McDonald, MD, Spartanburg Family Medicine Residency Program, 853 N. Church Street, Suite 510, Spartanburg, SC 29303; rmcdonald@srhs.com

When a patient presents with unilateral hearing loss—especially with a report of gradual onset— that is accompanied by tinnitus, consider an acoustic neuroma (AN). Also known as vestibular schwannoma, ANs represent just 9% of all intracranial tumors. But its relatively slow growth rate can insidiously lead to impaired quality of life and even complete hearing loss.¹ Vestibular symptoms, such as vertigo, may be present. And in some instances, tinnitus may be absent. Even without hearing loss or other symptoms, ANs may be detected incidentally on magnetic resonance imaging (MRI) performed for other reasons. In this article, I describe the diagnostic work-up for AN and 3 options for treatment.

How acoustic neuroma arises

ANs evolve from the abnormal growth and proliferation of Schwann cells, or neurolemmocytes, at their junction with glial cells surrounding the vestibular nerve. ANs represent 80% of all cerebellopontine angle tumors.¹ The incidence in the general population is about 1 in 100,000 people per year, with equal distribution between men and women.¹ Among adults with sensorineural hearing loss, about 1% have ANs.² Tumor growth within the internal auditory canal and resultant compression of cranial nerves VII and VIII causes associated symptoms. Unabated growth can lead to prolapse into the cerebellopontine angle with compression of the brainstem and cerebellum.¹

There are 2 major types of AN. The sporadic type, which will be the focus of this discussion, occurs in 95% of all cases, is unilateral, and usually affects individuals 40 to 60 years old. AN associated with neurofibromatosis type 2 is typically bilateral, autosomal dominant, and usually affects teens and young adults.¹

The only known possible risk factor for the development of AN is the use of cell phones, but data are conflicting. Although 2 meta-analyses did find a correlation between AN and ipsilateral cell phone use >10 years, these studies were limited by possible recall bias and misclassification.^3,4

How acoustic neuroma can present

Slowly progressive, high-frequency, sensori-neural hearing loss is typical for AN. In most cases, hearing loss is unilateral. Nerve compression and stretching from the growing neuroma cause hearing loss of gradual onset.¹ However, up to 25% of patients may present with sudden onset hearing loss due to total occlusion of the internal auditory canal and the artery supplying the cochlea.¹ Tinnitus is reported in up to 70% of patients with AN.¹ The mechanism of injury is the same as for hearing loss.

A feeling of imbalance or unsteadiness occurs in more than 50% of patients with AN.¹ One research group found that vertigo was the more common symptom in patients with smaller tumors, whereas patients with larger tumors complained more of dysequilibrium.¹

Other physical findings can include trigeminal nerve dysfunction (found in 50% of patients with AN, but patients rarely note the absent corneal reflex), facial nerve motor dysfunction (2%), increased intracranial pressure (rare in tumors <3 cm), and brainstem and cerebellar symptoms (rare).¹

Asymptomatic AN. Small tumors may be detected by MRI incidentally before the onset of hearing loss. Such a finding accounts for about 12% of all patients diagnosed with AN.⁵ A 2005 study by Lin et al found the prevalence of incidental AN to be about 2 per 10,000 people.⁶ This is higher than the 1 in 100,000 suggested by epidemiologic studies,⁶ but Lin’s study was performed at a large tertiary center.

Diagnostic evaluation

Contrast MRI is the gold standard for diagnosing AN.² One study did find that a heavily T2-weighted noncontrast scan in the hands of an experienced radiologist reduced the procedural cost and was as effective as contrast MRI in evaluating the VII and VIII cranial nerves within the cerebellopontine angle and internal auditory canal.⁷

Although not as sensitive for small tumors, the auditory brainstem response can be used in certain circumstances. During the initial evaluation, other diagnoses to consider are facial neuroma and jugular foramen tumors.¹

Three options for treatment

The goal of treatment is to slow or eliminate both tumor growth and deterioration in hearing and neurological function. Lin’s study found that 43% of patients with incidental AN had abnormal audiometry findings.⁶ A hearing evaluation may therefore be helpful in guiding patients through a meaningful discussion about prognosis, further testing and consultations, and the 3 therapeutic options—watchful waiting, microsurgery, and stereotactic radiosurgery.⁸

Watchful waiting has been recommended for the elderly and for infirm patients with tumors <1 cm who would be poor candidates for surgery or radiation. In up to 57% of AN cases, no further tumor growth occurs after diagnosis; in about 8% of these cases, tumor regression is noted.⁹ A little more than half of patients will experience further hearing loss.⁹

Unfortunately, there are no prediction rules for determining who is most at risk for tumor growth and hearing loss. A recent study found that conservative management was a cost-effective approach for tumors <1.5 cm in any age group,¹⁰ provided there was no increase in complications from continued tumor growth. This, then, is a third group of patients for whom watchful waiting might be an option.¹⁰ Follow-up MRI can be used as a surveillance tool.^8,9,11

Microsurgery. This option is the oldest and best-studied treatment for AN. Micro-surgery appears to provide the best tumor control, although morbidity and mortality remain risks. A systematic review by Yamakami in 2003 showed that microsurgery completely removed 96% of ANs, with tumor recurrence, mortality, and major disability rates of 1.8%, 0.63%, and 2.9%, respectively.¹² More recent reviews have shown mortality rates of approximately 0.1%.¹³ Surgery usually involves removal of cranial nerve VIII, with the risk of damage to cranial nerve VII. Nerve-sparing procedures are available. Cerebral spinal fluid leaks and meningitis are occasional adverse events. The experience of the surgical team can affect outcome, including complications and cost.¹⁴

Stereotactic radiosurgery. Through the use of sophisticated imaging devices and 3-dimensional treatment-planning computers, stereotactic irradiation allows much more specific targeting of the AN, with significantly less radiation delivered to surrounding healthy tissues.¹⁵ Dynamic beam shaping and intensity modulation provide flexibility and enable delivery of much higher radiation doses to the tumor, resulting in greater control rates and decreased complications. There are 3 delivery technologies: Gamma Knife, proton beam, and specially modified linear accelerators.

Whereas older studies did not provide sufficient evidence to support the use of low-dose over high-dose radiation for long-term control of ANs,¹⁶ a more recent systematic analysis by Yang et al seems to indicate that patients treated with the lower dose (12.5 Gy) did equally as well with better preservation of hearing.¹⁷

Applying the evidence in practice
A large randomized controlled trial comparing these treatment options has yet to be done and, indeed, would be difficult to conduct due to the small number of AN cases, varying surgical expertise among centers, the different treatment goals inherent in the 3 therapies, and the risk involved in each. Evidence to date generally indicates that observation is appropriate for small intracanalicular tumors (<1 cm) in the elderly, medically infirm, or asymptomatic patients who understand and opt for this management approach. For tumors ≥3 cm, evidence supports microsurgery as optimal management.^13,18 Tumors falling between these extremes pose the real challenge.

Over the last 10 years, numerous studies have demonstrated good tumor control with either microsurgery or radiosurgery, but with varying degrees of hearing preservation and permanent nerve injury to the facial and trigeminal nerve. There is also a concern for malignant transformation of AN after radiosurgery, with 8 cases reported in the literature.^8,13,19

Three evidence-based studies in the last 6 years have compared the 2 interventions. In 2002, Nikolopoulos et al reviewed 111 studies and concluded there was insufficient evidence to support one approach over the other.¹⁸ Pollock conducted a prospective cohort study in 2008 that showed superior outcomes in facial movement, hearing preservation, and Health Status Questionnaire subscales for patients undergoing stereotactic radiosurgery.¹³ This study was limited to nonfractionated radiosurgery, and follow-up varied from 12 to 62 months.

In 2009, a Norwegian prospective study of 91 patients reported better facial nerve and hearing outcomes from radiosurgery for medium and small tumors. This study was well performed, but it looked at only a small, non-randomized population.²⁰ The same author in 2005 had found that, from the patient perspective, cranial nerve function and overall outcomes were better in the radiosurgery group.²¹

Stereotactic radiosurgery does confer lower risks for acute treatment complications than microsurgery, and therefore can be advantageous for patients who are older, infirm, require anticoagulant therapy, are otherwise poor candidates for surgery or anesthesia, or have serviceable hearing and opt for a more conservative approach. Other advantages of stereotactic radiosurgery over microsurgery are its lower cost and its preferred use in patients with permanent hearing loss in the unaffected ear. These advantages of stereotactic radiosurgery may, however, be offset in the long term by cranial neuropathy and eventual hearing loss, which can be comparable to the experiences of patients after microsurgery.⁸

Based on these limited studies, patient-oriented outcomes can be comparable between stereotactic radiosurgery and micro-surgery in medium-sized tumors (1-2.9 cm), depending on the patient’s clinical presentation. Hearing and preservation of nerve VII are more likely with radiosurgery than with microsurgery. But several real and potentially large confounding factors limit this interpretation. How does one define tumor control in light of AN’s inherently slow growth? What about reports of less than optimal microsurgery outcomes if previous radiosurgery has failed? And, although it is small, a definite risk of malignant transformation exists after irradiation.^8,13

For patients to make good decisions, family physicians need to be aware of these issues when discussing treatment options. To aid in patient education and decision making, there is a helpful algorithm from the International RadioSurgery Association in Stereotactic radiosurgery for patients with vestibular schwannomas (available online at http://www.irsa.org/ANGuideline.pdf).¹⁵

Follow-up

Follow-up depends on the treatment modality, but usually relies on MRI to document tumor behavior. MRI studies are typically performed at predetermined intervals such as 6 months and 1, 2, and 4 years. For patients with preserved serviceable hearing, audiograms are recommended at intervals coinciding with clinical and neuroimaging re-evaluations. Tumors proven to be stable over 4 to 5 years can subsequently be reassessed at 2- to 4-year intervals.¹⁵

Enabling recovery. One of the most important educational opportunities involves early vestibular rehabilitation to facilitate recovery of postural control after treatment. Research has shown benefit from customized vestibular rehabilitation in addition to instructions that stress the need to engage in some type of activity, such as walking or other modes of exercise.²²

CORRESPONDENCE
Robert McDonald, MD, Spartanburg Family Medicine Residency Program, 853 N. Church Street, Suite 510, Spartanburg, SC 29303; rmcdonald@srhs.com

CASE Jan D, a 27-year-old woman, comes in requesting treatment for pelvic pain and urinary frequency, symptoms she’s had for about 6 months. She describes a feeling of pressure over the suprapubic area that’s relieved by voiding, sensitivity over the vulvar area, and both daytime frequency and nocturia. The patient has a history of allergies and chronic fatigue syndrome (CFS) of 2 years’ duration. When you inquire about her prior medical history, Jan reports that she had frequent urinary tract infections (UTIs) during adolescence.

You order a urinalysis and culture, both of which are negative. If Jan were your patient, what would your next step be?

Interstitial cystitis (IC) is a painful bladder disorder that predominantly affects young and middle-aged women, with an average age of onset of 40 years.^1,2 But men can also develop IC, as can women of any age.² Estimates of prevalence among US women range from less than 1% to more than 6%.^2,3 In recent years, however, the number of cases reported has multiplied, the combined result of greater awareness of IC and population surveys based on symptoms rather than on established criteria alone.⁴

Because the disorder is recognized as a major source of chronic pelvic pain and disability, the term interstitial cystitis/bladder pain syndrome (IC/BPS) is now used by the American Urological Association and many experts to describe it.^1,5

Early diagnosis and management of IC/BPS are keys to substantial symptom reduction and improved quality of life. Yet it is often under- or misdiagnosed, both because of the many comorbidities found in patients with the disorder and because its symptoms overlap with those of other common conditions.⁵

Family physicians are often the first practitioners whom patients with IC/BPS turn to for help. Yet a recent survey of physician practices found significant knowledge gaps with regard to IC/BPS among primary care physicians.⁶ This evidence-based review is designed to raise awareness of this chronic condition and better prepare you to diagnose and treat it.

IC/BPS: An overview

IC/BPS is characterized by at least 3 to 6 months of pain, pressure, or discomfort over the suprapubic area or the bladder, accompanied by frequency of urination during the day and night in a patient who does not have a UTI.¹ There is no known etiology or cure. While evidence suggests that about 90% of those affected are female, some urologists consider chronic bacterial prostatitis to be the male equivalent of IC/BPS, and therefore maintain that the proportion of men with IC/BPS may be considerably higher. ^2,3

Chronic pain—the most common symptom—is regional and diffuse over the lower pelvic area, and can be severe. In one study of more than 600 patients with IC/BPS, the most common locations of the pain were the lower abdomen, cited by 80% of those surveyed; the urethral area, cited by 74%; and the low back, by 65%.⁷ (Dyspareunia is also common, and contributes to the poor quality of life associated with this condition.⁸)

For about 40% of female patients, the pain and urinary frequency are highest perimenstrually.⁸ Physical or psychological stress, spicy foods, and smoking can exacerbate symptoms.^9,10

Genetics may play a role. Some evidence suggests a genetic predisposition to IC/BPS. In one study, 5 of 8 monozygotic twins of patients with the condition (but 0 of 8 dizygotic twins) were found to have either probable or confirmed IC/BPS. In addition, IC/BPS was 17 times more common in first-degree relatives of patients with the disorder than in the general population.¹¹

There is no established pathogenesis. No infectious organism (bacterial, fungal, or viral) has been identified as a cause for IC/BPS.¹² However, an increased number of activated bladder mast cells has been documented in patients with IC/BPS—a possible reason for the pain and some of the histology associated with the condition.⁹ Inflammation is present to variable degrees and not in all patients.

Some studies suggest that bladder glycosaminoglycans—which form a coating on the luminal surface of the bladder that creates an impermeable, protective barrier—may be compromised in patients with IC/BPS,¹³ which makes it possible for noxious molecules in the urine to activate sensory nerve endings and lead to chronic pelvic pain.

