Tanner Nissly, DO

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu

CASE

Erica S*, age 22, has intermittent asthma and presents to your clinic to discuss refills of her albuterol inhaler. Two years ago, she was hospitalized for a severe asthma exacerbation because she was unable to afford medications. Since then, her asthma has generally been well controlled, and she needs to use albuterol only 1 or 2 times per month. Ms. S says she has no morning chest tightness or nocturnal coughing, but she does experience increased wheezing and shortness of breath with activity.

What would you recommend? Would your recommendation differ if she had persistent asthma?

* The patient’s name has been changed to protect her identity .

As of 2020, more than 20 million adults and 4 million children younger than 18 years of age in the United States were living with asthma.¹ In 2019 alone, there were more than 1.8 million asthma-related emergency department visits for adults, and more than 790,000 asthma-related emergency department visits for children. Asthma caused more than 4000 deaths in the United States in 2020.¹ Given the scale of the burden of asthma, it is not surprising that approximately 60% of all asthma visits occur in primary care settings,² making it essential that primary care physicians stay abreast of recent developments in asthma diagnosis and management.

Since 1991, the major guidance on best practices for asthma management in the United States has been provided by the National Heart, Lung, and Blood Institute (NHLBI)’s National Asthma Education and Prevention Program (NAEPP). Its last major update on asthma was released in 2007 as the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3).³ Since that time, there has been significant progress in our understanding of asthma as a complex spectrum of phenotypes, which has advanced our knowledge of pathophysiology and helped refine treatment. In contrast to the NAEPP, the Global Initiative for Asthma (GINA) has published annual updates on asthma management incorporating up-to-date information.⁴ In response to the continuously evolving body of knowledge on asthma, the NAEPP Coordinating Committee Expert Panel Working Group published the 2020 Focused Updates to the Asthma Management Guidelines.⁵

Given the vast resources available on asthma, our purpose in this article is not to provide a comprehensive review of the stepwise approach to asthma management, but instead to summarize the major points presented in the 2020 Focused Updates and how these compare and contrast with the latest guidance from GINA.

A heterogeneous disease

Asthma is a chronic respiratory disease characterized by both variable symptoms and airflow limitation that change over time, often in response to external triggers such as exercise, allergens, and viral respiratory infections. Common symptoms include wheezing, cough, chest tightness, and shortness of breath. Despite the common symptomatology, asthma is a heterogeneous disease with several recognizable phenotypes including allergic, nonallergic, and asthma with persistent airflow limitation.

Continue to: The airflow limitation...

The airflow limitation in asthma occurs through both airway hyperresponsiveness to external stimuli and chronic airway inflammation. Airway constriction is regulated by nerves to the smooth muscles of the airway. Beta-2 nerve receptors have long been the target of asthma therapy with both short-acting beta-2 agonists (SABAs) as rescue treatment and long-acting beta-2 agonists (LABAs) as maintenance therapy.^3,4 However, there is increasing evidence that cholinergic nerves also have a role in airway regulation in asthma, and long-acting muscarinic antagonists (LAMAs) have recently shown benefit as add-on therapy in some types of asthma.^4-6 Inhaled corticosteroids (ICSs) have long held an important role in reducing airway inflammation, especially in the setting of allergic or eosinophilic inflammation.^3-5

Spirometry is essential to asthma Dx—but what about FeNO?

The mainstay of asthma diagnosis is confirming both a history of variable respiratory symptoms and variable expiratory airflow limitation exhibited by spirometry. Obstruction is defined as a reduced forced expiratory volume in 1 second (FEV₁) and as a decreased ratio of FEV₁ over forced vital capacity (FVC) based on predicted values. An increase of at least 12% in FEV₁ post bronchodilator use indicates asthma for adolescents and adults.

A fractional exhaled nitric oxide level > 50 ppb makes eosinophilic inflammation and treatment response to an inhaled corticosteroid more likely.

More recently, studies have examined the role of fractional exhaled nitric oxide (FeNO) in the diagnosis of asthma. The 2020 Focused Updates report states that FeNO may be useful when the diagnosis of asthma is uncertain using initial history, physical exam, and spirometry findings, or when spirometry cannot be performed reliably.⁵ Levels of FeNO > 50 ppb make eosinophilic inflammation and treatment response to an ICS more likely. FeNO levels < 25 ppb make inflammatory asthma less likely and should prompt a search for an alternate diagnosis.⁵ For patients with FeNO of 25 to 50 ppb, more detailed clinical context is needed. In contrast, the 2022 GINA updates conclude that FeNO is not yet an established diagnostic tool for asthma.⁴

Management

When to start and adjust an ICS

ICSs continue to be the primary controller treatment for patients with asthma. However, the NAEPP and GINA have provided different guidance on how to initiate step therapy (TABLE^3-5). NAEPP focuses on severity classification, while GINA recommends treatment initiation based on presenting symptoms. Since both guidelines recommend early ­follow-up and adjustment of therapy according to level of control, this difference becomes less apparent in ongoing care.

A more fundamental difference is seen in the recommended therapies for each step (TABLE^3-5). Whereas the 2020 Focused Updates prefers a SABA as needed in step 1, GINA favors a low-dose combination of ICS-formoterol as needed. The GINA recommendation is driven by supportive evidence for early initiation of low-dose ICS in any patient with asthma for greater improvement in lung function. This also addresses concerns that overuse of as-needed SABAs may increase the risk for severe exacerbations. Evidence also indicates that the risk for asthma-­related death and urgent asthma-related health care increases when a patient takes a SABA as needed as monotherapy compared with ICS therapy, even with good symptom control.^7,8

Continue to: Dosing of an ICS

Dosing of an ICS is based on step therapy regardless of the guideline used and is given at a total daily amount—low, medium, and high—for each age group. When initiating an ICS, consider differences between available treatment options (eg, cost, administration technique, likely patient adherence, patient preferences) and employ shared decision-making strategies. Dosing may need to be limited depending on the commercially available product, especially when used in combination with a LABA. However, as GINA emphasizes, a low-dose ICS provides the most clinical benefit. A high-dose ICS is needed by very few patients and is associated with greater risk for local and systemic adverse effects, such as adrenal suppression. With these considerations, both guidelines recommend using the lowest effective ICS dose and stepping up and down according to the patient’s comfort level.

Give an ICS time to work. Although an ICS can begin to reduce inflammation within days of initiation, the full benefit may be evident only after 2 to 3 months.⁴ Once the patient’s asthma is well controlled for 3 months, stepping down the dose can be considered and approached carefully. Complete cessation of ICSs is associated with significantly higher risk for exacerbations. Therefore, a general recommendation is to step down an ICS by 50% or reduce ICS-LABA from twice-daily administration to once daily. Risk for exacerbation after step-down therapy is heightened if the patient has a history of exacerbation or an emergency department visit in the past 12 months, a low baseline FEV₁, or a loss of control during a dose reduction (ie, airway hyperresponsiveness and sputum eosinophilia).

