2 | Guideline Summary – 2014 

DISCLAIMER

This Clinical Practice Guideline is based on a systematic review of both clinical and epidemiological evidence. Developed 

by a panel of multidisciplinary experts, it provides a clear explanation of the logical relationships between various care 

options and health outcomes while rating both the quality of the evidence and the strength of the recommendations.

These guidelines are not intended to represent TRICARE policy. Further, inclusion of recommendations for specific testing 

and/or therapeutic interventions within these guidelines does not guarantee coverage of civilian sector care. Additional 

information on current TRICARE benefits may be found at www.tricare.mil or by contacting your regional TRICARE 

Managed Care Support Contractor.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................................................................... 3

ALGORITHM...................................................................................................................................................................... 6

RECOMMENDATIONS....................................................................................................................................................... 8

PHARMACOLOGIC AGENTS FOR CHRONIC MULTISYMPTOM ILLNESS ....................................................................10
2 | Guideline Summary – 2014 

DISCLAIMER

This Clinical Practice Guideline is based on a systematic review of both clinical and epidemiological evidence. Developed 

by a panel of multidisciplinary experts, it provides a clear explanation of the logical relationships between various care 

options and health outcomes while rating both the quality of the evidence and the strength of the recommendations.

These guidelines are not intended to represent TRICARE policy. Further, inclusion of recommendations for specific testing 

and/or therapeutic interventions within these guidelines does not guarantee coverage of civilian sector care. Additional 

information on current TRICARE benefits may be found at www.tricare.mil or by contacting your regional TRICARE 

Managed Care Support Contractor.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................................................................... 3

ALGORITHM...................................................................................................................................................................... 6

RECOMMENDATIONS....................................................................................................................................................... 8

PHARMACOLOGIC AGENTS FOR CHRONIC MULTISYMPTOM ILLNESS ....................................................................10
4 | Guideline Summary – 2014 

Working Definition of Chronic Multisymptom Illness

Chronic multisymptom illness (CMI) is a label given to a diverse set of disorders including, but not limited to, chronic 

fatigue syndrome (CFS), fibromyalgia syndrome (FMS), and irritable bowel syndrome (IBS). CMI encompasses militaryspecific medically unexplained illnesses, such as Gulf War Illness, Gulf War Syndrome, or post-deployment syndrome. 

The definition of CMI also includes patients without accepted labels, defined by generally accepted criteria, who exhibit 

persistent or frequently recurring symptoms negatively impacting daily function for a minimum of six months duration 

from two or more of the following six categories: fatigue, mood and cognition, musculoskeletal (including pain), 

respiratory, gastrointestinal and neurologic (including headache). Patients with symptoms lasting less than six months, 

or who experience only one of the listed symptoms, or with a clearly organic-based disease that explains all/most 

of their symptoms were not covered in this report. Further consideration for inclusion should be given to symptoms 

affecting the following systems: genitourinary, cardiopulmonary, and sleep.

Scope of this CPG

Individuals who meet the above descriptive criteria and also meet established criteria for specific symptom-based 

syndromes (e.g., fibromyalgia, IBS, CFS) may derive benefit from this CPG. The CPG provides information on potential risk 

factors for CMI, diagnostic technologies that may be used for screening and assessment of CMI, management of CMI, 

and pharmacologic and non-pharmacologic therapies for the treatment of CMI. Risk factors that may be associated with 

predisposing, precipitating, and perpetuating CMI include medical (e.g., obesity), psychological (e.g., abuse history), and 

occupational/environmental (e.g., chemical exposure). The categories of diagnostic technologies considered under this 

CPG include biomarkers (biological markers and neuroimaging studies), neuropsychological test batteries, and sleep 

studies.

Some of the management approaches considered include team-based approaches, core competencies of the treatment team, patient-provider communication styles, the role of occupational and other rehabilitative services, behavioral 

health services, and patient follow-up practices.

Pharmacologic therapies include, among others, antibiotics, antidepressants, and pain medications, while non-pharmacologic therapies included psychological (i.e., hypnosis), physiological (i.e., exercise) and complementary and alternative 

treatments (i.e., acupuncture, biofeedback, and nutritional supplements).

Evidence Review

The recommendations presented in this CPG are based on a systematic appraisal of the published evidence on the 

management of Veterans and Service Members with Chronic Multisymptom Illness (CMI). In areas where the evidence 

is particularly lacking, expert opinion served as the basis for the recommendations. Published evidence was identified 

through extensive searches of several research databases. Searches were designed to identify unique reviews, trials, and 

technology assessments. Searches of the World Wide Web were also performed to capture relevant grey literature that 

has not been indexed to the databases listed previously. The searches covered an extended time period of January 2000 

through October 2013.