Overlapping symptoms, comorbidities are common
Symptoms associated with IC/BPS overlap with those of a number of other conditions, including UTIs, sensory urgency, recurrent cystitis, and overactive bladder (OAB), as well as chronic nonbacterial prostatitis in men.⁴ Comorbidities further complicate the picture.^14,15

IC/BPS patients often have a history of allergies,^14,15 although they may have negative results on radioallergosorbent (RAST) or skin prick tests, and a number of other comorbidities (TABLE 1). Studies have shown a high correlation between IC/BPS and chronic fatigue syndrome, irritable bowel syndrome, vulvodynia, fibromyalgia, endometriosis, and panic disorder.^16-20

TABLE 1
Interstitial cystitis/bladder pain syndrome: Common comorbidities^14-20

Rule out UTIs and overactive bladder

IC/BPS is largely a diagnosis of exclusion: When a patient presents with suprapubic pain, pressure, or discomfort related to bladder filling and increased urinary frequency lasting for several months, other related conditions—most notably, UTI and OAB—must be ruled out. Often, this can be done with urinalysis and culture, a complete medical history, and symptom assessment. But when doubt remains, a trial of antibiotics (for a UTI) or an anticholinergic agent (for OAB) may be appropriate.

A targeted history and symptom assessment
A history of allergic, gastrointestinal, gynecologic, and/or musculoskeletal disease is often significant.⁴ In addition, bladder problems in childhood and adolescence are notable, as they are far more common in women with IC/BPS than in the general population.^21,22

Identify voiding problems. Question the patient not only about how often she voids, but also about the extent to which the frequency is affecting her life. The severity of the persistent need to void is more significant for an IC/BPS diagnosis than the sudden urge to void for fear of leakage, which is typical of OAB.²³

Ask about abuse. Evidence suggests that 50% of women with IC/BPS have been abused, half of them sexually,²⁴ so it is important to include questions about past and present physical, emotional, and sexual abuse in the medical history. Physical or sexual trauma in childhood appears to increase an individual’s lifetime risk for chronic pain syndromes.²⁵

Use these tools to gauge symptoms and severity. Two tools that can aid in diagnosing—or ruling out—IC/BPS are the O’Leary-Sant Symptom and Problem Index, and the Pelvic Pain and Urgency/Frequency (PUF) questionnaire. Both are available at http://www.ichelp.org/Page.aspx?pid=444.

The O’Leary-Sant Index is a measure of urinary and pain symptoms, and of how problematic the symptoms are for the patient.²⁶ The PUF questionnaire also incorporates an assessment of sexual function and the impact of the pain and urinary symptoms,²⁷ but it has not been validated.

The medical work-up

Perform a full gynecologic evaluation of female patients and a rectal examination of men. Include the following laboratory tests in your evaluation: complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total immunoglobulin E, and liver and thyroid function; test leuteinizing hormone and follicle-stimulating hormone levels for women, as well. Also include urine culture and sensitivity tests in the work-up.

Referral to a urologist is indicated if microscopic hematuria and pyuria are present or the patient’s symptoms are severe. The urologist may conduct a number of tests, for further evaluation or to confirm an IC/BPS diagnosis. These include:

Digital and manometric pelvic floor muscle examination. Manometry is performed using a vaginal or rectal pressure-sensitive probe that measures the strength of contraction and the ability to relax the pelvic floor muscles. In one study, 87% of women with IC/BPS were found to have levator muscle pain described as “consistent with pelvic floor dysfunction.”²⁸

Kaufman Q-tip touch sensitivity test. This involves touching all 4 quadrants of the vulvar and vestibular Skene’s gland ostia to evaluate for vestibulodynia, using a visual analog scale to document the level of pain and sensitivity the patient is experiencing.

Potassium sensitivity test. The physician instills a high concentration of potassium chloride into the bladder to evaluate how much pain it elicits.²⁷ (Although this test is frequently included in the evaluation of patients suspected of having IC/BPS, its use is controversial because it is unnecessarily painful, while its sensitivity and specificity are low.¹)

Cystoscopy after hydrodistension, preferably with isotonic saline or isotonic glycine to avoid hypotonic damage to the urothelium, is performed under anesthesia (FIGURE 1). This is the most common procedure performed on patients with IC/BPS²⁹ because it allows visualization of the urothelial glomerulations, or petechiae, and submucosal hemorrhages, found in most patients with this condition. The test would also reveal the presence of the mucosal lesions (Hunner’s ulcers) found in those with “classic” IC/BPS, which represents 5% to 15% of all cases.⁴

FIGURE 1
IC/BPS: A cystoscopic image

Glomerulations can occur in other bladder conditions, however, and may even be found in normal bladders.³⁰ Thus, glomerulations are not diagnostic of IC/BPS in and of themselves, but this finding is often used to confirm the diagnosis.

CASE After Jan’s initial urinalysis, culture, and sensitivity tests, you follow up with a number of other laboratory tests, including CBC with differential, ESR, CRP, and hormonal and immune indexes. All are within the normal range. You also perform a gynecologic examination and use the O’Leary-Sant Symptom and Problem Index to diagnose IC/BPS, and refer the patient to a urologist for further evaluation. The urologist performs cystoscopy with bladder hydrodistension, which reveals multiple submucosal hemorrhages and glomerulations.

Treatment of IC/BPS is multimodal

In January 2011, the American Urological Association (AUA) approved diagnostic and treatment recommendations for IC/BPS (available at http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=ic-bps). The AUA recommends starting with the most conservative treatments, such as stress management, patient education, and self-care. Interventions may include dietary modification (eliminating bladder irritants such as caffeine and alcohol), self-guided imagery, meditation, yoga, deep breathing, self-hypnosis, and manual physical therapy to the pelvic floor myofascial trigger points, with oral or intravesical medications and other procedures added, as needed (FIGURE 2). Pain management, the AUA notes, should be considered throughout the course of therapy.³¹

FIGURE 2
Treatment algorithm for interstitial cystitis/bladder pain syndrome (IC/BPS)

The other professional society with treatment recommendations for IC/BPS is the International Continence Society (http://www.icsoffice.org/Documents/Documents.aspx?DocumentID=494). Because there is no known cure for IC/BPS, the Society focuses on alleviating symptoms and improving the patient’s quality of life. Treatment is highly individual, the Society states, and may consist of diet modification, oral drugs, bladder instillations or injections, and neuromodulation or surgical interventions, as a last resort. Multiple approaches may be used, often together. ²⁹

Both mild discomfort/pain and urinary frequency in newly diagnosed patients may be treated with a number of oral drugs used off label (TABLE 2), as well as with muscle relaxants, such as diazepam. Pentosan polysulfate—the only oral drug with US Food and Drug Administration approval for treatment of IC/BPS—was initially shown to be “modestly beneficial.”³² However, in 2 recent randomized studies, including one multicenter trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases, it was found to be little (or no) better than placebo.^33,34 Thus, we recommend that the drug be tried for no more than 4 to 6 months. If there is no benefit or adverse effects such as GI problems or hair loss develop, the drug should be discontinued.

TABLE 2
Frequently used medications for mild to moderate symptoms

The tricyclic antidepressant amitriptyline is often used to relieve symptoms—both urinary frequency and pain/discomfort—that are mild to moderate. In one small clinical trial, amitriptyline (self-titrated up to 100 mg/d for 4 months) produced a 64% response rate. But nearly a third of the patients in the intervention group (and many more on placebo) dropped out due to nonresponse.³⁵ A recent multicenter, randomized, placebo-controlled trial of amitriptyline showed that only patients who took >50 mg daily had a significantly higher response rate (P=.01) compared with the placebo group.³⁶

Amitriptyline may also be combined with hydroxyzine, especially in patients with allergies, but the combination could result in considerable sedation. The antidepressant doxepin, which is both a histamine-1 (H1) and histamine-2 (H2) receptor antagonist (RA), is an alternative that has been shown to reduce chronic neuropathic pain.³⁷ A doxepin cream may also be used locally for vulvodynia.

Although no comparative studies have been conducted, nontricyclic antidepressants do not appear to have the same benefit for IC symptoms. In an open-label study of 48 women with IC/BPS, the antidepressant duloxetine (titrated to 40 mg bid for 5 weeks) showed no significant improvement of symptoms.³⁸

Hydroxyzine is an H1 RA with mild anxiolytic and antiallergy properties. In an open-label study of IC/BPS patients with allergies (n=37), it was found to reduce symptoms by 55%.³⁹

Is there a role for dietary supplements? In developing its new recommendations for IC/BPS, the AUA did not review studies of dietary supplements.³¹ The Interstitial Cystitis Association (ICA), however, includes information on its Web site about a number of dietary supplements that may be helpful in controlling symptoms (http://www.ichelp.org/Page.aspx?pid=635).

One such product contains aloe vera, which the ICA describes as having anti-inflammatory actions that have been found to reduce IC/BPS symptoms.⁴⁰ Another is a dietary supplement that the author (TCT) developed, which contains quercetin, a flavonoid with anti-inflammatory properties, as well as chondroitin and hyaluronate—components of the glycosaminoglycan protective layer in the bladder that may be damaged in patients with ICS. In an open label study of 127 patients with refractory symptoms of IC/BPS, this supplement produced a 51% response rate (P<.0001).⁴¹

Pain management is particularly challenging
Intense chronic pain is the most difficult aspect of IC/BPS to treat. Tramadol, an opioid with weaker addiction potential and fewer adverse effects than morphine, is often helpful. Gabapentin, an antiseizure drug, and pregabalin, a similar drug recently approved for fibromyalgia, may also be useful. A fentanyl patch, as well as belladonna and opium suppositories, may be used under the care of a pain management specialist.

If these pain regimens fail, urologists often try intravesical approaches, such as bladder hydrodistension under anesthesia, which has been found to provide short-term (up to 5.3 months) symptom relief in 30% to 50% of patients.^4,42,43 Intravesical treatments, in which medication is directly instilled into the bladder, are frequently used, especially in patients with severe symptoms.⁴⁴

Intravesical dimethylsulfoxide (DMSO) may be given once a week for 6 weeks, but instillation often hurts and DMSO causes the patients to smell of garlic, which severely limits compliance. In one randomized double-blind study involving 11 patients with classic IC/BPS (ie, with Hunner’s ulcers) and 10 IC/BPS patients without Hunner’s ulcers, DMSO reduced urinary frequency and pain only in those with classic cases.⁴⁵

Intravesical hyaluronate sodium, given in weekly instillations for 4 weeks, resulted in some pain reduction in 2 open-label studies,⁴ but in a subsequent randomized, double-blind, placebo-controlled, multicenter study, instilling 10 times the amount of hyaluronate failed to show any benefit and was terminated by the sponsor (Seikagaku Corp., written correspondence, March 2004). In one small study, intravesical hyaluronate and chondroitin, given weekly for 20 weeks and then monthly for 3 months, led to significant improvement in frequency, urgency, and pain.⁴⁶

In a multicenter trial, intravesical instillation of lidocaine, together with sodium bicarbonate, led to 30% improvement, compared with the controls.⁴⁷ (Such intravesical “cocktails” are often supplemented with other agents, such as heparin or hydrocortisone.)

Other options for refractory pain include intravesical laser ablation, fulguration of bladder lesions, intravesical injections of botulinum toxin, and neuromodulation of the sacral or pudendal nerve via an implanted impulse generator.

CASE After the urologist confirmed Jan’s diagnosis, she returned to your office for treatment. Jan was started on dietary modification, hydroxyzine (50 mg at bedtime), and physical therapy. She had a 50% reduction in symptoms after 3 months of therapy.

CORRESPONDENCE
Theoharis C. Theoharides, MD, PhD, FAAAAI, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111; theoharis.theoharides@tufts.edu

CASE Jan D, a 27-year-old woman, comes in requesting treatment for pelvic pain and urinary frequency, symptoms she’s had for about 6 months. She describes a feeling of pressure over the suprapubic area that’s relieved by voiding, sensitivity over the vulvar area, and both daytime frequency and nocturia. The patient has a history of allergies and chronic fatigue syndrome (CFS) of 2 years’ duration. When you inquire about her prior medical history, Jan reports that she had frequent urinary tract infections (UTIs) during adolescence.

You order a urinalysis and culture, both of which are negative. If Jan were your patient, what would your next step be?

Interstitial cystitis (IC) is a painful bladder disorder that predominantly affects young and middle-aged women, with an average age of onset of 40 years.^1,2 But men can also develop IC, as can women of any age.² Estimates of prevalence among US women range from less than 1% to more than 6%.^2,3 In recent years, however, the number of cases reported has multiplied, the combined result of greater awareness of IC and population surveys based on symptoms rather than on established criteria alone.⁴

Because the disorder is recognized as a major source of chronic pelvic pain and disability, the term interstitial cystitis/bladder pain syndrome (IC/BPS) is now used by the American Urological Association and many experts to describe it.^1,5

Early diagnosis and management of IC/BPS are keys to substantial symptom reduction and improved quality of life. Yet it is often under- or misdiagnosed, both because of the many comorbidities found in patients with the disorder and because its symptoms overlap with those of other common conditions.⁵

Family physicians are often the first practitioners whom patients with IC/BPS turn to for help. Yet a recent survey of physician practices found significant knowledge gaps with regard to IC/BPS among primary care physicians.⁶ This evidence-based review is designed to raise awareness of this chronic condition and better prepare you to diagnose and treat it.

IC/BPS: An overview

IC/BPS is characterized by at least 3 to 6 months of pain, pressure, or discomfort over the suprapubic area or the bladder, accompanied by frequency of urination during the day and night in a patient who does not have a UTI.¹ There is no known etiology or cure. While evidence suggests that about 90% of those affected are female, some urologists consider chronic bacterial prostatitis to be the male equivalent of IC/BPS, and therefore maintain that the proportion of men with IC/BPS may be considerably higher. ^2,3

Chronic pain—the most common symptom—is regional and diffuse over the lower pelvic area, and can be severe. In one study of more than 600 patients with IC/BPS, the most common locations of the pain were the lower abdomen, cited by 80% of those surveyed; the urethral area, cited by 74%; and the low back, by 65%.⁷ (Dyspareunia is also common, and contributes to the poor quality of life associated with this condition.⁸)

For about 40% of female patients, the pain and urinary frequency are highest perimenstrually.⁸ Physical or psychological stress, spicy foods, and smoking can exacerbate symptoms.^9,10

Genetics may play a role. Some evidence suggests a genetic predisposition to IC/BPS. In one study, 5 of 8 monozygotic twins of patients with the condition (but 0 of 8 dizygotic twins) were found to have either probable or confirmed IC/BPS. In addition, IC/BPS was 17 times more common in first-degree relatives of patients with the disorder than in the general population.¹¹

There is no established pathogenesis. No infectious organism (bacterial, fungal, or viral) has been identified as a cause for IC/BPS.¹² However, an increased number of activated bladder mast cells has been documented in patients with IC/BPS—a possible reason for the pain and some of the histology associated with the condition.⁹ Inflammation is present to variable degrees and not in all patients.