Weigh the utility of FeNO measurement. The 2020 Focused Updates also recommend considering FeNO measurement to guide treatment choice and monitoring, although this is based on overall low certainty of evidence.⁵ GINA affirms the mixed evidence for FeNO, stating that while a few studies have shown significantly reduced exacerbations among children, adolescents, and pregnant women with FeNO-guided treatment, other studies have shown no significant difference in exacerbations.^4,9-15 At this time, the role for FeNO in asthma management remains inconclusive, and access to it is limited across primary care settings.

Inhaled corticosteroids can begin to reduce inflammation within days, but the full benefit may be evident only after 2 to 3 months.

When assessing response to ICS therapy (and before stepping up therapy), consider patient adherence, inhaler technique, whether allergen exposure is persistent, and possible comorbidities. Inhaler technique can be especially challenging, as each inhaler varies in appearance and operation. Employ patient education strategies (eg, videos, demonstration, teach-back methods). If stepping up therapy is indicated, adding a LABA is recommended over increasing the ICS dose. Since asthma is variable, stepping up therapy can be tried and reassessed in 2 to 3 months.

SMART is preferred

Single maintenance and reliever therapy (SMART) with ICS-formoterol, used as needed, is the preferred therapy for steps 3 and 4 in both GINA recommendations and the 2020 Focused Updates (TABLE^3-5). GINA also prefers SMART for step 5. The recommended SMART combination that has been studied contains budesonide (or beclomethasone, not available in combination in the United States) for the ICS and formoterol for the LABA in a single inhaler that is used both daily for control and as needed for rescue therapy.

Continue to: Other ICS-formoterol...

Other ICS-formoterol or ICS-LABA combinations can be considered for controller therapy, especially those described in the NAEPP and GINA alternative step therapy recommendations. However, SMART has been more effective than other combinations in reducing exacerbations and provides similar or better levels of control at lower average ICS doses (compared with ICS-LABA with SABA or ICS with SABA) for adolescent and adult patients.^3,4 As patients use greater amounts of ICS-formoterol during episodes of increased symptoms, this additional ICS may augment the anti-inflammatory effects. SMART may also improve adherence, especially among those who confuse multiple inhalers.

SMART is also recommended for use in children. Specifically, from the 2020 Focused Updates, any patient ≥ 4 years of age with a severe exacerbation in the past year is a good SMART candidate. Also consider SMART before higher-dose ICS-LABA and SABA as needed. Additional benefits in this younger patient population are fewer medical visits or less systemic corticosteroid use with improved control and quality of life.

Caveats. Patients who have a difficult time recognizing symptoms may not be good candidates for SMART, due to the potential for taking higher or lower ICS doses than necessary.

SMART specifically refers to formoterol combinations that produce bronchodilation within 1 to 3 minutes.¹⁶ For example, the SMART strategy is not recommended for patients using ICS-salmeterol as controller therapy.

Although guideline supported, SMART options are not approved by the US Food and Drug Administration for use as reliever therapy.

Continue to: With the single combination...

With the single combination inhaler, consider the dosing limits of formoterol. The maximum daily amount of formoterol for ­adolescents and adults is 54 μg (12 puffs) delivered with the budesonide-formoterol metered dose inhaler. When using SMART as reliever therapy, the low-dose ICS-­formoterol recommendation remains. However, depending on insurance coverage, a 1-month supply of ­ICS-formoterol may not be sufficient for additional reliever therapy use.

The role of LAMAs as add-on therapy

Bronchiolar smooth muscle tone is mediated by complex mechanisms that include cholinergic stimulation at muscarinic (M3) receptors.¹⁷ LAMAs, a mainstay in the management of chronic obstructive pulmonary disease (COPD), are likely to be effective in reducing asthma exacerbations and the need for oral steroids. When patients have not achieved control at step 4 of asthma therapy, both the 2020 Focused Updates and GINA now recommend considering a LAMA (eg, tiotropium) as add-on therapy for patients > 12 years of age already taking medium-dose ICS-LABA for modest improvements in lung function and reductions in severe exacerbations. GINA recommendations also now include a LAMA as add-on treatment for those ages 6 to 11 years, as some evidence supports the use in school-aged children.¹⁸ It is important to note that LAMAs should not replace a LABA for treatment, as the ICS-LABA combination is likely more effective than ICS-LAMA.

Addressing asthma-COPD overlap

Asthma and COPD are frequently and frustratingly intertwined without clear demarcation. This tends to occur as patients age and chronic lung changes appear from longstanding asthma. However, it is important to distinguish between these conditions, because there are clearly delineated treatments for each that can improve outcomes.

The priority in addressing asthma-COPD overlap (ACO) is to evaluate symptoms and determine if asthma or COPD is predominant.¹⁹ This includes establishing patient age at which symptoms began, variation and triggers of symptoms, and history of exposures to smoke/environmental respiratory toxins. Age 40 years is often used as the tipping point at which symptom onset favors a diagnosis of COPD. Serial spirometry may also be used to evaluate lung function over time and persistence of disease. If a firm diagnosis is evasive, consider a referral to a pulmonary specialist for further testing.

The priority in addressing asthma-COPD overlap is to evaluate symptoms and determine if asthma or COPD is predominant.

Choosing to use an ICS or LAMA depends on which underlying disorder is more likely. While early COPD management includes LAMA + LABA, the addition of an ICS is reserved for more severe disease. High-dose ICSs, particularly fluticasone, should be limited in COPD due to an increased risk for pneumonia. For asthma or ACO, the addition of an ICS is critical and prioritized to reduce airway inflammation and risk for exacerbations and death. While a LAMA is likely useful earlier in ACO, it is not used until step 5 of asthma therapy. Given the complexities of ACO treatment, further research is needed to provide adequate guidance.

CASE

For Ms. S, you would be wise to use an ICS-formoterol combination for as-needed symptom relief. If symptoms were more persistent, you could consider recommending the ICS-­formoterol inhaler as SMART therapy, with regular doses taken twice daily and extra ­doses taken as needed.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota School of Medicine, Department of Family Medicine and Community Health, 2426 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu

Opioids were involved in 42,249 deaths in the United States in 2016, and opioid overdoses have quintupled since 1999.¹ Among the causes behind these statistics is increased opiate prescribing by physicians—with primary care providers accounting for about one half of opiate prescriptions.² As a result, the Centers for Disease Control and Prevention has issued a 4-part response for physicians,³ which includes careful opiate prescribing, expanded access to naloxone, prevention of opioid use disorder (OUD), and expanded use of medication-assisted treatment (MAT) of addiction—with the goal of preventing and managing OUD.

CASE

Fred R, a 55-year-old man who has been taking oxycodone, 70 mg/d, for chronic pain for longer than 10 years, visits your clinic for a prescription refill. His prescription monitoring program confirms the long history of regular oxycodone use, with the dosage escalating over the past 6 months. He recently was discharged from the hospital after an overdose of opiates.