Evidence Assessment

In order for the clinician to be aware of the evidence base behind the recommendations and the weight that should be 

given to each recommendation, the recommendations are graded according to the level of confidence with which each 

recommendation is made. This CPG uses the GRADE methodology to assess the quality of the evidence base and assign 

a grade for the strength for each recommendation. The GRADE system uses the following four domains to assess the 

strength of each recommendation: 

• Balance of desirable and undesirable outcomes

• Confidence in the quality of the evidence

• Values and preferences

• Other implications, as appropriate, (e.g.,: Resource use, feasibility, subgroup considerations.)

The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects 

of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four 

domains. 
4 | Guideline Summary – 2014 

Working Definition of Chronic Multisymptom Illness

Chronic multisymptom illness (CMI) is a label given to a diverse set of disorders including, but not limited to, chronic 

fatigue syndrome (CFS), fibromyalgia syndrome (FMS), and irritable bowel syndrome (IBS). CMI encompasses militaryspecific medically unexplained illnesses, such as Gulf War Illness, Gulf War Syndrome, or post-deployment syndrome. 

The definition of CMI also includes patients without accepted labels, defined by generally accepted criteria, who exhibit 

persistent or frequently recurring symptoms negatively impacting daily function for a minimum of six months duration 

from two or more of the following six categories: fatigue, mood and cognition, musculoskeletal (including pain), 

respiratory, gastrointestinal and neurologic (including headache). Patients with symptoms lasting less than six months, 

or who experience only one of the listed symptoms, or with a clearly organic-based disease that explains all/most 

of their symptoms were not covered in this report. Further consideration for inclusion should be given to symptoms 

affecting the following systems: genitourinary, cardiopulmonary, and sleep.

Scope of this CPG

Individuals who meet the above descriptive criteria and also meet established criteria for specific symptom-based 

syndromes (e.g., fibromyalgia, IBS, CFS) may derive benefit from this CPG. The CPG provides information on potential risk 

factors for CMI, diagnostic technologies that may be used for screening and assessment of CMI, management of CMI, 

and pharmacologic and non-pharmacologic therapies for the treatment of CMI. Risk factors that may be associated with 

predisposing, precipitating, and perpetuating CMI include medical (e.g., obesity), psychological (e.g., abuse history), and 

occupational/environmental (e.g., chemical exposure). The categories of diagnostic technologies considered under this 

CPG include biomarkers (biological markers and neuroimaging studies), neuropsychological test batteries, and sleep 

studies.

Some of the management approaches considered include team-based approaches, core competencies of the treatment team, patient-provider communication styles, the role of occupational and other rehabilitative services, behavioral 

health services, and patient follow-up practices.

Pharmacologic therapies include, among others, antibiotics, antidepressants, and pain medications, while non-pharmacologic therapies included psychological (i.e., hypnosis), physiological (i.e., exercise) and complementary and alternative 

treatments (i.e., acupuncture, biofeedback, and nutritional supplements).

Evidence Review

The recommendations presented in this CPG are based on a systematic appraisal of the published evidence on the 

management of Veterans and Service Members with Chronic Multisymptom Illness (CMI). In areas where the evidence 

is particularly lacking, expert opinion served as the basis for the recommendations. Published evidence was identified 

through extensive searches of several research databases. Searches were designed to identify unique reviews, trials, and 

technology assessments. Searches of the World Wide Web were also performed to capture relevant grey literature that 

has not been indexed to the databases listed previously. The searches covered an extended time period of January 2000 

through October 2013.

Evidence Assessment

In order for the clinician to be aware of the evidence base behind the recommendations and the weight that should be 

given to each recommendation, the recommendations are graded according to the level of confidence with which each 

recommendation is made. This CPG uses the GRADE methodology to assess the quality of the evidence base and assign 

a grade for the strength for each recommendation. The GRADE system uses the following four domains to assess the 

strength of each recommendation: 

• Balance of desirable and undesirable outcomes

• Confidence in the quality of the evidence

• Values and preferences

• Other implications, as appropriate, (e.g.,: Resource use, feasibility, subgroup considerations.)

The strength of a recommendation is defined as the extent to which one can be confident that the desirable effects 

of an intervention outweigh its undesirable effects and is based on the framework above, which combines the four 

domains. 
6 | Guideline Summary – 2014 

Algorithm Evaluation and Management 

2

3

6

4

5

7

8

1

N

N

Y

Y

Conduct a thorough evaluation of symptoms and 

assess for comorbid conditions (See Box B)

[ A ]

Are unstable or urgent 

condition(s) present? 

Does CMI co-exist with another 

medical or psychiatric condition that 

may explain the symptoms? 

Refer or treat, as indicated, 

before continuing in this 

algorithm

Refer or treat as indicated using 

appropriate evidence-based 

clinical practice guidelines

- Build therapeutic patient-provider alliance

- Consider discussing risk factors for CMI

- Use collaborative team-based approach and principles of shared 

decision-making to develop comprehensive and personalized 

treatment plan including physical activity.