Some studies suggest that bladder glycosaminoglycans—which form a coating on the luminal surface of the bladder that creates an impermeable, protective barrier—may be compromised in patients with IC/BPS,¹³ which makes it possible for noxious molecules in the urine to activate sensory nerve endings and lead to chronic pelvic pain.

Overlapping symptoms, comorbidities are common
Symptoms associated with IC/BPS overlap with those of a number of other conditions, including UTIs, sensory urgency, recurrent cystitis, and overactive bladder (OAB), as well as chronic nonbacterial prostatitis in men.⁴ Comorbidities further complicate the picture.^14,15

IC/BPS patients often have a history of allergies,^14,15 although they may have negative results on radioallergosorbent (RAST) or skin prick tests, and a number of other comorbidities (TABLE 1). Studies have shown a high correlation between IC/BPS and chronic fatigue syndrome, irritable bowel syndrome, vulvodynia, fibromyalgia, endometriosis, and panic disorder.^16-20

TABLE 1
Interstitial cystitis/bladder pain syndrome: Common comorbidities^14-20

Rule out UTIs and overactive bladder

IC/BPS is largely a diagnosis of exclusion: When a patient presents with suprapubic pain, pressure, or discomfort related to bladder filling and increased urinary frequency lasting for several months, other related conditions—most notably, UTI and OAB—must be ruled out. Often, this can be done with urinalysis and culture, a complete medical history, and symptom assessment. But when doubt remains, a trial of antibiotics (for a UTI) or an anticholinergic agent (for OAB) may be appropriate.

A targeted history and symptom assessment
A history of allergic, gastrointestinal, gynecologic, and/or musculoskeletal disease is often significant.⁴ In addition, bladder problems in childhood and adolescence are notable, as they are far more common in women with IC/BPS than in the general population.^21,22

Identify voiding problems. Question the patient not only about how often she voids, but also about the extent to which the frequency is affecting her life. The severity of the persistent need to void is more significant for an IC/BPS diagnosis than the sudden urge to void for fear of leakage, which is typical of OAB.²³

Ask about abuse. Evidence suggests that 50% of women with IC/BPS have been abused, half of them sexually,²⁴ so it is important to include questions about past and present physical, emotional, and sexual abuse in the medical history. Physical or sexual trauma in childhood appears to increase an individual’s lifetime risk for chronic pain syndromes.²⁵

Use these tools to gauge symptoms and severity. Two tools that can aid in diagnosing—or ruling out—IC/BPS are the O’Leary-Sant Symptom and Problem Index, and the Pelvic Pain and Urgency/Frequency (PUF) questionnaire. Both are available at http://www.ichelp.org/Page.aspx?pid=444.

The O’Leary-Sant Index is a measure of urinary and pain symptoms, and of how problematic the symptoms are for the patient.²⁶ The PUF questionnaire also incorporates an assessment of sexual function and the impact of the pain and urinary symptoms,²⁷ but it has not been validated.

The medical work-up

Perform a full gynecologic evaluation of female patients and a rectal examination of men. Include the following laboratory tests in your evaluation: complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total immunoglobulin E, and liver and thyroid function; test leuteinizing hormone and follicle-stimulating hormone levels for women, as well. Also include urine culture and sensitivity tests in the work-up.

Referral to a urologist is indicated if microscopic hematuria and pyuria are present or the patient’s symptoms are severe. The urologist may conduct a number of tests, for further evaluation or to confirm an IC/BPS diagnosis. These include:

Digital and manometric pelvic floor muscle examination. Manometry is performed using a vaginal or rectal pressure-sensitive probe that measures the strength of contraction and the ability to relax the pelvic floor muscles. In one study, 87% of women with IC/BPS were found to have levator muscle pain described as “consistent with pelvic floor dysfunction.”²⁸

Kaufman Q-tip touch sensitivity test. This involves touching all 4 quadrants of the vulvar and vestibular Skene’s gland ostia to evaluate for vestibulodynia, using a visual analog scale to document the level of pain and sensitivity the patient is experiencing.

Potassium sensitivity test. The physician instills a high concentration of potassium chloride into the bladder to evaluate how much pain it elicits.²⁷ (Although this test is frequently included in the evaluation of patients suspected of having IC/BPS, its use is controversial because it is unnecessarily painful, while its sensitivity and specificity are low.¹)

Cystoscopy after hydrodistension, preferably with isotonic saline or isotonic glycine to avoid hypotonic damage to the urothelium, is performed under anesthesia (FIGURE 1). This is the most common procedure performed on patients with IC/BPS²⁹ because it allows visualization of the urothelial glomerulations, or petechiae, and submucosal hemorrhages, found in most patients with this condition. The test would also reveal the presence of the mucosal lesions (Hunner’s ulcers) found in those with “classic” IC/BPS, which represents 5% to 15% of all cases.⁴

FIGURE 1
IC/BPS: A cystoscopic image

Glomerulations can occur in other bladder conditions, however, and may even be found in normal bladders.³⁰ Thus, glomerulations are not diagnostic of IC/BPS in and of themselves, but this finding is often used to confirm the diagnosis.

CASE After Jan’s initial urinalysis, culture, and sensitivity tests, you follow up with a number of other laboratory tests, including CBC with differential, ESR, CRP, and hormonal and immune indexes. All are within the normal range. You also perform a gynecologic examination and use the O’Leary-Sant Symptom and Problem Index to diagnose IC/BPS, and refer the patient to a urologist for further evaluation. The urologist performs cystoscopy with bladder hydrodistension, which reveals multiple submucosal hemorrhages and glomerulations.

Treatment of IC/BPS is multimodal

In January 2011, the American Urological Association (AUA) approved diagnostic and treatment recommendations for IC/BPS (available at http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=ic-bps). The AUA recommends starting with the most conservative treatments, such as stress management, patient education, and self-care. Interventions may include dietary modification (eliminating bladder irritants such as caffeine and alcohol), self-guided imagery, meditation, yoga, deep breathing, self-hypnosis, and manual physical therapy to the pelvic floor myofascial trigger points, with oral or intravesical medications and other procedures added, as needed (FIGURE 2). Pain management, the AUA notes, should be considered throughout the course of therapy.³¹

FIGURE 2
Treatment algorithm for interstitial cystitis/bladder pain syndrome (IC/BPS)

The other professional society with treatment recommendations for IC/BPS is the International Continence Society (http://www.icsoffice.org/Documents/Documents.aspx?DocumentID=494). Because there is no known cure for IC/BPS, the Society focuses on alleviating symptoms and improving the patient’s quality of life. Treatment is highly individual, the Society states, and may consist of diet modification, oral drugs, bladder instillations or injections, and neuromodulation or surgical interventions, as a last resort. Multiple approaches may be used, often together. ²⁹

Both mild discomfort/pain and urinary frequency in newly diagnosed patients may be treated with a number of oral drugs used off label (TABLE 2), as well as with muscle relaxants, such as diazepam. Pentosan polysulfate—the only oral drug with US Food and Drug Administration approval for treatment of IC/BPS—was initially shown to be “modestly beneficial.”³² However, in 2 recent randomized studies, including one multicenter trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases, it was found to be little (or no) better than placebo.^33,34 Thus, we recommend that the drug be tried for no more than 4 to 6 months. If there is no benefit or adverse effects such as GI problems or hair loss develop, the drug should be discontinued.

TABLE 2
Frequently used medications for mild to moderate symptoms

The tricyclic antidepressant amitriptyline is often used to relieve symptoms—both urinary frequency and pain/discomfort—that are mild to moderate. In one small clinical trial, amitriptyline (self-titrated up to 100 mg/d for 4 months) produced a 64% response rate. But nearly a third of the patients in the intervention group (and many more on placebo) dropped out due to nonresponse.³⁵ A recent multicenter, randomized, placebo-controlled trial of amitriptyline showed that only patients who took >50 mg daily had a significantly higher response rate (P=.01) compared with the placebo group.³⁶

Amitriptyline may also be combined with hydroxyzine, especially in patients with allergies, but the combination could result in considerable sedation. The antidepressant doxepin, which is both a histamine-1 (H1) and histamine-2 (H2) receptor antagonist (RA), is an alternative that has been shown to reduce chronic neuropathic pain.³⁷ A doxepin cream may also be used locally for vulvodynia.

Although no comparative studies have been conducted, nontricyclic antidepressants do not appear to have the same benefit for IC symptoms. In an open-label study of 48 women with IC/BPS, the antidepressant duloxetine (titrated to 40 mg bid for 5 weeks) showed no significant improvement of symptoms.³⁸

Hydroxyzine is an H1 RA with mild anxiolytic and antiallergy properties. In an open-label study of IC/BPS patients with allergies (n=37), it was found to reduce symptoms by 55%.³⁹

Is there a role for dietary supplements? In developing its new recommendations for IC/BPS, the AUA did not review studies of dietary supplements.³¹ The Interstitial Cystitis Association (ICA), however, includes information on its Web site about a number of dietary supplements that may be helpful in controlling symptoms (http://www.ichelp.org/Page.aspx?pid=635).

One such product contains aloe vera, which the ICA describes as having anti-inflammatory actions that have been found to reduce IC/BPS symptoms.⁴⁰ Another is a dietary supplement that the author (TCT) developed, which contains quercetin, a flavonoid with anti-inflammatory properties, as well as chondroitin and hyaluronate—components of the glycosaminoglycan protective layer in the bladder that may be damaged in patients with ICS. In an open label study of 127 patients with refractory symptoms of IC/BPS, this supplement produced a 51% response rate (P<.0001).⁴¹

Pain management is particularly challenging
Intense chronic pain is the most difficult aspect of IC/BPS to treat. Tramadol, an opioid with weaker addiction potential and fewer adverse effects than morphine, is often helpful. Gabapentin, an antiseizure drug, and pregabalin, a similar drug recently approved for fibromyalgia, may also be useful. A fentanyl patch, as well as belladonna and opium suppositories, may be used under the care of a pain management specialist.

If these pain regimens fail, urologists often try intravesical approaches, such as bladder hydrodistension under anesthesia, which has been found to provide short-term (up to 5.3 months) symptom relief in 30% to 50% of patients.^4,42,43 Intravesical treatments, in which medication is directly instilled into the bladder, are frequently used, especially in patients with severe symptoms.⁴⁴

Intravesical dimethylsulfoxide (DMSO) may be given once a week for 6 weeks, but instillation often hurts and DMSO causes the patients to smell of garlic, which severely limits compliance. In one randomized double-blind study involving 11 patients with classic IC/BPS (ie, with Hunner’s ulcers) and 10 IC/BPS patients without Hunner’s ulcers, DMSO reduced urinary frequency and pain only in those with classic cases.⁴⁵

Intravesical hyaluronate sodium, given in weekly instillations for 4 weeks, resulted in some pain reduction in 2 open-label studies,⁴ but in a subsequent randomized, double-blind, placebo-controlled, multicenter study, instilling 10 times the amount of hyaluronate failed to show any benefit and was terminated by the sponsor (Seikagaku Corp., written correspondence, March 2004). In one small study, intravesical hyaluronate and chondroitin, given weekly for 20 weeks and then monthly for 3 months, led to significant improvement in frequency, urgency, and pain.⁴⁶

In a multicenter trial, intravesical instillation of lidocaine, together with sodium bicarbonate, led to 30% improvement, compared with the controls.⁴⁷ (Such intravesical “cocktails” are often supplemented with other agents, such as heparin or hydrocortisone.)

Other options for refractory pain include intravesical laser ablation, fulguration of bladder lesions, intravesical injections of botulinum toxin, and neuromodulation of the sacral or pudendal nerve via an implanted impulse generator.

CASE After the urologist confirmed Jan’s diagnosis, she returned to your office for treatment. Jan was started on dietary modification, hydroxyzine (50 mg at bedtime), and physical therapy. She had a 50% reduction in symptoms after 3 months of therapy.

CORRESPONDENCE
Theoharis C. Theoharides, MD, PhD, FAAAAI, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111; theoharis.theoharides@tufts.edu

CASE Jan D, a 27-year-old woman, comes in requesting treatment for pelvic pain and urinary frequency, symptoms she’s had for about 6 months. She describes a feeling of pressure over the suprapubic area that’s relieved by voiding, sensitivity over the vulvar area, and both daytime frequency and nocturia. The patient has a history of allergies and chronic fatigue syndrome (CFS) of 2 years’ duration. When you inquire about her prior medical history, Jan reports that she had frequent urinary tract infections (UTIs) during adolescence.

You order a urinalysis and culture, both of which are negative. If Jan were your patient, what would your next step be?

Interstitial cystitis (IC) is a painful bladder disorder that predominantly affects young and middle-aged women, with an average age of onset of 40 years.^1,2 But men can also develop IC, as can women of any age.² Estimates of prevalence among US women range from less than 1% to more than 6%.^2,3 In recent years, however, the number of cases reported has multiplied, the combined result of greater awareness of IC and population surveys based on symptoms rather than on established criteria alone.⁴

Because the disorder is recognized as a major source of chronic pelvic pain and disability, the term interstitial cystitis/bladder pain syndrome (IC/BPS) is now used by the American Urological Association and many experts to describe it.^1,5

Early diagnosis and management of IC/BPS are keys to substantial symptom reduction and improved quality of life. Yet it is often under- or misdiagnosed, both because of the many comorbidities found in patients with the disorder and because its symptoms overlap with those of other common conditions.⁵

Family physicians are often the first practitioners whom patients with IC/BPS turn to for help. Yet a recent survey of physician practices found significant knowledge gaps with regard to IC/BPS among primary care physicians.⁶ This evidence-based review is designed to raise awareness of this chronic condition and better prepare you to diagnose and treat it.