Treat addiction as you would any chronic disease: Anticipate relapse, engage support systems, and work with the patient to obtain a higher level of care.

Mr. R admits to using heroin after running out of oxycodone. He is in mild withdrawal, with a score of 8 (of a possible 48) on the Clinical Opioid Withdrawal Scale⁴ (COWS, which assigns point values to 11 common symptoms to gauge the severity of opioid withdrawal and, by inference, the patient’s degree of physical dependence). You determine that Mr. R is frightened about his use of oxycodone and would like to stop; he has tried to stop several times on his own but always relapses when withdrawal becomes severe.

How would you proceed with the care of this patient?

What is OUD? How is the diagnosis made?

OUD is a combination of cognitive, behavioral, and physiologic symptoms arising from continued use of opioids despite significant health, legal, or relationship problems related to their use. The disorder is diagnosed based on specific criteria provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)(TABLE 1)⁵ and is revealed by 1) a careful history that delineates a problematic pattern of opioid use, 2) physical examination, and 3) urine toxicology screen.

Identification of acute opioid intoxication can also be useful when working up a patient in whom OUD is suspected; findings of acute opioid intoxication on physical examination include constricted pupils, head-nodding, excessive sleepiness, and drooping eyelids. Other physical signs of illicit opioid use include track marks around veins of the arm, evidence of repeated trauma, and stigmata of liver dysfunction. Withdrawal can present as agitation, rhinorrhea, dilated pupils, nausea, diarrhea, yawning, and gooseflesh. The COWS, which, as noted in the case, assigns point values to withdrawal symptoms, can be helpful in determining the severity of withdrawal.⁴

What is the differential Dx of OUD?

When OUD is likely, but not clearly diagnosable, on the basis of findings, consider a mental health disorder: depressive disorder, bipolar disorder, attention deficit–hyperactivity disorder, personality disorder, and polysubstance use disorder. Concurrent diagnosis of substance abuse and a mental health disorder is common; treatment requires that both disorders be addressed simultaneously.⁶ Assessing for use or abuse of, and addiction to, other substances is vital to ensure proper diagnosis and effective therapy. Polysubstance dependence can be more difficult to treat than single-substance abuse or addiction alone.

Continue to: How is OUD treated?

How is OUD treated?

This article reviews MAT with buprenorphine; other MAT options include methadone and naltrexone. Regardless of the indicated agent chosen, MAT has been shown to be superior to abstinence alone or abstinence with counseling interventions in maintaining sobriety.⁷

Evidence of efficacy. In a longitudinal cohort study of patients who received MAT with buprenorphine initiated in general practice, patients in whom buprenorphine therapy was interrupted had a greatly increased risk of all-cause mortality (hazard ratio=29.04; 95% confidence interval, 10.04-83.99).⁸ The study highlights the harm-reduction treatment philosophy of MAT with buprenorphine: The regimen can be used to keep a patient alive while working toward sobriety.

We encourage physicians to treat addiction as they would any chronic disease. The strategy includes anticipating relapse, engaging support systems (eg, family, counselors, social groups, Alcoholics Anonymous, Narcotics Anonymous [NA]), and working with the patient to obtain a higher level of care, as indicated.

Pharmacology and induction. Alone or in combination with naloxone, buprenorphine can be used as in-office-based MAT. Buprenorphine is a partial opiate agonist that binds tightly to opioid receptors and can block the effects of other opiates. An advantage of buprenorphine is its low likelihood of overdose, due to the drug’s so-called ceiling effect at a dosage of 24 mg/d;⁹ dosages above this amount have little increased medication effect.

Dosing of buprenorphine is variable from patient to patient, with a maximum dosage of 24 mg/d. Therapy can be initiated safely at home, although some physicians prefer in-office induction. It is important that the patient be in moderate withdrawal (as determined by the score on the COWS) before initiation, because buprenorphine, as a partial agonist, can precipitate withdrawal by displacing full opiate agonists from opioid receptors.

Continue to: In our experience...

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms. This can be repeated for multiple doses until withdrawal is relieved, usually with a maximum dosage of 6 to 8 mg in the initial 1 or 2 days of treatment. Rapid reassessment is required after induction, preferably in 1 to 3 days. Dosing should be gradually increased in 2- to 4-mg increments until 1) the patient has no withdrawal symptoms in a 24-hour period and 2) craving for opiates is adequately controlled.

Note: Primary care physicians must complete an 8-hour online training course to obtain a US Drug Enforcement Administration waiver to prescribe buprenorphine.

How should coordination of care be approached?

Actual prescribing and monitoring of buprenorphine is not complex, but many physicians are intimidated by the perceived difficulty of coordination of care. The American Society of Addiction Medicine's national practice guideline recommends that buprenorphine and other MAT protocols be offered as a part of a comprehensive treatment plan that includes psychosocial treatment.⁷ This combination leads to the greatest potential for ongoing remission of OUD. Although many primary care clinics do not have chemical dependency counseling available at their primary location, partnering with community organizations and other mental health resources can meet this need. Coordination of care with home services, behavioral health, and psychiatry is common in primary care, and is no different for OUD.

There are administrative requirements for a clinic that offers MAT (TABLE 2),⁷ including tracking of numbers of patients who are taking buprenorphine. During the first year of prescribing buprenorphine, a physician or other provider is permitted to care for only 30 patients; once the first year has passed, that provider can apply to care for as many as 100 patients. In addition, the Drug Enforcement Administration might conduct site visits to ensure that proper documentation and tracking of patients is being undertaken. These requirements can seem daunting, but careful monitoring of patient panels can alleviate concerns. For clinics that use an electronic medical record, we recommend developing the capability to pull lists by either buprenorphine prescriptions or diagnosis codes.

Continue to: CASE

CASE

After you and Mr. R discuss his addiction, you decide to initiate treatment that includes buprenorphine. You have a specimen collected for a urine toxicology screen and blood drawn for a baseline liver function panel, hepatitis panel, and human immunodeficiency virus screen, and provide him with resources (nearby treatment center, an NA meeting location) for treating OUD. You write a prescription for #8 buprenorphine and naloxone, 2 mg/0.5 mg films, and instruct Mr. R to: take 1 film when withdrawal symptoms become worse; wait 1 hour; and take another film if he is still experiencing withdrawal symptoms. He can repeat this dosing regimen until he reaches 8 mg/d of buprenorphine (4 films). You schedule follow-up in 2 days.

At follow-up, the patient reports that taking 3 films alleviated withdrawal symptoms, but that symptoms returned approximately 12 hours later, at which time he took the fourth film. This helped him through until the next day, when he again took 3 films in the morning and 1 film in the late evening. He feels that this regimen is helping relieve withdrawal symptoms and cravings. You provide a prescription for buprenorphine and naloxone, 8 mg/2 mg daily, and request a follow-up visit in 5 days.

At the next visit, Mr. R reports that he still has cravings for oxycodone. You increase the dosage of buprenorphine and naloxone to 12 mg/3 mg daily.