IC/BPS: An overview

IC/BPS is characterized by at least 3 to 6 months of pain, pressure, or discomfort over the suprapubic area or the bladder, accompanied by frequency of urination during the day and night in a patient who does not have a UTI.¹ There is no known etiology or cure. While evidence suggests that about 90% of those affected are female, some urologists consider chronic bacterial prostatitis to be the male equivalent of IC/BPS, and therefore maintain that the proportion of men with IC/BPS may be considerably higher. ^2,3

Chronic pain—the most common symptom—is regional and diffuse over the lower pelvic area, and can be severe. In one study of more than 600 patients with IC/BPS, the most common locations of the pain were the lower abdomen, cited by 80% of those surveyed; the urethral area, cited by 74%; and the low back, by 65%.⁷ (Dyspareunia is also common, and contributes to the poor quality of life associated with this condition.⁸)

For about 40% of female patients, the pain and urinary frequency are highest perimenstrually.⁸ Physical or psychological stress, spicy foods, and smoking can exacerbate symptoms.^9,10

Genetics may play a role. Some evidence suggests a genetic predisposition to IC/BPS. In one study, 5 of 8 monozygotic twins of patients with the condition (but 0 of 8 dizygotic twins) were found to have either probable or confirmed IC/BPS. In addition, IC/BPS was 17 times more common in first-degree relatives of patients with the disorder than in the general population.¹¹

There is no established pathogenesis. No infectious organism (bacterial, fungal, or viral) has been identified as a cause for IC/BPS.¹² However, an increased number of activated bladder mast cells has been documented in patients with IC/BPS—a possible reason for the pain and some of the histology associated with the condition.⁹ Inflammation is present to variable degrees and not in all patients.

Some studies suggest that bladder glycosaminoglycans—which form a coating on the luminal surface of the bladder that creates an impermeable, protective barrier—may be compromised in patients with IC/BPS,¹³ which makes it possible for noxious molecules in the urine to activate sensory nerve endings and lead to chronic pelvic pain.

Overlapping symptoms, comorbidities are common
Symptoms associated with IC/BPS overlap with those of a number of other conditions, including UTIs, sensory urgency, recurrent cystitis, and overactive bladder (OAB), as well as chronic nonbacterial prostatitis in men.⁴ Comorbidities further complicate the picture.^14,15

IC/BPS patients often have a history of allergies,^14,15 although they may have negative results on radioallergosorbent (RAST) or skin prick tests, and a number of other comorbidities (TABLE 1). Studies have shown a high correlation between IC/BPS and chronic fatigue syndrome, irritable bowel syndrome, vulvodynia, fibromyalgia, endometriosis, and panic disorder.^16-20

TABLE 1
Interstitial cystitis/bladder pain syndrome: Common comorbidities^14-20

Rule out UTIs and overactive bladder

IC/BPS is largely a diagnosis of exclusion: When a patient presents with suprapubic pain, pressure, or discomfort related to bladder filling and increased urinary frequency lasting for several months, other related conditions—most notably, UTI and OAB—must be ruled out. Often, this can be done with urinalysis and culture, a complete medical history, and symptom assessment. But when doubt remains, a trial of antibiotics (for a UTI) or an anticholinergic agent (for OAB) may be appropriate.

A targeted history and symptom assessment
A history of allergic, gastrointestinal, gynecologic, and/or musculoskeletal disease is often significant.⁴ In addition, bladder problems in childhood and adolescence are notable, as they are far more common in women with IC/BPS than in the general population.^21,22

Identify voiding problems. Question the patient not only about how often she voids, but also about the extent to which the frequency is affecting her life. The severity of the persistent need to void is more significant for an IC/BPS diagnosis than the sudden urge to void for fear of leakage, which is typical of OAB.²³

Ask about abuse. Evidence suggests that 50% of women with IC/BPS have been abused, half of them sexually,²⁴ so it is important to include questions about past and present physical, emotional, and sexual abuse in the medical history. Physical or sexual trauma in childhood appears to increase an individual’s lifetime risk for chronic pain syndromes.²⁵

Use these tools to gauge symptoms and severity. Two tools that can aid in diagnosing—or ruling out—IC/BPS are the O’Leary-Sant Symptom and Problem Index, and the Pelvic Pain and Urgency/Frequency (PUF) questionnaire. Both are available at http://www.ichelp.org/Page.aspx?pid=444.

The O’Leary-Sant Index is a measure of urinary and pain symptoms, and of how problematic the symptoms are for the patient.²⁶ The PUF questionnaire also incorporates an assessment of sexual function and the impact of the pain and urinary symptoms,²⁷ but it has not been validated.

The medical work-up

Perform a full gynecologic evaluation of female patients and a rectal examination of men. Include the following laboratory tests in your evaluation: complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), total immunoglobulin E, and liver and thyroid function; test leuteinizing hormone and follicle-stimulating hormone levels for women, as well. Also include urine culture and sensitivity tests in the work-up.

Referral to a urologist is indicated if microscopic hematuria and pyuria are present or the patient’s symptoms are severe. The urologist may conduct a number of tests, for further evaluation or to confirm an IC/BPS diagnosis. These include:

Digital and manometric pelvic floor muscle examination. Manometry is performed using a vaginal or rectal pressure-sensitive probe that measures the strength of contraction and the ability to relax the pelvic floor muscles. In one study, 87% of women with IC/BPS were found to have levator muscle pain described as “consistent with pelvic floor dysfunction.”²⁸

Kaufman Q-tip touch sensitivity test. This involves touching all 4 quadrants of the vulvar and vestibular Skene’s gland ostia to evaluate for vestibulodynia, using a visual analog scale to document the level of pain and sensitivity the patient is experiencing.

Potassium sensitivity test. The physician instills a high concentration of potassium chloride into the bladder to evaluate how much pain it elicits.²⁷ (Although this test is frequently included in the evaluation of patients suspected of having IC/BPS, its use is controversial because it is unnecessarily painful, while its sensitivity and specificity are low.¹)

Cystoscopy after hydrodistension, preferably with isotonic saline or isotonic glycine to avoid hypotonic damage to the urothelium, is performed under anesthesia (FIGURE 1). This is the most common procedure performed on patients with IC/BPS²⁹ because it allows visualization of the urothelial glomerulations, or petechiae, and submucosal hemorrhages, found in most patients with this condition. The test would also reveal the presence of the mucosal lesions (Hunner’s ulcers) found in those with “classic” IC/BPS, which represents 5% to 15% of all cases.⁴

FIGURE 1
IC/BPS: A cystoscopic image

Glomerulations can occur in other bladder conditions, however, and may even be found in normal bladders.³⁰ Thus, glomerulations are not diagnostic of IC/BPS in and of themselves, but this finding is often used to confirm the diagnosis.

CASE After Jan’s initial urinalysis, culture, and sensitivity tests, you follow up with a number of other laboratory tests, including CBC with differential, ESR, CRP, and hormonal and immune indexes. All are within the normal range. You also perform a gynecologic examination and use the O’Leary-Sant Symptom and Problem Index to diagnose IC/BPS, and refer the patient to a urologist for further evaluation. The urologist performs cystoscopy with bladder hydrodistension, which reveals multiple submucosal hemorrhages and glomerulations.

Treatment of IC/BPS is multimodal

In January 2011, the American Urological Association (AUA) approved diagnostic and treatment recommendations for IC/BPS (available at http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=ic-bps). The AUA recommends starting with the most conservative treatments, such as stress management, patient education, and self-care. Interventions may include dietary modification (eliminating bladder irritants such as caffeine and alcohol), self-guided imagery, meditation, yoga, deep breathing, self-hypnosis, and manual physical therapy to the pelvic floor myofascial trigger points, with oral or intravesical medications and other procedures added, as needed (FIGURE 2). Pain management, the AUA notes, should be considered throughout the course of therapy.³¹

FIGURE 2
Treatment algorithm for interstitial cystitis/bladder pain syndrome (IC/BPS)

The other professional society with treatment recommendations for IC/BPS is the International Continence Society (http://www.icsoffice.org/Documents/Documents.aspx?DocumentID=494). Because there is no known cure for IC/BPS, the Society focuses on alleviating symptoms and improving the patient’s quality of life. Treatment is highly individual, the Society states, and may consist of diet modification, oral drugs, bladder instillations or injections, and neuromodulation or surgical interventions, as a last resort. Multiple approaches may be used, often together. ²⁹

Both mild discomfort/pain and urinary frequency in newly diagnosed patients may be treated with a number of oral drugs used off label (TABLE 2), as well as with muscle relaxants, such as diazepam. Pentosan polysulfate—the only oral drug with US Food and Drug Administration approval for treatment of IC/BPS—was initially shown to be “modestly beneficial.”³² However, in 2 recent randomized studies, including one multicenter trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases, it was found to be little (or no) better than placebo.^33,34 Thus, we recommend that the drug be tried for no more than 4 to 6 months. If there is no benefit or adverse effects such as GI problems or hair loss develop, the drug should be discontinued.

TABLE 2
Frequently used medications for mild to moderate symptoms

The tricyclic antidepressant amitriptyline is often used to relieve symptoms—both urinary frequency and pain/discomfort—that are mild to moderate. In one small clinical trial, amitriptyline (self-titrated up to 100 mg/d for 4 months) produced a 64% response rate. But nearly a third of the patients in the intervention group (and many more on placebo) dropped out due to nonresponse.³⁵ A recent multicenter, randomized, placebo-controlled trial of amitriptyline showed that only patients who took >50 mg daily had a significantly higher response rate (P=.01) compared with the placebo group.³⁶

Amitriptyline may also be combined with hydroxyzine, especially in patients with allergies, but the combination could result in considerable sedation. The antidepressant doxepin, which is both a histamine-1 (H1) and histamine-2 (H2) receptor antagonist (RA), is an alternative that has been shown to reduce chronic neuropathic pain.³⁷ A doxepin cream may also be used locally for vulvodynia.

Although no comparative studies have been conducted, nontricyclic antidepressants do not appear to have the same benefit for IC symptoms. In an open-label study of 48 women with IC/BPS, the antidepressant duloxetine (titrated to 40 mg bid for 5 weeks) showed no significant improvement of symptoms.³⁸

Hydroxyzine is an H1 RA with mild anxiolytic and antiallergy properties. In an open-label study of IC/BPS patients with allergies (n=37), it was found to reduce symptoms by 55%.³⁹

Is there a role for dietary supplements? In developing its new recommendations for IC/BPS, the AUA did not review studies of dietary supplements.³¹ The Interstitial Cystitis Association (ICA), however, includes information on its Web site about a number of dietary supplements that may be helpful in controlling symptoms (http://www.ichelp.org/Page.aspx?pid=635).

One such product contains aloe vera, which the ICA describes as having anti-inflammatory actions that have been found to reduce IC/BPS symptoms.⁴⁰ Another is a dietary supplement that the author (TCT) developed, which contains quercetin, a flavonoid with anti-inflammatory properties, as well as chondroitin and hyaluronate—components of the glycosaminoglycan protective layer in the bladder that may be damaged in patients with ICS. In an open label study of 127 patients with refractory symptoms of IC/BPS, this supplement produced a 51% response rate (P<.0001).⁴¹

Pain management is particularly challenging
Intense chronic pain is the most difficult aspect of IC/BPS to treat. Tramadol, an opioid with weaker addiction potential and fewer adverse effects than morphine, is often helpful. Gabapentin, an antiseizure drug, and pregabalin, a similar drug recently approved for fibromyalgia, may also be useful. A fentanyl patch, as well as belladonna and opium suppositories, may be used under the care of a pain management specialist.

If these pain regimens fail, urologists often try intravesical approaches, such as bladder hydrodistension under anesthesia, which has been found to provide short-term (up to 5.3 months) symptom relief in 30% to 50% of patients.^4,42,43 Intravesical treatments, in which medication is directly instilled into the bladder, are frequently used, especially in patients with severe symptoms.⁴⁴

Intravesical dimethylsulfoxide (DMSO) may be given once a week for 6 weeks, but instillation often hurts and DMSO causes the patients to smell of garlic, which severely limits compliance. In one randomized double-blind study involving 11 patients with classic IC/BPS (ie, with Hunner’s ulcers) and 10 IC/BPS patients without Hunner’s ulcers, DMSO reduced urinary frequency and pain only in those with classic cases.⁴⁵

Intravesical hyaluronate sodium, given in weekly instillations for 4 weeks, resulted in some pain reduction in 2 open-label studies,⁴ but in a subsequent randomized, double-blind, placebo-controlled, multicenter study, instilling 10 times the amount of hyaluronate failed to show any benefit and was terminated by the sponsor (Seikagaku Corp., written correspondence, March 2004). In one small study, intravesical hyaluronate and chondroitin, given weekly for 20 weeks and then monthly for 3 months, led to significant improvement in frequency, urgency, and pain.⁴⁶

In a multicenter trial, intravesical instillation of lidocaine, together with sodium bicarbonate, led to 30% improvement, compared with the controls.⁴⁷ (Such intravesical “cocktails” are often supplemented with other agents, such as heparin or hydrocortisone.)

Other options for refractory pain include intravesical laser ablation, fulguration of bladder lesions, intravesical injections of botulinum toxin, and neuromodulation of the sacral or pudendal nerve via an implanted impulse generator.

CASE After the urologist confirmed Jan’s diagnosis, she returned to your office for treatment. Jan was started on dietary modification, hydroxyzine (50 mg at bedtime), and physical therapy. She had a 50% reduction in symptoms after 3 months of therapy.

CORRESPONDENCE
Theoharis C. Theoharides, MD, PhD, FAAAAI, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111; theoharis.theoharides@tufts.edu

Hot flashes are the most prevalent and most bothersome symptoms of the menopausal transition and the leading cause for seeking medical attention during that period of a woman’s life.¹ They may last for a few seconds or for several minutes and may occur as frequently as every hour to several times per week. On average, women experience hot flashes for a period of 6 months to 2 years, but the symptoms may last up to 10 years or more.^2,3

Hot flashes have been reported by up to 70% of women undergoing natural menopause, and by almost all women undergoing surgical menopause.⁴ For many women, these symptoms are mild and can be managed with reassurance and counseling. For others, the symptoms are severe, overwhelming, last for many years, and impair the quality of life.

According to a community-based survey of 16,000 women, hot flashes occur most often in late perimenopause and among those with a body mass index ≥27. Hot flashes are also more common among African Americans and women who are less physically active and have a lower income.⁵

Since the publication of the Women’s Health Initiative study in 2002 raised concerns about the long-term safety of hormone therapy (HT), nonhormonal remedies have emerged as potential alternative treatments.^6,7 A wealth of evidence has accumulated on the efficacy and safety of these, and various other approaches to the management of hot flashes. This review will summarize that evidence to help you provide optimal care and assist patients in making informed choices about their treatment.

Hormone replacement therapy

HT, given as estrogen alone in women without a uterus or estrogen plus progestin in women with a uterus, is the most studied and most effective therapy for vasomotor symptoms attributable to menopause. Data from one Cochrane review showed a significant reduction in the frequency of weekly hot flashes for oral estrogen compared with placebo, with a weighted mean difference (WMD) of -17.92 (95% confidence interval [CI], -22.86 to -12.99).⁸ This was equivalent to a 75% reduction in frequency (95% CI, 64.3-82.3) for HT relative to placebo. Results were similar for both opposed and unopposed estrogen regimens.⁸

Transdermal vs oral therapy. Another review compared oral estradiol, transdermal estradiol, and placebo in terms of reduction of hot flash frequency or severity, or both.⁹ The review revealed a pooled WMD in hot flashes of -16.8 per week (95% CI, -23.4 to -10.2) for oral estradiol and -22.4 per week (95% CI, -35.9 to -10.4) for transdermal estradiol. Results were similar for opposed and unopposed estrogen regimens.⁹

Transdermal delivery of estrogen as patches, gels, and sprays delivers unmetabolized estradiol directly to the blood stream, so that lower doses can achieve similar efficacy to doses administered orally.¹⁰ Thus, the transdermal route would be in keeping with current guidelines to prescribe the lowest effective dose that relieves symptoms. Emerging research should provide more insight regarding safety and the potential for fewer health risks with transdermal HT compared with oral therapy.

Best way to discontinue? When HT is discontinued, hot flashes may return—sometimes immediately, sometimes after a few months. No evidence-based guidelines exist on the best way to discontinue HT with the least recurrence and severity of hot flashes. No optimal tapering regimen (either by dose or number of days per week that HT is taken) has yet been described in any studies, nor have any randomized controlled trials (RCTs)revealed a significant difference between tapered or abrupt discontinuation.^11,12

The breast cancer connection. The relationship between HT and breast cancer has generated considerable controversy. In the Women’s Health Initiative (WHI) trial, which included participants on estrogen-only and estrogen plus progesterone regimens, an overall increased risk (hazard ratio [HR]=1.26; 95% CI, 1.00-1.59) was reported. The increased risk fell short of statistical significance, and varied with the duration of exposure.⁶

In subsequent studies, the magnitude of the associated risk was substantially greater for the estrogen-progestogen preparation, and also higher for longer-term exposure.¹³ Additionally, a meta-analysis of 8 studies of the risk of breast cancer with combination HT resulted in an odds ratio (OR) of 1.39 (95% CI, 1.12-1.72). Estimates were higher for more than 5 years of use (OR=1.63; 95% CI, 1.22-2.18) when compared with estimates for less than 5 years of use (OR=1.35; CI, 1.16-1.57).¹⁴ Recent studies have reported a decline in the incidence of breast cancer in the United States, which has been attributed to a parallel reduction in HT use.¹⁵

In contrast to the findings for women taking combination HT, the estrogen-only arm of the WHI study showed a decrease in the overall risk of breast cancer.¹⁶ A new analysis of data on participants in the estrogen-only arm of the study shows that, 10 years after the intervention ended, a decreased risk of breast cancer persists. In addition, the increased risk of stroke and deep vein thrombosis found in the original study had dissipated, and the decreased risk of hip fracture was not maintained.

Age matters. Health outcomes in this new analysis were more favorable for younger women for coronary heart disease, heart attack, colorectal cancer, total mortality, and a global index of chronic diseases.¹⁷ Pooled results of systematic reviews and meta-analyses on HT risks are available in TABLE 1.^14,16,18-21

Progestins
Progesterone in the form of injections (Depo-Provera 150 mg, for example) or oral medroxyprogesterone acetate 20 mg daily has shown a significant reduction in hot flashes compared with placebo.²² However, associated side effects (withdrawal bleeding and weight gain) and concerns about breast cancer often limit the use of this medication.²³ Because of the paucity of evidence, transdermal progesterone creams should not be recommended.²⁴

Tibolone
Tibolone is a synthetic steroid that is structurally related to 19-nortestosterone derivatives. It has weak estrogenic, progestogenic, and androgenic properties and has shown significant reduction in hot flashes and night sweating compared with placebo.²⁵ Tibolone has also been shown to enhance mood and sexual function.²⁶ However, evidence of its safety on outcomes such as breast cancer and cardiovascular events is obscure and has shown conflicting results, especially for breast cancer.^25,26

A recent double-blinded trial on women with breast cancer found that although tibolone significantly improved vasomotor symptoms, it was associated with an increased risk of breast cancer recurrence (HR=1.40; 95% CI, 1.14-1.70]; P=.001).²⁷ Tibolone is not approved for sale in the United States.

Nonhormonal options

Lifestyle modifications
According to recent reviews, exercise is less effective than HT in relieving hot flashes, but does seems to have beneficial effects on mood, sleep, and overall quality of life.^28,29 Other lifestyle modifications such as smoking cessation and weight loss may also be of use.⁵

Antidepressants
Data from one meta-analysis showed that selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) were significantly more effective than placebo in reducing daily frequency of hot flashes (WMD=-1.13; 95% CI, -1.70 to -0.57).³⁰ Efficacy varied for individual drugs.

Venlafaxine, an SNRI, has been shown to be more effective than placebo in managing hot flashes.³¹ The effect on hot flashes was noticed after 4 weeks of treatment with the 75- and 150-mg doses, but the higher dosage was associated with more adverse effects such as dry mouth, sleeplessness, and decreased appetite.³² Even so, 93% of the participants in the venlafaxine group chose to continue treatment, because the reduction in hot flashes had significantly improved their daily lives.³¹ Desvenlafaxine, a metabolite of venlafaxine, has been shown to reduce the number of hot flashes by almost 65% from baseline at Weeks 4 and 12, with dosages of 100 and 150 mg/d.³³

The SSRIs fluoxetine, citalopram, and paroxetine in 10-, 20-, and 30-mg doses and paroxetine CR (12.5 and 25 mg) have been studied in many RCTs. All have demonstrated a significant decrease in hot flashes compared with placebo with various dosages used. SSRIs reduce hot flashes by as much as 50% to 60%, compared with 80% for estrogen.³⁴ The duration of treatment ranged from 4 weeks to 6 months.

Gabapentin
Gabapentin is approved by the FDA for the treatment of partial seizures and postherpetic neuralgia.³⁵ A meta-analysis of multiple studies published in 2006 showed that gabapentin reduced the mean number of daily hot flashes by 2.05 (95% CI, -2.80 to -1.30).³⁰ Two recent reviews evaluated the efficacy and safety of gabapentin in the treatment of hot flashes in menopausal women and reported that gabapentin in daily doses ranging from 900 to 2400 mg and titration periods lasting 3 to12 days was well tolerated and effective.^35,36

A meta-analysis published in 2009 that included 4 RCTs reported significant heterogeneity from one study to another, but comparisons of gabapentin and placebo showed reductions of 20% to 30% in the frequency and severity of hot flashes with gabapentin.³⁶ The most commonly reported adverse effects included somnolence, dizziness, ataxia, fatigue, nystagmus, and peripheral edema.

Clonidine
Clonidine has been studied in oral and transdermal forms for the treatment of hot flashes in menopausal women, especially in women with breast cancer.^37-39 Data from one meta-analysis revealed significant reductions in daily hot flashes in the clonidine group compared with placebo at 4 weeks (mean difference [MD]=-0.95; 95% CI, -1.44 to -0.47) and at 8 weeks (MD=-1.63; 95% CI, -2.76 to -0.50).³⁰ Adverse effects included dry mouth, drowsiness, and dizziness. The transdermal route may avoid some of these side effects.⁴⁰

Alternative remedies

Phytoestrogen and isoflavones. Phytoestrogens are sterol molecules produced by plants. They are similar in structure to human estrogens and have been shown to have estrogen-like activity.⁴⁰ They are available as dietary soy, soy extract, and red clover extracts. Isoflavones are a type of phytoestrogen.

Comparing trials of effects of soy or isoflavone is difficult, as various formulations and amounts of these products have been used. Combining the data from these trials yielded nonsignificant results for Promensil, a red clover extract (WMD=-0.6; 95% CI, -1.8 to 0.6), and inconsistent results (sometimes favoring the intervention, other times the placebo) for soy food and soy extracts.^41-43

There is no evidence of estrogenic stimulation of the endometrium with phytoestrogens used for up to 2 years.⁴¹ Nevertheless, in the absence of evidence on the safety of long-term use, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian) or thromboembolic events should be cautious about using soy-based therapies.⁴² Long-term safety of these products has to be established before any evidence-based recommendations can be made.

Black cohosh. Actaea racemosa (formerly Cimicifuga racemosa) is the most studied and perhaps the most widely used herbal remedy for hot flashes. It is commonly known as black cohosh and has been used traditionally by Native Americans for the treatment of various medical conditions, including amenorrhea and menopause.^44,45

Remifemin is an available standardized extract. Evidence for effectiveness is limited and contradictory. Data from a recent meta-analysis showed that although there was significant heterogeneity between included trials, preparations containing black cohosh improved vasomotor symptoms overall by 26% (95% CI, 11%-40%).⁴⁵

A recent well-conducted RCT concluded that neither black cohosh nor red clover significantly reduced the frequency of symptoms compared with placebo.⁴⁶ The same study found that both botanicals were safe as administered for a 12-month period. Some case reports have identified serious adverse events including acute hepatocellular damage, which warrants further investigation, although no causal relationship has been established.⁴⁷

Evidence for safety and efficacy of antidepressants, gabapentin, clonidine, isoflavones, black cohosh, yoga, acupuncture, and herbal remedies is summarized in TABLE 2.^{30,36,41,47-55}

For more on the treatment of hot flashes, see “Clinical approach to managing hot flashes”.⁴⁰

What the future holds
The selective estrogen receptor agonist MF-101, which can induce tissue-specific estrogen-like effects, has been shown to be effective in reducing menopausal hot flashes compared with placebo in a phase II trial.⁵⁶ A larger phase III trial is in progress.

Lower and ultra-lower doses of systemic estrogen are now available and approved by the FDA, and were found effective in relieving vasomotor symptoms.^57-59 The drawback of these preparations is that they may take longer than standard-dose estrogen to achieve maximum relief of symptoms (8-12 weeks vs 4 weeks, respectively). The lower doses have been associated with fewer adverse effects (such as vaginal bleeding and breast tenderness) compared with the standard doses.^58,59 Their long-term effects on the cardiovascular system, bone, and breast are still being tested and need to be established.

Newer selective estrogen receptor modulators, especially in combination with estrogen, are another approach to menopausal symptoms currently in testing.⁶⁰

CORRESPONDENCE
Ghufran A. Jassim, MD, ABMS, MSc, Department of Family and Community Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, PO Box 15503, Adliya, Bahrain; gjassim@rcsi-mub.com

Hot flashes are the most prevalent and most bothersome symptoms of the menopausal transition and the leading cause for seeking medical attention during that period of a woman’s life.¹ They may last for a few seconds or for several minutes and may occur as frequently as every hour to several times per week. On average, women experience hot flashes for a period of 6 months to 2 years, but the symptoms may last up to 10 years or more.^2,3

Hot flashes have been reported by up to 70% of women undergoing natural menopause, and by almost all women undergoing surgical menopause.⁴ For many women, these symptoms are mild and can be managed with reassurance and counseling. For others, the symptoms are severe, overwhelming, last for many years, and impair the quality of life.

According to a community-based survey of 16,000 women, hot flashes occur most often in late perimenopause and among those with a body mass index ≥27. Hot flashes are also more common among African Americans and women who are less physically active and have a lower income.⁵

Since the publication of the Women’s Health Initiative study in 2002 raised concerns about the long-term safety of hormone therapy (HT), nonhormonal remedies have emerged as potential alternative treatments.^6,7 A wealth of evidence has accumulated on the efficacy and safety of these, and various other approaches to the management of hot flashes. This review will summarize that evidence to help you provide optimal care and assist patients in making informed choices about their treatment.

Hormone replacement therapy

HT, given as estrogen alone in women without a uterus or estrogen plus progestin in women with a uterus, is the most studied and most effective therapy for vasomotor symptoms attributable to menopause. Data from one Cochrane review showed a significant reduction in the frequency of weekly hot flashes for oral estrogen compared with placebo, with a weighted mean difference (WMD) of -17.92 (95% confidence interval [CI], -22.86 to -12.99).⁸ This was equivalent to a 75% reduction in frequency (95% CI, 64.3-82.3) for HT relative to placebo. Results were similar for both opposed and unopposed estrogen regimens.⁸

Transdermal vs oral therapy. Another review compared oral estradiol, transdermal estradiol, and placebo in terms of reduction of hot flash frequency or severity, or both.⁹ The review revealed a pooled WMD in hot flashes of -16.8 per week (95% CI, -23.4 to -10.2) for oral estradiol and -22.4 per week (95% CI, -35.9 to -10.4) for transdermal estradiol. Results were similar for opposed and unopposed estrogen regimens.⁹

Transdermal delivery of estrogen as patches, gels, and sprays delivers unmetabolized estradiol directly to the blood stream, so that lower doses can achieve similar efficacy to doses administered orally.¹⁰ Thus, the transdermal route would be in keeping with current guidelines to prescribe the lowest effective dose that relieves symptoms. Emerging research should provide more insight regarding safety and the potential for fewer health risks with transdermal HT compared with oral therapy.

Best way to discontinue? When HT is discontinued, hot flashes may return—sometimes immediately, sometimes after a few months. No evidence-based guidelines exist on the best way to discontinue HT with the least recurrence and severity of hot flashes. No optimal tapering regimen (either by dose or number of days per week that HT is taken) has yet been described in any studies, nor have any randomized controlled trials (RCTs)revealed a significant difference between tapered or abrupt discontinuation.^11,12

The breast cancer connection. The relationship between HT and breast cancer has generated considerable controversy. In the Women’s Health Initiative (WHI) trial, which included participants on estrogen-only and estrogen plus progesterone regimens, an overall increased risk (hazard ratio [HR]=1.26; 95% CI, 1.00-1.59) was reported. The increased risk fell short of statistical significance, and varied with the duration of exposure.⁶

In subsequent studies, the magnitude of the associated risk was substantially greater for the estrogen-progestogen preparation, and also higher for longer-term exposure.¹³ Additionally, a meta-analysis of 8 studies of the risk of breast cancer with combination HT resulted in an odds ratio (OR) of 1.39 (95% CI, 1.12-1.72). Estimates were higher for more than 5 years of use (OR=1.63; 95% CI, 1.22-2.18) when compared with estimates for less than 5 years of use (OR=1.35; CI, 1.16-1.57).¹⁴ Recent studies have reported a decline in the incidence of breast cancer in the United States, which has been attributed to a parallel reduction in HT use.¹⁵

In contrast to the findings for women taking combination HT, the estrogen-only arm of the WHI study showed a decrease in the overall risk of breast cancer.¹⁶ A new analysis of data on participants in the estrogen-only arm of the study shows that, 10 years after the intervention ended, a decreased risk of breast cancer persists. In addition, the increased risk of stroke and deep vein thrombosis found in the original study had dissipated, and the decreased risk of hip fracture was not maintained.