At the next visit, he reports no longer having cravings.

You continue to monitor Mr. R with urine drug screening and discussion of his recovery with the help of his family and support network. After 3 months of consistent visits, he fails to show up for his every-2-or-3-week appointment.

Continue to: Four days later...

Four days later, Mr. R shows up at the clinic, apologizing for missing the appointment and assuring you that this won’t happen again. Rapid urine drug screening is positive for morphine. When confronted, he admits using heroin. He reports that his cravings had increased, for which he took buprenorphine and naloxone above the prescribed dosage, and ran out of films early. He then used heroin 3 times to prevent withdrawal.

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms.

Mr. R admits that he has been having cravings for oxycodone since the start of treatment for addiction, but thought he was strong enough to overcome the cravings. He feels disappointed and embarrassed about this; he wants to continue with buprenorphine, he tells you, but worries that you will refuse to continue seeing him now.

Using shared decision-making, you opt to increase the buprenorphine dosage by 4 mg (to 16 mg/d—ie, 2 films of buprenorphine and naloxone, 8 mg/2 mg) to alleviate cravings. You instruct him to engage his support network, including his family and NA sponsor, and to start outpatient group therapy. He tells you that he is willing to go back to weekly clinic visits until he is stabilized.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota Medical School Twin Cities, Department of Family Medicine and Community Health, 1020 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu.

Opioids were involved in 42,249 deaths in the United States in 2016, and opioid overdoses have quintupled since 1999.¹ Among the causes behind these statistics is increased opiate prescribing by physicians—with primary care providers accounting for about one half of opiate prescriptions.² As a result, the Centers for Disease Control and Prevention has issued a 4-part response for physicians,³ which includes careful opiate prescribing, expanded access to naloxone, prevention of opioid use disorder (OUD), and expanded use of medication-assisted treatment (MAT) of addiction—with the goal of preventing and managing OUD.

CASE

Fred R, a 55-year-old man who has been taking oxycodone, 70 mg/d, for chronic pain for longer than 10 years, visits your clinic for a prescription refill. His prescription monitoring program confirms the long history of regular oxycodone use, with the dosage escalating over the past 6 months. He recently was discharged from the hospital after an overdose of opiates.

Treat addiction as you would any chronic disease: Anticipate relapse, engage support systems, and work with the patient to obtain a higher level of care.

Mr. R admits to using heroin after running out of oxycodone. He is in mild withdrawal, with a score of 8 (of a possible 48) on the Clinical Opioid Withdrawal Scale⁴ (COWS, which assigns point values to 11 common symptoms to gauge the severity of opioid withdrawal and, by inference, the patient’s degree of physical dependence). You determine that Mr. R is frightened about his use of oxycodone and would like to stop; he has tried to stop several times on his own but always relapses when withdrawal becomes severe.

How would you proceed with the care of this patient?

What is OUD? How is the diagnosis made?

OUD is a combination of cognitive, behavioral, and physiologic symptoms arising from continued use of opioids despite significant health, legal, or relationship problems related to their use. The disorder is diagnosed based on specific criteria provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)(TABLE 1)⁵ and is revealed by 1) a careful history that delineates a problematic pattern of opioid use, 2) physical examination, and 3) urine toxicology screen.

Identification of acute opioid intoxication can also be useful when working up a patient in whom OUD is suspected; findings of acute opioid intoxication on physical examination include constricted pupils, head-nodding, excessive sleepiness, and drooping eyelids. Other physical signs of illicit opioid use include track marks around veins of the arm, evidence of repeated trauma, and stigmata of liver dysfunction. Withdrawal can present as agitation, rhinorrhea, dilated pupils, nausea, diarrhea, yawning, and gooseflesh. The COWS, which, as noted in the case, assigns point values to withdrawal symptoms, can be helpful in determining the severity of withdrawal.⁴

What is the differential Dx of OUD?

When OUD is likely, but not clearly diagnosable, on the basis of findings, consider a mental health disorder: depressive disorder, bipolar disorder, attention deficit–hyperactivity disorder, personality disorder, and polysubstance use disorder. Concurrent diagnosis of substance abuse and a mental health disorder is common; treatment requires that both disorders be addressed simultaneously.⁶ Assessing for use or abuse of, and addiction to, other substances is vital to ensure proper diagnosis and effective therapy. Polysubstance dependence can be more difficult to treat than single-substance abuse or addiction alone.

Continue to: How is OUD treated?

How is OUD treated?

This article reviews MAT with buprenorphine; other MAT options include methadone and naltrexone. Regardless of the indicated agent chosen, MAT has been shown to be superior to abstinence alone or abstinence with counseling interventions in maintaining sobriety.⁷

Evidence of efficacy. In a longitudinal cohort study of patients who received MAT with buprenorphine initiated in general practice, patients in whom buprenorphine therapy was interrupted had a greatly increased risk of all-cause mortality (hazard ratio=29.04; 95% confidence interval, 10.04-83.99).⁸ The study highlights the harm-reduction treatment philosophy of MAT with buprenorphine: The regimen can be used to keep a patient alive while working toward sobriety.

We encourage physicians to treat addiction as they would any chronic disease. The strategy includes anticipating relapse, engaging support systems (eg, family, counselors, social groups, Alcoholics Anonymous, Narcotics Anonymous [NA]), and working with the patient to obtain a higher level of care, as indicated.

Pharmacology and induction. Alone or in combination with naloxone, buprenorphine can be used as in-office-based MAT. Buprenorphine is a partial opiate agonist that binds tightly to opioid receptors and can block the effects of other opiates. An advantage of buprenorphine is its low likelihood of overdose, due to the drug’s so-called ceiling effect at a dosage of 24 mg/d;⁹ dosages above this amount have little increased medication effect.

Dosing of buprenorphine is variable from patient to patient, with a maximum dosage of 24 mg/d. Therapy can be initiated safely at home, although some physicians prefer in-office induction. It is important that the patient be in moderate withdrawal (as determined by the score on the COWS) before initiation, because buprenorphine, as a partial agonist, can precipitate withdrawal by displacing full opiate agonists from opioid receptors.

Continue to: In our experience...

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms. This can be repeated for multiple doses until withdrawal is relieved, usually with a maximum dosage of 6 to 8 mg in the initial 1 or 2 days of treatment. Rapid reassessment is required after induction, preferably in 1 to 3 days. Dosing should be gradually increased in 2- to 4-mg increments until 1) the patient has no withdrawal symptoms in a 24-hour period and 2) craving for opiates is adequately controlled.

Note: Primary care physicians must complete an 8-hour online training course to obtain a US Drug Enforcement Administration waiver to prescribe buprenorphine.

How should coordination of care be approached?