Age matters. Health outcomes in this new analysis were more favorable for younger women for coronary heart disease, heart attack, colorectal cancer, total mortality, and a global index of chronic diseases.¹⁷ Pooled results of systematic reviews and meta-analyses on HT risks are available in TABLE 1.^14,16,18-21

Progestins
Progesterone in the form of injections (Depo-Provera 150 mg, for example) or oral medroxyprogesterone acetate 20 mg daily has shown a significant reduction in hot flashes compared with placebo.²² However, associated side effects (withdrawal bleeding and weight gain) and concerns about breast cancer often limit the use of this medication.²³ Because of the paucity of evidence, transdermal progesterone creams should not be recommended.²⁴

Tibolone
Tibolone is a synthetic steroid that is structurally related to 19-nortestosterone derivatives. It has weak estrogenic, progestogenic, and androgenic properties and has shown significant reduction in hot flashes and night sweating compared with placebo.²⁵ Tibolone has also been shown to enhance mood and sexual function.²⁶ However, evidence of its safety on outcomes such as breast cancer and cardiovascular events is obscure and has shown conflicting results, especially for breast cancer.^25,26

A recent double-blinded trial on women with breast cancer found that although tibolone significantly improved vasomotor symptoms, it was associated with an increased risk of breast cancer recurrence (HR=1.40; 95% CI, 1.14-1.70]; P=.001).²⁷ Tibolone is not approved for sale in the United States.

Nonhormonal options

Lifestyle modifications
According to recent reviews, exercise is less effective than HT in relieving hot flashes, but does seems to have beneficial effects on mood, sleep, and overall quality of life.^28,29 Other lifestyle modifications such as smoking cessation and weight loss may also be of use.⁵

Antidepressants
Data from one meta-analysis showed that selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) were significantly more effective than placebo in reducing daily frequency of hot flashes (WMD=-1.13; 95% CI, -1.70 to -0.57).³⁰ Efficacy varied for individual drugs.

Venlafaxine, an SNRI, has been shown to be more effective than placebo in managing hot flashes.³¹ The effect on hot flashes was noticed after 4 weeks of treatment with the 75- and 150-mg doses, but the higher dosage was associated with more adverse effects such as dry mouth, sleeplessness, and decreased appetite.³² Even so, 93% of the participants in the venlafaxine group chose to continue treatment, because the reduction in hot flashes had significantly improved their daily lives.³¹ Desvenlafaxine, a metabolite of venlafaxine, has been shown to reduce the number of hot flashes by almost 65% from baseline at Weeks 4 and 12, with dosages of 100 and 150 mg/d.³³

The SSRIs fluoxetine, citalopram, and paroxetine in 10-, 20-, and 30-mg doses and paroxetine CR (12.5 and 25 mg) have been studied in many RCTs. All have demonstrated a significant decrease in hot flashes compared with placebo with various dosages used. SSRIs reduce hot flashes by as much as 50% to 60%, compared with 80% for estrogen.³⁴ The duration of treatment ranged from 4 weeks to 6 months.

Gabapentin
Gabapentin is approved by the FDA for the treatment of partial seizures and postherpetic neuralgia.³⁵ A meta-analysis of multiple studies published in 2006 showed that gabapentin reduced the mean number of daily hot flashes by 2.05 (95% CI, -2.80 to -1.30).³⁰ Two recent reviews evaluated the efficacy and safety of gabapentin in the treatment of hot flashes in menopausal women and reported that gabapentin in daily doses ranging from 900 to 2400 mg and titration periods lasting 3 to12 days was well tolerated and effective.^35,36

A meta-analysis published in 2009 that included 4 RCTs reported significant heterogeneity from one study to another, but comparisons of gabapentin and placebo showed reductions of 20% to 30% in the frequency and severity of hot flashes with gabapentin.³⁶ The most commonly reported adverse effects included somnolence, dizziness, ataxia, fatigue, nystagmus, and peripheral edema.

Clonidine
Clonidine has been studied in oral and transdermal forms for the treatment of hot flashes in menopausal women, especially in women with breast cancer.^37-39 Data from one meta-analysis revealed significant reductions in daily hot flashes in the clonidine group compared with placebo at 4 weeks (mean difference [MD]=-0.95; 95% CI, -1.44 to -0.47) and at 8 weeks (MD=-1.63; 95% CI, -2.76 to -0.50).³⁰ Adverse effects included dry mouth, drowsiness, and dizziness. The transdermal route may avoid some of these side effects.⁴⁰

Alternative remedies

Phytoestrogen and isoflavones. Phytoestrogens are sterol molecules produced by plants. They are similar in structure to human estrogens and have been shown to have estrogen-like activity.⁴⁰ They are available as dietary soy, soy extract, and red clover extracts. Isoflavones are a type of phytoestrogen.

Comparing trials of effects of soy or isoflavone is difficult, as various formulations and amounts of these products have been used. Combining the data from these trials yielded nonsignificant results for Promensil, a red clover extract (WMD=-0.6; 95% CI, -1.8 to 0.6), and inconsistent results (sometimes favoring the intervention, other times the placebo) for soy food and soy extracts.^41-43

There is no evidence of estrogenic stimulation of the endometrium with phytoestrogens used for up to 2 years.⁴¹ Nevertheless, in the absence of evidence on the safety of long-term use, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian) or thromboembolic events should be cautious about using soy-based therapies.⁴² Long-term safety of these products has to be established before any evidence-based recommendations can be made.

Black cohosh. Actaea racemosa (formerly Cimicifuga racemosa) is the most studied and perhaps the most widely used herbal remedy for hot flashes. It is commonly known as black cohosh and has been used traditionally by Native Americans for the treatment of various medical conditions, including amenorrhea and menopause.^44,45

Remifemin is an available standardized extract. Evidence for effectiveness is limited and contradictory. Data from a recent meta-analysis showed that although there was significant heterogeneity between included trials, preparations containing black cohosh improved vasomotor symptoms overall by 26% (95% CI, 11%-40%).⁴⁵

A recent well-conducted RCT concluded that neither black cohosh nor red clover significantly reduced the frequency of symptoms compared with placebo.⁴⁶ The same study found that both botanicals were safe as administered for a 12-month period. Some case reports have identified serious adverse events including acute hepatocellular damage, which warrants further investigation, although no causal relationship has been established.⁴⁷

Evidence for safety and efficacy of antidepressants, gabapentin, clonidine, isoflavones, black cohosh, yoga, acupuncture, and herbal remedies is summarized in TABLE 2.^{30,36,41,47-55}

For more on the treatment of hot flashes, see “Clinical approach to managing hot flashes”.⁴⁰

What the future holds
The selective estrogen receptor agonist MF-101, which can induce tissue-specific estrogen-like effects, has been shown to be effective in reducing menopausal hot flashes compared with placebo in a phase II trial.⁵⁶ A larger phase III trial is in progress.

Lower and ultra-lower doses of systemic estrogen are now available and approved by the FDA, and were found effective in relieving vasomotor symptoms.^57-59 The drawback of these preparations is that they may take longer than standard-dose estrogen to achieve maximum relief of symptoms (8-12 weeks vs 4 weeks, respectively). The lower doses have been associated with fewer adverse effects (such as vaginal bleeding and breast tenderness) compared with the standard doses.^58,59 Their long-term effects on the cardiovascular system, bone, and breast are still being tested and need to be established.

Newer selective estrogen receptor modulators, especially in combination with estrogen, are another approach to menopausal symptoms currently in testing.⁶⁰

CORRESPONDENCE
Ghufran A. Jassim, MD, ABMS, MSc, Department of Family and Community Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, PO Box 15503, Adliya, Bahrain; gjassim@rcsi-mub.com

Hot flashes are the most prevalent and most bothersome symptoms of the menopausal transition and the leading cause for seeking medical attention during that period of a woman’s life.¹ They may last for a few seconds or for several minutes and may occur as frequently as every hour to several times per week. On average, women experience hot flashes for a period of 6 months to 2 years, but the symptoms may last up to 10 years or more.^2,3

Hot flashes have been reported by up to 70% of women undergoing natural menopause, and by almost all women undergoing surgical menopause.⁴ For many women, these symptoms are mild and can be managed with reassurance and counseling. For others, the symptoms are severe, overwhelming, last for many years, and impair the quality of life.

According to a community-based survey of 16,000 women, hot flashes occur most often in late perimenopause and among those with a body mass index ≥27. Hot flashes are also more common among African Americans and women who are less physically active and have a lower income.⁵

Since the publication of the Women’s Health Initiative study in 2002 raised concerns about the long-term safety of hormone therapy (HT), nonhormonal remedies have emerged as potential alternative treatments.^6,7 A wealth of evidence has accumulated on the efficacy and safety of these, and various other approaches to the management of hot flashes. This review will summarize that evidence to help you provide optimal care and assist patients in making informed choices about their treatment.

Hormone replacement therapy

HT, given as estrogen alone in women without a uterus or estrogen plus progestin in women with a uterus, is the most studied and most effective therapy for vasomotor symptoms attributable to menopause. Data from one Cochrane review showed a significant reduction in the frequency of weekly hot flashes for oral estrogen compared with placebo, with a weighted mean difference (WMD) of -17.92 (95% confidence interval [CI], -22.86 to -12.99).⁸ This was equivalent to a 75% reduction in frequency (95% CI, 64.3-82.3) for HT relative to placebo. Results were similar for both opposed and unopposed estrogen regimens.⁸

Transdermal vs oral therapy. Another review compared oral estradiol, transdermal estradiol, and placebo in terms of reduction of hot flash frequency or severity, or both.⁹ The review revealed a pooled WMD in hot flashes of -16.8 per week (95% CI, -23.4 to -10.2) for oral estradiol and -22.4 per week (95% CI, -35.9 to -10.4) for transdermal estradiol. Results were similar for opposed and unopposed estrogen regimens.⁹

Transdermal delivery of estrogen as patches, gels, and sprays delivers unmetabolized estradiol directly to the blood stream, so that lower doses can achieve similar efficacy to doses administered orally.¹⁰ Thus, the transdermal route would be in keeping with current guidelines to prescribe the lowest effective dose that relieves symptoms. Emerging research should provide more insight regarding safety and the potential for fewer health risks with transdermal HT compared with oral therapy.

Best way to discontinue? When HT is discontinued, hot flashes may return—sometimes immediately, sometimes after a few months. No evidence-based guidelines exist on the best way to discontinue HT with the least recurrence and severity of hot flashes. No optimal tapering regimen (either by dose or number of days per week that HT is taken) has yet been described in any studies, nor have any randomized controlled trials (RCTs)revealed a significant difference between tapered or abrupt discontinuation.^11,12

The breast cancer connection. The relationship between HT and breast cancer has generated considerable controversy. In the Women’s Health Initiative (WHI) trial, which included participants on estrogen-only and estrogen plus progesterone regimens, an overall increased risk (hazard ratio [HR]=1.26; 95% CI, 1.00-1.59) was reported. The increased risk fell short of statistical significance, and varied with the duration of exposure.⁶

In subsequent studies, the magnitude of the associated risk was substantially greater for the estrogen-progestogen preparation, and also higher for longer-term exposure.¹³ Additionally, a meta-analysis of 8 studies of the risk of breast cancer with combination HT resulted in an odds ratio (OR) of 1.39 (95% CI, 1.12-1.72). Estimates were higher for more than 5 years of use (OR=1.63; 95% CI, 1.22-2.18) when compared with estimates for less than 5 years of use (OR=1.35; CI, 1.16-1.57).¹⁴ Recent studies have reported a decline in the incidence of breast cancer in the United States, which has been attributed to a parallel reduction in HT use.¹⁵

In contrast to the findings for women taking combination HT, the estrogen-only arm of the WHI study showed a decrease in the overall risk of breast cancer.¹⁶ A new analysis of data on participants in the estrogen-only arm of the study shows that, 10 years after the intervention ended, a decreased risk of breast cancer persists. In addition, the increased risk of stroke and deep vein thrombosis found in the original study had dissipated, and the decreased risk of hip fracture was not maintained.

Age matters. Health outcomes in this new analysis were more favorable for younger women for coronary heart disease, heart attack, colorectal cancer, total mortality, and a global index of chronic diseases.¹⁷ Pooled results of systematic reviews and meta-analyses on HT risks are available in TABLE 1.^14,16,18-21

Progestins
Progesterone in the form of injections (Depo-Provera 150 mg, for example) or oral medroxyprogesterone acetate 20 mg daily has shown a significant reduction in hot flashes compared with placebo.²² However, associated side effects (withdrawal bleeding and weight gain) and concerns about breast cancer often limit the use of this medication.²³ Because of the paucity of evidence, transdermal progesterone creams should not be recommended.²⁴

Tibolone
Tibolone is a synthetic steroid that is structurally related to 19-nortestosterone derivatives. It has weak estrogenic, progestogenic, and androgenic properties and has shown significant reduction in hot flashes and night sweating compared with placebo.²⁵ Tibolone has also been shown to enhance mood and sexual function.²⁶ However, evidence of its safety on outcomes such as breast cancer and cardiovascular events is obscure and has shown conflicting results, especially for breast cancer.^25,26

A recent double-blinded trial on women with breast cancer found that although tibolone significantly improved vasomotor symptoms, it was associated with an increased risk of breast cancer recurrence (HR=1.40; 95% CI, 1.14-1.70]; P=.001).²⁷ Tibolone is not approved for sale in the United States.

Nonhormonal options

Lifestyle modifications
According to recent reviews, exercise is less effective than HT in relieving hot flashes, but does seems to have beneficial effects on mood, sleep, and overall quality of life.^28,29 Other lifestyle modifications such as smoking cessation and weight loss may also be of use.⁵

Antidepressants
Data from one meta-analysis showed that selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) were significantly more effective than placebo in reducing daily frequency of hot flashes (WMD=-1.13; 95% CI, -1.70 to -0.57).³⁰ Efficacy varied for individual drugs.