Actual prescribing and monitoring of buprenorphine is not complex, but many physicians are intimidated by the perceived difficulty of coordination of care. The American Society of Addiction Medicine's national practice guideline recommends that buprenorphine and other MAT protocols be offered as a part of a comprehensive treatment plan that includes psychosocial treatment.⁷ This combination leads to the greatest potential for ongoing remission of OUD. Although many primary care clinics do not have chemical dependency counseling available at their primary location, partnering with community organizations and other mental health resources can meet this need. Coordination of care with home services, behavioral health, and psychiatry is common in primary care, and is no different for OUD.

There are administrative requirements for a clinic that offers MAT (TABLE 2),⁷ including tracking of numbers of patients who are taking buprenorphine. During the first year of prescribing buprenorphine, a physician or other provider is permitted to care for only 30 patients; once the first year has passed, that provider can apply to care for as many as 100 patients. In addition, the Drug Enforcement Administration might conduct site visits to ensure that proper documentation and tracking of patients is being undertaken. These requirements can seem daunting, but careful monitoring of patient panels can alleviate concerns. For clinics that use an electronic medical record, we recommend developing the capability to pull lists by either buprenorphine prescriptions or diagnosis codes.

Continue to: CASE

CASE

After you and Mr. R discuss his addiction, you decide to initiate treatment that includes buprenorphine. You have a specimen collected for a urine toxicology screen and blood drawn for a baseline liver function panel, hepatitis panel, and human immunodeficiency virus screen, and provide him with resources (nearby treatment center, an NA meeting location) for treating OUD. You write a prescription for #8 buprenorphine and naloxone, 2 mg/0.5 mg films, and instruct Mr. R to: take 1 film when withdrawal symptoms become worse; wait 1 hour; and take another film if he is still experiencing withdrawal symptoms. He can repeat this dosing regimen until he reaches 8 mg/d of buprenorphine (4 films). You schedule follow-up in 2 days.

At follow-up, the patient reports that taking 3 films alleviated withdrawal symptoms, but that symptoms returned approximately 12 hours later, at which time he took the fourth film. This helped him through until the next day, when he again took 3 films in the morning and 1 film in the late evening. He feels that this regimen is helping relieve withdrawal symptoms and cravings. You provide a prescription for buprenorphine and naloxone, 8 mg/2 mg daily, and request a follow-up visit in 5 days.

At the next visit, Mr. R reports that he still has cravings for oxycodone. You increase the dosage of buprenorphine and naloxone to 12 mg/3 mg daily.

At the next visit, he reports no longer having cravings.

You continue to monitor Mr. R with urine drug screening and discussion of his recovery with the help of his family and support network. After 3 months of consistent visits, he fails to show up for his every-2-or-3-week appointment.

Continue to: Four days later...

Four days later, Mr. R shows up at the clinic, apologizing for missing the appointment and assuring you that this won’t happen again. Rapid urine drug screening is positive for morphine. When confronted, he admits using heroin. He reports that his cravings had increased, for which he took buprenorphine and naloxone above the prescribed dosage, and ran out of films early. He then used heroin 3 times to prevent withdrawal.

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms.

Mr. R admits that he has been having cravings for oxycodone since the start of treatment for addiction, but thought he was strong enough to overcome the cravings. He feels disappointed and embarrassed about this; he wants to continue with buprenorphine, he tells you, but worries that you will refuse to continue seeing him now.

Using shared decision-making, you opt to increase the buprenorphine dosage by 4 mg (to 16 mg/d—ie, 2 films of buprenorphine and naloxone, 8 mg/2 mg) to alleviate cravings. You instruct him to engage his support network, including his family and NA sponsor, and to start outpatient group therapy. He tells you that he is willing to go back to weekly clinic visits until he is stabilized.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota Medical School Twin Cities, Department of Family Medicine and Community Health, 1020 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu.

Opioids were involved in 42,249 deaths in the United States in 2016, and opioid overdoses have quintupled since 1999.¹ Among the causes behind these statistics is increased opiate prescribing by physicians—with primary care providers accounting for about one half of opiate prescriptions.² As a result, the Centers for Disease Control and Prevention has issued a 4-part response for physicians,³ which includes careful opiate prescribing, expanded access to naloxone, prevention of opioid use disorder (OUD), and expanded use of medication-assisted treatment (MAT) of addiction—with the goal of preventing and managing OUD.

CASE

Fred R, a 55-year-old man who has been taking oxycodone, 70 mg/d, for chronic pain for longer than 10 years, visits your clinic for a prescription refill. His prescription monitoring program confirms the long history of regular oxycodone use, with the dosage escalating over the past 6 months. He recently was discharged from the hospital after an overdose of opiates.

Treat addiction as you would any chronic disease: Anticipate relapse, engage support systems, and work with the patient to obtain a higher level of care.

Mr. R admits to using heroin after running out of oxycodone. He is in mild withdrawal, with a score of 8 (of a possible 48) on the Clinical Opioid Withdrawal Scale⁴ (COWS, which assigns point values to 11 common symptoms to gauge the severity of opioid withdrawal and, by inference, the patient’s degree of physical dependence). You determine that Mr. R is frightened about his use of oxycodone and would like to stop; he has tried to stop several times on his own but always relapses when withdrawal becomes severe.

How would you proceed with the care of this patient?

What is OUD? How is the diagnosis made?

OUD is a combination of cognitive, behavioral, and physiologic symptoms arising from continued use of opioids despite significant health, legal, or relationship problems related to their use. The disorder is diagnosed based on specific criteria provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)(TABLE 1)⁵ and is revealed by 1) a careful history that delineates a problematic pattern of opioid use, 2) physical examination, and 3) urine toxicology screen.

Identification of acute opioid intoxication can also be useful when working up a patient in whom OUD is suspected; findings of acute opioid intoxication on physical examination include constricted pupils, head-nodding, excessive sleepiness, and drooping eyelids. Other physical signs of illicit opioid use include track marks around veins of the arm, evidence of repeated trauma, and stigmata of liver dysfunction. Withdrawal can present as agitation, rhinorrhea, dilated pupils, nausea, diarrhea, yawning, and gooseflesh. The COWS, which, as noted in the case, assigns point values to withdrawal symptoms, can be helpful in determining the severity of withdrawal.⁴

What is the differential Dx of OUD?

When OUD is likely, but not clearly diagnosable, on the basis of findings, consider a mental health disorder: depressive disorder, bipolar disorder, attention deficit–hyperactivity disorder, personality disorder, and polysubstance use disorder. Concurrent diagnosis of substance abuse and a mental health disorder is common; treatment requires that both disorders be addressed simultaneously.⁶ Assessing for use or abuse of, and addiction to, other substances is vital to ensure proper diagnosis and effective therapy. Polysubstance dependence can be more difficult to treat than single-substance abuse or addiction alone.

Continue to: How is OUD treated?

How is OUD treated?

This article reviews MAT with buprenorphine; other MAT options include methadone and naltrexone. Regardless of the indicated agent chosen, MAT has been shown to be superior to abstinence alone or abstinence with counseling interventions in maintaining sobriety.⁷

Evidence of efficacy. In a longitudinal cohort study of patients who received MAT with buprenorphine initiated in general practice, patients in whom buprenorphine therapy was interrupted had a greatly increased risk of all-cause mortality (hazard ratio=29.04; 95% confidence interval, 10.04-83.99).⁸ The study highlights the harm-reduction treatment philosophy of MAT with buprenorphine: The regimen can be used to keep a patient alive while working toward sobriety.

We encourage physicians to treat addiction as they would any chronic disease. The strategy includes anticipating relapse, engaging support systems (eg, family, counselors, social groups, Alcoholics Anonymous, Narcotics Anonymous [NA]), and working with the patient to obtain a higher level of care, as indicated.

Pharmacology and induction. Alone or in combination with naloxone, buprenorphine can be used as in-office-based MAT. Buprenorphine is a partial opiate agonist that binds tightly to opioid receptors and can block the effects of other opiates. An advantage of buprenorphine is its low likelihood of overdose, due to the drug’s so-called ceiling effect at a dosage of 24 mg/d;⁹ dosages above this amount have little increased medication effect.

Dosing of buprenorphine is variable from patient to patient, with a maximum dosage of 24 mg/d. Therapy can be initiated safely at home, although some physicians prefer in-office induction. It is important that the patient be in moderate withdrawal (as determined by the score on the COWS) before initiation, because buprenorphine, as a partial agonist, can precipitate withdrawal by displacing full opiate agonists from opioid receptors.

Continue to: In our experience...

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms. This can be repeated for multiple doses until withdrawal is relieved, usually with a maximum dosage of 6 to 8 mg in the initial 1 or 2 days of treatment. Rapid reassessment is required after induction, preferably in 1 to 3 days. Dosing should be gradually increased in 2- to 4-mg increments until 1) the patient has no withdrawal symptoms in a 24-hour period and 2) craving for opiates is adequately controlled.

Note: Primary care physicians must complete an 8-hour online training course to obtain a US Drug Enforcement Administration waiver to prescribe buprenorphine.

How should coordination of care be approached?

Actual prescribing and monitoring of buprenorphine is not complex, but many physicians are intimidated by the perceived difficulty of coordination of care. The American Society of Addiction Medicine's national practice guideline recommends that buprenorphine and other MAT protocols be offered as a part of a comprehensive treatment plan that includes psychosocial treatment.⁷ This combination leads to the greatest potential for ongoing remission of OUD. Although many primary care clinics do not have chemical dependency counseling available at their primary location, partnering with community organizations and other mental health resources can meet this need. Coordination of care with home services, behavioral health, and psychiatry is common in primary care, and is no different for OUD.

There are administrative requirements for a clinic that offers MAT (TABLE 2),⁷ including tracking of numbers of patients who are taking buprenorphine. During the first year of prescribing buprenorphine, a physician or other provider is permitted to care for only 30 patients; once the first year has passed, that provider can apply to care for as many as 100 patients. In addition, the Drug Enforcement Administration might conduct site visits to ensure that proper documentation and tracking of patients is being undertaken. These requirements can seem daunting, but careful monitoring of patient panels can alleviate concerns. For clinics that use an electronic medical record, we recommend developing the capability to pull lists by either buprenorphine prescriptions or diagnosis codes.

Continue to: CASE

CASE

After you and Mr. R discuss his addiction, you decide to initiate treatment that includes buprenorphine. You have a specimen collected for a urine toxicology screen and blood drawn for a baseline liver function panel, hepatitis panel, and human immunodeficiency virus screen, and provide him with resources (nearby treatment center, an NA meeting location) for treating OUD. You write a prescription for #8 buprenorphine and naloxone, 2 mg/0.5 mg films, and instruct Mr. R to: take 1 film when withdrawal symptoms become worse; wait 1 hour; and take another film if he is still experiencing withdrawal symptoms. He can repeat this dosing regimen until he reaches 8 mg/d of buprenorphine (4 films). You schedule follow-up in 2 days.

At follow-up, the patient reports that taking 3 films alleviated withdrawal symptoms, but that symptoms returned approximately 12 hours later, at which time he took the fourth film. This helped him through until the next day, when he again took 3 films in the morning and 1 film in the late evening. He feels that this regimen is helping relieve withdrawal symptoms and cravings. You provide a prescription for buprenorphine and naloxone, 8 mg/2 mg daily, and request a follow-up visit in 5 days.

At the next visit, Mr. R reports that he still has cravings for oxycodone. You increase the dosage of buprenorphine and naloxone to 12 mg/3 mg daily.

At the next visit, he reports no longer having cravings.

You continue to monitor Mr. R with urine drug screening and discussion of his recovery with the help of his family and support network. After 3 months of consistent visits, he fails to show up for his every-2-or-3-week appointment.

Continue to: Four days later...

Four days later, Mr. R shows up at the clinic, apologizing for missing the appointment and assuring you that this won’t happen again. Rapid urine drug screening is positive for morphine. When confronted, he admits using heroin. He reports that his cravings had increased, for which he took buprenorphine and naloxone above the prescribed dosage, and ran out of films early. He then used heroin 3 times to prevent withdrawal.

In our experience, a common induction method is to give 2 to 4 mg buprenorphine, followed by a 1-hour assessment of withdrawal symptoms.

Mr. R admits that he has been having cravings for oxycodone since the start of treatment for addiction, but thought he was strong enough to overcome the cravings. He feels disappointed and embarrassed about this; he wants to continue with buprenorphine, he tells you, but worries that you will refuse to continue seeing him now.

Using shared decision-making, you opt to increase the buprenorphine dosage by 4 mg (to 16 mg/d—ie, 2 films of buprenorphine and naloxone, 8 mg/2 mg) to alleviate cravings. You instruct him to engage his support network, including his family and NA sponsor, and to start outpatient group therapy. He tells you that he is willing to go back to weekly clinic visits until he is stabilized.

CORRESPONDENCE
Tanner Nissly, DO, University of Minnesota Medical School Twin Cities, Department of Family Medicine and Community Health, 1020 West Broadway Avenue, Minneapolis, MN 55411; nissl003@umn.edu.

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; aslatten@umn.edu.

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; aslatten@umn.edu.

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; aslatten@umn.edu.

Illustrative case

A 10-year-old boy is brought in by his father for asthma follow-up. The child uses an albuterol inhaler, but has had increased coughing and wheezing recently. You are ready to step up his asthma therapy to include ICS. But the patient’s father questions this, noting that he recently read that steroids may reduce a child’s growth. How should you respond?

Inhaled corticosteroids (ICS) are a mainstay in the treatment of asthma ranging from mild persistent to severe. Standards of care for asthma treatment involve a stepwise approach, with ICS added if symptoms are not controlled with short-acting beta antagonists alone.² In addition, monotherapy with ICS is more effective for controlling symptoms than leukotriene inhibitors or other controller medications, while also decreasing hospitalizations and nocturnal awakenings and improving quality of life—with few side effects.³

What we know about ICS and children’s growth
One adverse effect of ICS, however, is that of “decreased linear growth velocity”⁴—ie, slowing the rate at which children grow. Until recently, children were thought to “catch up” later in life, either by growing for a longer period of time than they would had they not taken ICS or by growing at an increased velocity after ICS medications are discontinued.^4-6

Study summary: The effect on growth is small, but long-lasting

Kelly et al conducted a prospective observational cohort study that followed 943 (90.7%) participants in the Childhood Asthma Management Program (CAMP) in the years after the randomized controlled trial (RCT) ended.