Venlafaxine, an SNRI, has been shown to be more effective than placebo in managing hot flashes.³¹ The effect on hot flashes was noticed after 4 weeks of treatment with the 75- and 150-mg doses, but the higher dosage was associated with more adverse effects such as dry mouth, sleeplessness, and decreased appetite.³² Even so, 93% of the participants in the venlafaxine group chose to continue treatment, because the reduction in hot flashes had significantly improved their daily lives.³¹ Desvenlafaxine, a metabolite of venlafaxine, has been shown to reduce the number of hot flashes by almost 65% from baseline at Weeks 4 and 12, with dosages of 100 and 150 mg/d.³³

The SSRIs fluoxetine, citalopram, and paroxetine in 10-, 20-, and 30-mg doses and paroxetine CR (12.5 and 25 mg) have been studied in many RCTs. All have demonstrated a significant decrease in hot flashes compared with placebo with various dosages used. SSRIs reduce hot flashes by as much as 50% to 60%, compared with 80% for estrogen.³⁴ The duration of treatment ranged from 4 weeks to 6 months.

Gabapentin
Gabapentin is approved by the FDA for the treatment of partial seizures and postherpetic neuralgia.³⁵ A meta-analysis of multiple studies published in 2006 showed that gabapentin reduced the mean number of daily hot flashes by 2.05 (95% CI, -2.80 to -1.30).³⁰ Two recent reviews evaluated the efficacy and safety of gabapentin in the treatment of hot flashes in menopausal women and reported that gabapentin in daily doses ranging from 900 to 2400 mg and titration periods lasting 3 to12 days was well tolerated and effective.^35,36

A meta-analysis published in 2009 that included 4 RCTs reported significant heterogeneity from one study to another, but comparisons of gabapentin and placebo showed reductions of 20% to 30% in the frequency and severity of hot flashes with gabapentin.³⁶ The most commonly reported adverse effects included somnolence, dizziness, ataxia, fatigue, nystagmus, and peripheral edema.

Clonidine
Clonidine has been studied in oral and transdermal forms for the treatment of hot flashes in menopausal women, especially in women with breast cancer.^37-39 Data from one meta-analysis revealed significant reductions in daily hot flashes in the clonidine group compared with placebo at 4 weeks (mean difference [MD]=-0.95; 95% CI, -1.44 to -0.47) and at 8 weeks (MD=-1.63; 95% CI, -2.76 to -0.50).³⁰ Adverse effects included dry mouth, drowsiness, and dizziness. The transdermal route may avoid some of these side effects.⁴⁰

Alternative remedies

Phytoestrogen and isoflavones. Phytoestrogens are sterol molecules produced by plants. They are similar in structure to human estrogens and have been shown to have estrogen-like activity.⁴⁰ They are available as dietary soy, soy extract, and red clover extracts. Isoflavones are a type of phytoestrogen.

Comparing trials of effects of soy or isoflavone is difficult, as various formulations and amounts of these products have been used. Combining the data from these trials yielded nonsignificant results for Promensil, a red clover extract (WMD=-0.6; 95% CI, -1.8 to 0.6), and inconsistent results (sometimes favoring the intervention, other times the placebo) for soy food and soy extracts.^41-43

There is no evidence of estrogenic stimulation of the endometrium with phytoestrogens used for up to 2 years.⁴¹ Nevertheless, in the absence of evidence on the safety of long-term use, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian) or thromboembolic events should be cautious about using soy-based therapies.⁴² Long-term safety of these products has to be established before any evidence-based recommendations can be made.

Black cohosh. Actaea racemosa (formerly Cimicifuga racemosa) is the most studied and perhaps the most widely used herbal remedy for hot flashes. It is commonly known as black cohosh and has been used traditionally by Native Americans for the treatment of various medical conditions, including amenorrhea and menopause.^44,45

Remifemin is an available standardized extract. Evidence for effectiveness is limited and contradictory. Data from a recent meta-analysis showed that although there was significant heterogeneity between included trials, preparations containing black cohosh improved vasomotor symptoms overall by 26% (95% CI, 11%-40%).⁴⁵

A recent well-conducted RCT concluded that neither black cohosh nor red clover significantly reduced the frequency of symptoms compared with placebo.⁴⁶ The same study found that both botanicals were safe as administered for a 12-month period. Some case reports have identified serious adverse events including acute hepatocellular damage, which warrants further investigation, although no causal relationship has been established.⁴⁷

Evidence for safety and efficacy of antidepressants, gabapentin, clonidine, isoflavones, black cohosh, yoga, acupuncture, and herbal remedies is summarized in TABLE 2.^{30,36,41,47-55}

For more on the treatment of hot flashes, see “Clinical approach to managing hot flashes”.⁴⁰

What the future holds
The selective estrogen receptor agonist MF-101, which can induce tissue-specific estrogen-like effects, has been shown to be effective in reducing menopausal hot flashes compared with placebo in a phase II trial.⁵⁶ A larger phase III trial is in progress.

Lower and ultra-lower doses of systemic estrogen are now available and approved by the FDA, and were found effective in relieving vasomotor symptoms.^57-59 The drawback of these preparations is that they may take longer than standard-dose estrogen to achieve maximum relief of symptoms (8-12 weeks vs 4 weeks, respectively). The lower doses have been associated with fewer adverse effects (such as vaginal bleeding and breast tenderness) compared with the standard doses.^58,59 Their long-term effects on the cardiovascular system, bone, and breast are still being tested and need to be established.

Newer selective estrogen receptor modulators, especially in combination with estrogen, are another approach to menopausal symptoms currently in testing.⁶⁰

CORRESPONDENCE
Ghufran A. Jassim, MD, ABMS, MSc, Department of Family and Community Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, PO Box 15503, Adliya, Bahrain; gjassim@rcsi-mub.com

Among the many insulin management systems that have been developed, none has been as widely used as the sliding scale. Despite its acceptance by physicians and patients throughout the world, however, there is little evidence of the sliding scale�s efficacy.^1-11

A number of studies have focused on potential problems associated with the sliding scale, primarily related to the �roller coaster� blood glucose levels that often result. The authors of a recent literature review concluded that fluctuating glucose levels are more harmful physiologically than levels that are continuously elevated, even when the elevation is mild.¹²

In this review, we take a closer look at the failings of the sliding scale system and the advantages of adopting an insulin regimen that more closely resembles a natural physiologic state. To enable you to provide optimal support for patients with insulin-dependent diabetes, we highlight 5 principles of insulin management.

Premeal glucose levels do not reflect insulin need

In a sliding scale system, insulin administration is based primarily�and in some cases, entirely�on a single point in time. Blood glucose levels are tested before meals and at bedtime or every 6 hours, and the amount of insulin administered at that time is based on the test result.

But a premeal blood glucose level is not an accurate predictor of the insulin needed at that time; it is simply a reflection of the insulin previously administered. Insulin given in response to the current blood glucose, then, may compound a prior dosing error, leading to serious drops or spikes in blood sugar. These wide fluctuations present challenges in both inpatient and outpatient settings, although each uses a different sliding scale system.

In the hospital, basal insulin is often withheld
In an inpatient setting, an IV insulin protocol is typically used, and patients may be placed on a sliding scale regimen even if their prehospital HbA1c was in a satisfactory range. The sliding scale is usually dependent on blood glucose levels obtained by bedside monitoring,¹³ tested every 6 hours. Hospitalized patients often receive no basal insulin, and, because rapid-acting insulin lasts only 3 to 4 hours, the results of their glucose tests are based on the intake of short-acting (regular) insulin alone. Short-acting insulin lasts about 6 to 8 hours, depending on dosage.

A sliding scale regimen generally has a cutoff point, below which no insulin is given. But skipping a dose because a patient�s glucose levels dip below the cut point can leave him or her without insulin for many hours, resulting in a spike in blood sugar.

Standing orders: One size does not �fit� all. Failure to individualize the insulin protocol is another problem with the use of sliding scales in an inpatient setting.⁷ Typically the sliding scale protocol is preprinted on standing orders, which are the same for all patients who require insulin and are under the care of a particular physician. Rarely are the orders adjusted for factors such as age, weight, IV glucose intake, time of day, size of the upcoming meal (or absence of food, at midnight), or type of diabetes. Outcomes studies of a sliding scale protocol in a hospital setting found that its use did not consistently achieve the desired results.⁷

Outpatient sliding scale fails to normalize blood glucose levels
Unlike the sliding scale regimen commonly used in hospitals, outpatient protocols often incorporate basal insulin. But that fact alone is not enough to eliminate the peaks and dips in blood glucose levels associated with this approach.

The dose of basal insulin�a long-acting or twice-a-day intermediate-acting insulin�is sometimes given on a sliding scale. More commonly, the sliding scale is used to determine the dose of rapid- or short-acting insulin administered prior to meals, based on the preprandial blood glucose reading and/or the expected caloric or carbohydrate intake. The wide fluctuations and excessive spikes in blood glucose levels associated with sliding scale management may cause reactive oxidative stress�a trigger for vascular damage, especially in patients with type 2 diabetes.^14,15

CASE Louis C, an 8-year-old boy diagnosed with type 1 diabetes at age 4, was under the care of a pediatric endocrinologist, who used a �pattern� insulin management system to achieve blood glucose control. Louis was maintained on a 4-dose-per-day schedule: Rapid-acting insulin was administered before each meal (with the dosage adjusted based on the pattern of postprandial glucose values over the last 2 or 3 days and by his expected caloric intake and activity level) and a basal insulin given once a day. His HbA1c was 7.2%. He rarely experienced even mild hypoglycemia.

When his family relocated, Louis was taken to another specialist�a pediatric endocrinologist at a medical school affiliated with a children�s hospital. This physician thought that pattern management was out of date, and insisted that sliding scale was the only acceptable approach.

Thus, Louis was put on a regimen of intermediate-acting insulin before breakfast and at bedtime and rapid-acting insulin, given on a sliding scale, at mealtimes. The rapid-acting insulin was withheld if his blood glucose level was ?100 mg/dL; one unit was administered if his level was 101-150 mg/dL, 2 units for a reading of 151-200 mg/dL, and so on. Within 3 months, Louis� HbA1c had risen to 9.8%, and he developed significant hypoglycemia, especially in the afternoon and during the night. Louis� mother reported that he was tired all the time and wondered if it was because his blood glucose levels were �on a roller coaster.�

Adjust�don�t skip�insulin doses

The best medical care aims to reproduce the physiologic state to the extent possible. For patients with insulin-dependent diabetes, that means receiving 24-hour basal insulin coverage, as well as a bolus of insulin with each meal, to mimic normal insulin secretion.^16,17

Pharmacodynamically, short-acting insulin lasts 6 to 8 hours. It should be given every 6 hours, in 4 equal doses, without ever skipping a dose. Rapid-acting insulin, too, should never be skipped. Because food or caloric intake requires insulin at the time of ingestion to facilitate glucose transport across the cell membrane, rapid-acting insulin should be administered before each meal (in 3 daily doses if the patient is also taking a long-acting or intermediate-acting insulin, or 6 times a day if used without basal insulin).

Rapid-acting insulin is essentially out of the system by the time of the next preprandial blood glucose test. Therefore, premeal levels mainly measure the action of the basal (long- or intermediate-acting) insulin. The package inserts for rapid-acting insulin state that a 2-hour postprandial blood glucose level should be used to adjust the next dose of rapid-acting insulin.^18,19 (See �5 principles of insulin management�)

A closer look at pattern management
Measuring�and recording�both fasting and 1- or 2-hour postprandial blood glucose levels over a 2- to 3-day period is the first step in pattern management. The patient�s insulin intake is determined by the pattern of these values, with adjustments made for anticipated need. Here�s how it works in an outpatient setting:

• In the morning, the patient receives short- or rapid-acting insulin; the number of units is determined by his or her previous after-breakfast blood glucose levels, with adjustments depending on the caloric intake expected at breakfast and any deviation in the patient�s normal activity level to follow.
• At noon, the short- or rapid-acting insulin is adjusted for the size of the lunch and the patient�s recorded blood glucose levels 1 to 2 hours after lunch.
• At suppertime, the amount of insulin depends on the meal and the patient�s previous after-supper blood glucose levels.
• At bedtime, intermediate- or long-acting insulin is administered in an amount adjusted according to the patient�s fasting and/or premeal blood glucose levels. If the values are elevated because of extra eating or decreased activity, a correction dose (See �Calculating a correction dose�) may be needed to restore his or her blood sugar to within an acceptable range.²⁰

Calculating a correction dose

If a patient�s blood glucose level rises above a predetermined value, he or she may need an insulin bolus to bring it down. Calculating the supplemental dose is a 2-step process: First, an insulin sensitivity factor (ISF) is calculated; then, the desired blood glucose level is subtracted from the actual blood glucose reading and divided by the ISF.

Step 1: Divide 1700 by the total daily dose (eg, 50 units)

Step 2: Subtract the desired blood glucose level (110 mg/dL) from the actual blood glucose reading (eg, 240 mg/dL) and divide by the ISF

Commentary: For an adult of average size,* an additional 3.8 (or 4) units of rapid-acting insulin should bring the patient�s blood glucose level down to 110 mg/dL. If the elevated blood glucose level occurs at this same time on subsequent days, it is an indication that the dose at the previous meal should be increased.

*An insulin-sensitive child might require less insulin, and an overweight adult might require more. When in doubt, give half of the calculated correction dose and repeat in an hour, if needed.

Other factors that may influence blood glucose levels include the injection site (insulin is absorbed faster when administered in the abdomen vs the leg); the type, or combination, of insulin used, ie, long-acting basal insulin vs intermediate-acting vs (or combined with) short- or rapid-acting insulin; and lifestyle (sedentary, active, very active, or suddenly becoming very active), which also affects the absorption of insulin.²¹

CASE After 5 months, Louis and his family returned to their former home. But by then, Louis had an HbA1c of 10.2%. On the advice of the pediatric endocrinologist who had treated him initially, Louis was put back on a pattern management system, using both rapid- and long-acting insulin. Three months later, his HbA1c was down to 7.6%�close to its previous level�and he no longer had problems with hypoglycemia.