A double-blind, placebo-controlled RCT, CAMP studied the linear growth of 1041 children with mild-to-moderate persistent asthma who were divided into 3 treatment groups: One group received 200 mcg inhaled budesonide twice daily; a second group received 8 mg inhaled nedocromil twice daily; and a third group received placebo. Albuterol was used symptomatically by all 3 groups.⁷ The children ranged in age from 5 to 13 years at the start of the study; 98 patients—split evenly among the 3 treatment arms—were lost to follow-up.

During the 4 to 6 years of the CAMP trial, the budesonide group received a mean total of 636 mg ICS, whereas the nedocromil and placebo groups received an average of 88.5 and 109.4 mg ICS, respectively. After the RCT ended, all participants had standardized asthma treatment, receiving mean adjusted total doses of ICS of 381 mg for the budesonide group, 347.9 mg for the nedocromil group, and 355 mg for the placebo group.

Patients’ height was measured every 6 months for the next 4.5 years, and once or twice a year thereafter until they reached adult height (at a mean age of 24.9±2.7 years).

ICS users were a half inch shorter
Long-term ICS use was linked to a lower adult height. The adjusted mean height was 171.1 cm for the budesonide group vs 172.3 cm for those on placebo, a difference of 1.2 cm, or 0.47 inch (95% confidence interval [CI], −1.9 to −0.5; P=.001); the mean adult height in the nedocromil group (172.1 cm) was similar to that of the placebo group (−0.2 cm; 95% CI, −0.9 to 0.5; P=.61).

The lower adult height in the ICS group did not vary significantly based on sex, age at trial entry, race, or duration of asthma prior to trial entry; however, dose was a key factor. A larger daily dose of budesonide—particularly in the first 2 years of the RCT—was associated with a lower adult height (about −0.1 cm for each mcg/kg in that 2-year time frame). This was consistent with results from studies that looked at other types of ICS (beclomethasone, fluticasone, and mometasone).^8-11

The study also showed that growth velocity was reduced in the first 2 years of assigned treatment with budesonide, and this was primarily among prepubertal participants. After the initial 2-year slowing in growth rate, the children resumed growing at normal speeds.

What’s new: Now we know: Children don’t “catch up"

Retrospective studies have reported that children on ICS for mild persistent to moderate asthma would have an initial slowing in growth velocity but then “catch up” by growing for a longer period of time.^3-5 This is the first prospective study with good follow-up to show that ICS use affects long-term growth and adult height. While the effect is not large, some children and their families might be concerned about it.

Caveats: ICS use was atypical

The randomized controlled portion of the study used a prescribed dose of budesonide without regard to symptoms. This is not the typical pattern of ICS use. In addition, compliance with ICS varies significantly.¹² Because the effect on adult height appears to be dose dependent, however, we think the results of this study are valid.

In addition, there was a placebo control group (and big differences in exposure to ICS) only for the duration of the RCT. During the subsequent study, all patients received equivalent doses of ICS. This means that the variation in mean adult height achieved can be primarily ascribed to participants’ use of ICS during the 4- to 6-year CAMP trial. Of note, the effect of ICS was greatest in prepubertal participants, so there may be a diminished effect as teens approach their final height.

The study did not look at the effect of ICS use in patients with severe asthma—the group most likely to use ICS. However, the benefits of ICS for those with severe asthma likely outweigh any negative effects on adult height.

Challenges to implementation: What to tell patients

The message we convey to patients (and parents) about ICS use is a nuanced one. We can stress that ICS remain very important in the treatment of asthma and, while it appears that their use causes a slight decrease in adult height, most children with persistent asthma benefit from ICS.

Acknowledgement

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

Illustrative case

A 10-year-old boy is brought in by his father for asthma follow-up. The child uses an albuterol inhaler, but has had increased coughing and wheezing recently. You are ready to step up his asthma therapy to include ICS. But the patient’s father questions this, noting that he recently read that steroids may reduce a child’s growth. How should you respond?

Inhaled corticosteroids (ICS) are a mainstay in the treatment of asthma ranging from mild persistent to severe. Standards of care for asthma treatment involve a stepwise approach, with ICS added if symptoms are not controlled with short-acting beta antagonists alone.² In addition, monotherapy with ICS is more effective for controlling symptoms than leukotriene inhibitors or other controller medications, while also decreasing hospitalizations and nocturnal awakenings and improving quality of life—with few side effects.³

What we know about ICS and children’s growth
One adverse effect of ICS, however, is that of “decreased linear growth velocity”⁴—ie, slowing the rate at which children grow. Until recently, children were thought to “catch up” later in life, either by growing for a longer period of time than they would had they not taken ICS or by growing at an increased velocity after ICS medications are discontinued.^4-6

Study summary: The effect on growth is small, but long-lasting

Kelly et al conducted a prospective observational cohort study that followed 943 (90.7%) participants in the Childhood Asthma Management Program (CAMP) in the years after the randomized controlled trial (RCT) ended.

A double-blind, placebo-controlled RCT, CAMP studied the linear growth of 1041 children with mild-to-moderate persistent asthma who were divided into 3 treatment groups: One group received 200 mcg inhaled budesonide twice daily; a second group received 8 mg inhaled nedocromil twice daily; and a third group received placebo. Albuterol was used symptomatically by all 3 groups.⁷ The children ranged in age from 5 to 13 years at the start of the study; 98 patients—split evenly among the 3 treatment arms—were lost to follow-up.

During the 4 to 6 years of the CAMP trial, the budesonide group received a mean total of 636 mg ICS, whereas the nedocromil and placebo groups received an average of 88.5 and 109.4 mg ICS, respectively. After the RCT ended, all participants had standardized asthma treatment, receiving mean adjusted total doses of ICS of 381 mg for the budesonide group, 347.9 mg for the nedocromil group, and 355 mg for the placebo group.

Patients’ height was measured every 6 months for the next 4.5 years, and once or twice a year thereafter until they reached adult height (at a mean age of 24.9±2.7 years).

ICS users were a half inch shorter
Long-term ICS use was linked to a lower adult height. The adjusted mean height was 171.1 cm for the budesonide group vs 172.3 cm for those on placebo, a difference of 1.2 cm, or 0.47 inch (95% confidence interval [CI], −1.9 to −0.5; P=.001); the mean adult height in the nedocromil group (172.1 cm) was similar to that of the placebo group (−0.2 cm; 95% CI, −0.9 to 0.5; P=.61).