CORRESPONDENCE
Diana W. Guthrie, PhD, Mid-America Diabetes Associates, 200 South Hillside, Wichita, KS 672111; dguthrie@kumc.edu

Among the many insulin management systems that have been developed, none has been as widely used as the sliding scale. Despite its acceptance by physicians and patients throughout the world, however, there is little evidence of the sliding scale�s efficacy.^1-11

A number of studies have focused on potential problems associated with the sliding scale, primarily related to the �roller coaster� blood glucose levels that often result. The authors of a recent literature review concluded that fluctuating glucose levels are more harmful physiologically than levels that are continuously elevated, even when the elevation is mild.¹²

In this review, we take a closer look at the failings of the sliding scale system and the advantages of adopting an insulin regimen that more closely resembles a natural physiologic state. To enable you to provide optimal support for patients with insulin-dependent diabetes, we highlight 5 principles of insulin management.

Premeal glucose levels do not reflect insulin need

In a sliding scale system, insulin administration is based primarily�and in some cases, entirely�on a single point in time. Blood glucose levels are tested before meals and at bedtime or every 6 hours, and the amount of insulin administered at that time is based on the test result.

But a premeal blood glucose level is not an accurate predictor of the insulin needed at that time; it is simply a reflection of the insulin previously administered. Insulin given in response to the current blood glucose, then, may compound a prior dosing error, leading to serious drops or spikes in blood sugar. These wide fluctuations present challenges in both inpatient and outpatient settings, although each uses a different sliding scale system.

In the hospital, basal insulin is often withheld
In an inpatient setting, an IV insulin protocol is typically used, and patients may be placed on a sliding scale regimen even if their prehospital HbA1c was in a satisfactory range. The sliding scale is usually dependent on blood glucose levels obtained by bedside monitoring,¹³ tested every 6 hours. Hospitalized patients often receive no basal insulin, and, because rapid-acting insulin lasts only 3 to 4 hours, the results of their glucose tests are based on the intake of short-acting (regular) insulin alone. Short-acting insulin lasts about 6 to 8 hours, depending on dosage.

A sliding scale regimen generally has a cutoff point, below which no insulin is given. But skipping a dose because a patient�s glucose levels dip below the cut point can leave him or her without insulin for many hours, resulting in a spike in blood sugar.

Standing orders: One size does not �fit� all. Failure to individualize the insulin protocol is another problem with the use of sliding scales in an inpatient setting.⁷ Typically the sliding scale protocol is preprinted on standing orders, which are the same for all patients who require insulin and are under the care of a particular physician. Rarely are the orders adjusted for factors such as age, weight, IV glucose intake, time of day, size of the upcoming meal (or absence of food, at midnight), or type of diabetes. Outcomes studies of a sliding scale protocol in a hospital setting found that its use did not consistently achieve the desired results.⁷

Outpatient sliding scale fails to normalize blood glucose levels
Unlike the sliding scale regimen commonly used in hospitals, outpatient protocols often incorporate basal insulin. But that fact alone is not enough to eliminate the peaks and dips in blood glucose levels associated with this approach.

The dose of basal insulin�a long-acting or twice-a-day intermediate-acting insulin�is sometimes given on a sliding scale. More commonly, the sliding scale is used to determine the dose of rapid- or short-acting insulin administered prior to meals, based on the preprandial blood glucose reading and/or the expected caloric or carbohydrate intake. The wide fluctuations and excessive spikes in blood glucose levels associated with sliding scale management may cause reactive oxidative stress�a trigger for vascular damage, especially in patients with type 2 diabetes.^14,15

CASE Louis C, an 8-year-old boy diagnosed with type 1 diabetes at age 4, was under the care of a pediatric endocrinologist, who used a �pattern� insulin management system to achieve blood glucose control. Louis was maintained on a 4-dose-per-day schedule: Rapid-acting insulin was administered before each meal (with the dosage adjusted based on the pattern of postprandial glucose values over the last 2 or 3 days and by his expected caloric intake and activity level) and a basal insulin given once a day. His HbA1c was 7.2%. He rarely experienced even mild hypoglycemia.

When his family relocated, Louis was taken to another specialist�a pediatric endocrinologist at a medical school affiliated with a children�s hospital. This physician thought that pattern management was out of date, and insisted that sliding scale was the only acceptable approach.

Thus, Louis was put on a regimen of intermediate-acting insulin before breakfast and at bedtime and rapid-acting insulin, given on a sliding scale, at mealtimes. The rapid-acting insulin was withheld if his blood glucose level was ?100 mg/dL; one unit was administered if his level was 101-150 mg/dL, 2 units for a reading of 151-200 mg/dL, and so on. Within 3 months, Louis� HbA1c had risen to 9.8%, and he developed significant hypoglycemia, especially in the afternoon and during the night. Louis� mother reported that he was tired all the time and wondered if it was because his blood glucose levels were �on a roller coaster.�

Adjust�don�t skip�insulin doses

The best medical care aims to reproduce the physiologic state to the extent possible. For patients with insulin-dependent diabetes, that means receiving 24-hour basal insulin coverage, as well as a bolus of insulin with each meal, to mimic normal insulin secretion.^16,17

Pharmacodynamically, short-acting insulin lasts 6 to 8 hours. It should be given every 6 hours, in 4 equal doses, without ever skipping a dose. Rapid-acting insulin, too, should never be skipped. Because food or caloric intake requires insulin at the time of ingestion to facilitate glucose transport across the cell membrane, rapid-acting insulin should be administered before each meal (in 3 daily doses if the patient is also taking a long-acting or intermediate-acting insulin, or 6 times a day if used without basal insulin).

Rapid-acting insulin is essentially out of the system by the time of the next preprandial blood glucose test. Therefore, premeal levels mainly measure the action of the basal (long- or intermediate-acting) insulin. The package inserts for rapid-acting insulin state that a 2-hour postprandial blood glucose level should be used to adjust the next dose of rapid-acting insulin.^18,19 (See �5 principles of insulin management�)

A closer look at pattern management
Measuring�and recording�both fasting and 1- or 2-hour postprandial blood glucose levels over a 2- to 3-day period is the first step in pattern management. The patient�s insulin intake is determined by the pattern of these values, with adjustments made for anticipated need. Here�s how it works in an outpatient setting:

• In the morning, the patient receives short- or rapid-acting insulin; the number of units is determined by his or her previous after-breakfast blood glucose levels, with adjustments depending on the caloric intake expected at breakfast and any deviation in the patient�s normal activity level to follow.
• At noon, the short- or rapid-acting insulin is adjusted for the size of the lunch and the patient�s recorded blood glucose levels 1 to 2 hours after lunch.
• At suppertime, the amount of insulin depends on the meal and the patient�s previous after-supper blood glucose levels.
• At bedtime, intermediate- or long-acting insulin is administered in an amount adjusted according to the patient�s fasting and/or premeal blood glucose levels. If the values are elevated because of extra eating or decreased activity, a correction dose (See �Calculating a correction dose�) may be needed to restore his or her blood sugar to within an acceptable range.²⁰

Calculating a correction dose

If a patient�s blood glucose level rises above a predetermined value, he or she may need an insulin bolus to bring it down. Calculating the supplemental dose is a 2-step process: First, an insulin sensitivity factor (ISF) is calculated; then, the desired blood glucose level is subtracted from the actual blood glucose reading and divided by the ISF.

Step 1: Divide 1700 by the total daily dose (eg, 50 units)

Step 2: Subtract the desired blood glucose level (110 mg/dL) from the actual blood glucose reading (eg, 240 mg/dL) and divide by the ISF

Commentary: For an adult of average size,* an additional 3.8 (or 4) units of rapid-acting insulin should bring the patient�s blood glucose level down to 110 mg/dL. If the elevated blood glucose level occurs at this same time on subsequent days, it is an indication that the dose at the previous meal should be increased.

*An insulin-sensitive child might require less insulin, and an overweight adult might require more. When in doubt, give half of the calculated correction dose and repeat in an hour, if needed.

Other factors that may influence blood glucose levels include the injection site (insulin is absorbed faster when administered in the abdomen vs the leg); the type, or combination, of insulin used, ie, long-acting basal insulin vs intermediate-acting vs (or combined with) short- or rapid-acting insulin; and lifestyle (sedentary, active, very active, or suddenly becoming very active), which also affects the absorption of insulin.²¹

CASE After 5 months, Louis and his family returned to their former home. But by then, Louis had an HbA1c of 10.2%. On the advice of the pediatric endocrinologist who had treated him initially, Louis was put back on a pattern management system, using both rapid- and long-acting insulin. Three months later, his HbA1c was down to 7.6%�close to its previous level�and he no longer had problems with hypoglycemia.

CORRESPONDENCE
Diana W. Guthrie, PhD, Mid-America Diabetes Associates, 200 South Hillside, Wichita, KS 672111; dguthrie@kumc.edu

Among the many insulin management systems that have been developed, none has been as widely used as the sliding scale. Despite its acceptance by physicians and patients throughout the world, however, there is little evidence of the sliding scale�s efficacy.^1-11

A number of studies have focused on potential problems associated with the sliding scale, primarily related to the �roller coaster� blood glucose levels that often result. The authors of a recent literature review concluded that fluctuating glucose levels are more harmful physiologically than levels that are continuously elevated, even when the elevation is mild.¹²

In this review, we take a closer look at the failings of the sliding scale system and the advantages of adopting an insulin regimen that more closely resembles a natural physiologic state. To enable you to provide optimal support for patients with insulin-dependent diabetes, we highlight 5 principles of insulin management.

Premeal glucose levels do not reflect insulin need

In a sliding scale system, insulin administration is based primarily�and in some cases, entirely�on a single point in time. Blood glucose levels are tested before meals and at bedtime or every 6 hours, and the amount of insulin administered at that time is based on the test result.

But a premeal blood glucose level is not an accurate predictor of the insulin needed at that time; it is simply a reflection of the insulin previously administered. Insulin given in response to the current blood glucose, then, may compound a prior dosing error, leading to serious drops or spikes in blood sugar. These wide fluctuations present challenges in both inpatient and outpatient settings, although each uses a different sliding scale system.

In the hospital, basal insulin is often withheld
In an inpatient setting, an IV insulin protocol is typically used, and patients may be placed on a sliding scale regimen even if their prehospital HbA1c was in a satisfactory range. The sliding scale is usually dependent on blood glucose levels obtained by bedside monitoring,¹³ tested every 6 hours. Hospitalized patients often receive no basal insulin, and, because rapid-acting insulin lasts only 3 to 4 hours, the results of their glucose tests are based on the intake of short-acting (regular) insulin alone. Short-acting insulin lasts about 6 to 8 hours, depending on dosage.

A sliding scale regimen generally has a cutoff point, below which no insulin is given. But skipping a dose because a patient�s glucose levels dip below the cut point can leave him or her without insulin for many hours, resulting in a spike in blood sugar.

Standing orders: One size does not �fit� all. Failure to individualize the insulin protocol is another problem with the use of sliding scales in an inpatient setting.⁷ Typically the sliding scale protocol is preprinted on standing orders, which are the same for all patients who require insulin and are under the care of a particular physician. Rarely are the orders adjusted for factors such as age, weight, IV glucose intake, time of day, size of the upcoming meal (or absence of food, at midnight), or type of diabetes. Outcomes studies of a sliding scale protocol in a hospital setting found that its use did not consistently achieve the desired results.⁷

Outpatient sliding scale fails to normalize blood glucose levels
Unlike the sliding scale regimen commonly used in hospitals, outpatient protocols often incorporate basal insulin. But that fact alone is not enough to eliminate the peaks and dips in blood glucose levels associated with this approach.

The dose of basal insulin�a long-acting or twice-a-day intermediate-acting insulin�is sometimes given on a sliding scale. More commonly, the sliding scale is used to determine the dose of rapid- or short-acting insulin administered prior to meals, based on the preprandial blood glucose reading and/or the expected caloric or carbohydrate intake. The wide fluctuations and excessive spikes in blood glucose levels associated with sliding scale management may cause reactive oxidative stress�a trigger for vascular damage, especially in patients with type 2 diabetes.^14,15

CASE Louis C, an 8-year-old boy diagnosed with type 1 diabetes at age 4, was under the care of a pediatric endocrinologist, who used a �pattern� insulin management system to achieve blood glucose control. Louis was maintained on a 4-dose-per-day schedule: Rapid-acting insulin was administered before each meal (with the dosage adjusted based on the pattern of postprandial glucose values over the last 2 or 3 days and by his expected caloric intake and activity level) and a basal insulin given once a day. His HbA1c was 7.2%. He rarely experienced even mild hypoglycemia.

When his family relocated, Louis was taken to another specialist�a pediatric endocrinologist at a medical school affiliated with a children�s hospital. This physician thought that pattern management was out of date, and insisted that sliding scale was the only acceptable approach.

Thus, Louis was put on a regimen of intermediate-acting insulin before breakfast and at bedtime and rapid-acting insulin, given on a sliding scale, at mealtimes. The rapid-acting insulin was withheld if his blood glucose level was ?100 mg/dL; one unit was administered if his level was 101-150 mg/dL, 2 units for a reading of 151-200 mg/dL, and so on. Within 3 months, Louis� HbA1c had risen to 9.8%, and he developed significant hypoglycemia, especially in the afternoon and during the night. Louis� mother reported that he was tired all the time and wondered if it was because his blood glucose levels were �on a roller coaster.�

Adjust�don�t skip�insulin doses

The best medical care aims to reproduce the physiologic state to the extent possible. For patients with insulin-dependent diabetes, that means receiving 24-hour basal insulin coverage, as well as a bolus of insulin with each meal, to mimic normal insulin secretion.^16,17

Pharmacodynamically, short-acting insulin lasts 6 to 8 hours. It should be given every 6 hours, in 4 equal doses, without ever skipping a dose. Rapid-acting insulin, too, should never be skipped. Because food or caloric intake requires insulin at the time of ingestion to facilitate glucose transport across the cell membrane, rapid-acting insulin should be administered before each meal (in 3 daily doses if the patient is also taking a long-acting or intermediate-acting insulin, or 6 times a day if used without basal insulin).

Rapid-acting insulin is essentially out of the system by the time of the next preprandial blood glucose test. Therefore, premeal levels mainly measure the action of the basal (long- or intermediate-acting) insulin. The package inserts for rapid-acting insulin state that a 2-hour postprandial blood glucose level should be used to adjust the next dose of rapid-acting insulin.^18,19 (See �5 principles of insulin management�)