The lower adult height in the ICS group did not vary significantly based on sex, age at trial entry, race, or duration of asthma prior to trial entry; however, dose was a key factor. A larger daily dose of budesonide—particularly in the first 2 years of the RCT—was associated with a lower adult height (about −0.1 cm for each mcg/kg in that 2-year time frame). This was consistent with results from studies that looked at other types of ICS (beclomethasone, fluticasone, and mometasone).^8-11

The study also showed that growth velocity was reduced in the first 2 years of assigned treatment with budesonide, and this was primarily among prepubertal participants. After the initial 2-year slowing in growth rate, the children resumed growing at normal speeds.

What’s new: Now we know: Children don’t “catch up"

Retrospective studies have reported that children on ICS for mild persistent to moderate asthma would have an initial slowing in growth velocity but then “catch up” by growing for a longer period of time.^3-5 This is the first prospective study with good follow-up to show that ICS use affects long-term growth and adult height. While the effect is not large, some children and their families might be concerned about it.

Caveats: ICS use was atypical

The randomized controlled portion of the study used a prescribed dose of budesonide without regard to symptoms. This is not the typical pattern of ICS use. In addition, compliance with ICS varies significantly.¹² Because the effect on adult height appears to be dose dependent, however, we think the results of this study are valid.

In addition, there was a placebo control group (and big differences in exposure to ICS) only for the duration of the RCT. During the subsequent study, all patients received equivalent doses of ICS. This means that the variation in mean adult height achieved can be primarily ascribed to participants’ use of ICS during the 4- to 6-year CAMP trial. Of note, the effect of ICS was greatest in prepubertal participants, so there may be a diminished effect as teens approach their final height.

The study did not look at the effect of ICS use in patients with severe asthma—the group most likely to use ICS. However, the benefits of ICS for those with severe asthma likely outweigh any negative effects on adult height.

Challenges to implementation: What to tell patients

The message we convey to patients (and parents) about ICS use is a nuanced one. We can stress that ICS remain very important in the treatment of asthma and, while it appears that their use causes a slight decrease in adult height, most children with persistent asthma benefit from ICS.

Acknowledgement

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

Illustrative case

A 10-year-old boy is brought in by his father for asthma follow-up. The child uses an albuterol inhaler, but has had increased coughing and wheezing recently. You are ready to step up his asthma therapy to include ICS. But the patient’s father questions this, noting that he recently read that steroids may reduce a child’s growth. How should you respond?

Inhaled corticosteroids (ICS) are a mainstay in the treatment of asthma ranging from mild persistent to severe. Standards of care for asthma treatment involve a stepwise approach, with ICS added if symptoms are not controlled with short-acting beta antagonists alone.² In addition, monotherapy with ICS is more effective for controlling symptoms than leukotriene inhibitors or other controller medications, while also decreasing hospitalizations and nocturnal awakenings and improving quality of life—with few side effects.³

What we know about ICS and children’s growth
One adverse effect of ICS, however, is that of “decreased linear growth velocity”⁴—ie, slowing the rate at which children grow. Until recently, children were thought to “catch up” later in life, either by growing for a longer period of time than they would had they not taken ICS or by growing at an increased velocity after ICS medications are discontinued.^4-6

Study summary: The effect on growth is small, but long-lasting

Kelly et al conducted a prospective observational cohort study that followed 943 (90.7%) participants in the Childhood Asthma Management Program (CAMP) in the years after the randomized controlled trial (RCT) ended.

A double-blind, placebo-controlled RCT, CAMP studied the linear growth of 1041 children with mild-to-moderate persistent asthma who were divided into 3 treatment groups: One group received 200 mcg inhaled budesonide twice daily; a second group received 8 mg inhaled nedocromil twice daily; and a third group received placebo. Albuterol was used symptomatically by all 3 groups.⁷ The children ranged in age from 5 to 13 years at the start of the study; 98 patients—split evenly among the 3 treatment arms—were lost to follow-up.

During the 4 to 6 years of the CAMP trial, the budesonide group received a mean total of 636 mg ICS, whereas the nedocromil and placebo groups received an average of 88.5 and 109.4 mg ICS, respectively. After the RCT ended, all participants had standardized asthma treatment, receiving mean adjusted total doses of ICS of 381 mg for the budesonide group, 347.9 mg for the nedocromil group, and 355 mg for the placebo group.

Patients’ height was measured every 6 months for the next 4.5 years, and once or twice a year thereafter until they reached adult height (at a mean age of 24.9±2.7 years).

ICS users were a half inch shorter
Long-term ICS use was linked to a lower adult height. The adjusted mean height was 171.1 cm for the budesonide group vs 172.3 cm for those on placebo, a difference of 1.2 cm, or 0.47 inch (95% confidence interval [CI], −1.9 to −0.5; P=.001); the mean adult height in the nedocromil group (172.1 cm) was similar to that of the placebo group (−0.2 cm; 95% CI, −0.9 to 0.5; P=.61).

The lower adult height in the ICS group did not vary significantly based on sex, age at trial entry, race, or duration of asthma prior to trial entry; however, dose was a key factor. A larger daily dose of budesonide—particularly in the first 2 years of the RCT—was associated with a lower adult height (about −0.1 cm for each mcg/kg in that 2-year time frame). This was consistent with results from studies that looked at other types of ICS (beclomethasone, fluticasone, and mometasone).^8-11

The study also showed that growth velocity was reduced in the first 2 years of assigned treatment with budesonide, and this was primarily among prepubertal participants. After the initial 2-year slowing in growth rate, the children resumed growing at normal speeds.

What’s new: Now we know: Children don’t “catch up"

Retrospective studies have reported that children on ICS for mild persistent to moderate asthma would have an initial slowing in growth velocity but then “catch up” by growing for a longer period of time.^3-5 This is the first prospective study with good follow-up to show that ICS use affects long-term growth and adult height. While the effect is not large, some children and their families might be concerned about it.

Caveats: ICS use was atypical

The randomized controlled portion of the study used a prescribed dose of budesonide without regard to symptoms. This is not the typical pattern of ICS use. In addition, compliance with ICS varies significantly.¹² Because the effect on adult height appears to be dose dependent, however, we think the results of this study are valid.

In addition, there was a placebo control group (and big differences in exposure to ICS) only for the duration of the RCT. During the subsequent study, all patients received equivalent doses of ICS. This means that the variation in mean adult height achieved can be primarily ascribed to participants’ use of ICS during the 4- to 6-year CAMP trial. Of note, the effect of ICS was greatest in prepubertal participants, so there may be a diminished effect as teens approach their final height.

The study did not look at the effect of ICS use in patients with severe asthma—the group most likely to use ICS. However, the benefits of ICS for those with severe asthma likely outweigh any negative effects on adult height.

Challenges to implementation: What to tell patients

The message we convey to patients (and parents) about ICS use is a nuanced one. We can stress that ICS remain very important in the treatment of asthma and, while it appears that their use causes a slight decrease in adult height, most children with persistent asthma benefit from ICS.

Acknowledgement

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