- Do not consider long-term use of opioid medications

[ B ]

Initiate trial of non-pharmacologic interventions

- Offer cognitive behavioral therapy

- Consider complementary and integrative medicine interventions

- Consider:

 - mindfulness based therapy,

 - reattribution,

 - behavioral medical intervention, and/or

 - brief psychodynamic interpersonal psychotherapy

[ C ]

Patient presents with a spectrum of chronic symptoms

 not explained by other disorders and 

meeting the criteria for Chronic Multisymptom Illness (CMI)

(See Box A)

Continue to next page:

Treatment interventions

Box A: Definition of CMI

Patients without a formal diagnosis but 

who exhibit symptoms from two of the 

following six categories for a minimum of 

six months duration: fatigue, mood and 

cognition, musculoskeletal , respiratory, 

gastrointestinal and neurologic.

Box B: Elements of Assessment

Obtain medical history, conduct physical 

examination and psychological assessment.

- Consider diagnostic studies, as indicated* 

- Consider additional and /or longer 

duration encounters.

* For alternative diagnosis only. Avoid 

any test for which there may be limited 

additional benefit
6 | Guideline Summary – 2014 

Algorithm Evaluation and Management 

2

3

6

4

5

7

8

1

N

N

Y

Y

Conduct a thorough evaluation of symptoms and 

assess for comorbid conditions (See Box B)

[ A ]

Are unstable or urgent 

condition(s) present? 

Does CMI co-exist with another 

medical or psychiatric condition that 

may explain the symptoms? 

Refer or treat, as indicated, 

before continuing in this 

algorithm

Refer or treat as indicated using 

appropriate evidence-based 

clinical practice guidelines

- Build therapeutic patient-provider alliance

- Consider discussing risk factors for CMI

- Use collaborative team-based approach and principles of shared 

decision-making to develop comprehensive and personalized 

treatment plan including physical activity.

- Do not consider long-term use of opioid medications

[ B ]

Initiate trial of non-pharmacologic interventions

- Offer cognitive behavioral therapy

- Consider complementary and integrative medicine interventions

- Consider:

 - mindfulness based therapy,

 - reattribution,

 - behavioral medical intervention, and/or

 - brief psychodynamic interpersonal psychotherapy

[ C ]

Patient presents with a spectrum of chronic symptoms

 not explained by other disorders and 

meeting the criteria for Chronic Multisymptom Illness (CMI)

(See Box A)

Continue to next page:

Treatment interventions

Box A: Definition of CMI

Patients without a formal diagnosis but 

who exhibit symptoms from two of the 

following six categories for a minimum of 

six months duration: fatigue, mood and 

cognition, musculoskeletal , respiratory, 

gastrointestinal and neurologic.

Box B: Elements of Assessment

Obtain medical history, conduct physical 

examination and psychological assessment.

- Consider diagnostic studies, as indicated* 

- Consider additional and /or longer 

duration encounters.

* For alternative diagnosis only. Avoid 

any test for which there may be limited 

additional benefit
8 | Guideline Summary – 2014 

Recommendations

A. Conduct a Thorough Evaluation of Symptoms

1. The guideline panel recommends that all patients receive a thorough evaluation of symptoms based on clinical 

judgment. [ Strong For ]

2. This guideline panel recommends against the use of any test for which there may be limited additional benefit 

to confirm the diagnosis of CMI. Testing for rare exposures or biologic effects should only be done in the 

presence of supportive history or physical findings. [ Strong Against ]

3. This guideline panel suggests discussing risk factors using principles of health risk communication within a 

therapeutic patient-provider alliance for those patients who wish to further understand factors that could 

contribute to their condition. [ Weak For ]

B. Management Strategies for Care of Patients with CMI 

4. The guideline panel recommends using a collaborative, team-based approach, including a behavioral health 

specialist, for the primary care management of patients with CMI. [ Strong For ]

5. The guideline panel recommends that the healthcare team use shared decision-making principles to develop a 

comprehensive and personalized treatment plan in the care and management of patients with CMI. [ Strong For ]

6. The guideline panel suggests that all providers involved in the care of patients with CMI enhance their 

knowledge of the following critical domains:

a. Communication skills (e.g. active listening, risk communication/perception)

b. Empathy skills

c. Working with interdisciplinary teams

d. The biopsychosocial model

e. Risk factors for CMI and analogous conditions

f. Military cultural competency

g. Deployment related exposures

[ Weak For ]

C. Therapeutic Interventions for Global CMI

7. The guideline panel suggests incorporating appropriate elements of physical activity as part of a comprehensive 

and integrated treatment plan for patients with CMI. [ Strong For ]

8. The guideline panel recommends offering cognitive behavioral therapy, delivered by trained professionals, for 

patients with CMI. [ Strong For ]

9. The guideline panel recommends considering mindfulness-based therapy, reattribution, behavioral medical 

intervention, and/or brief psychodynamic interpersonal psychotherapy, delivered by trained professionals, for 

patients with CMI. [ Weak For ]

10. The guideline panel recommends considering complementary and integrated medicine interventions as a 

component of personalized, proactive patient-driven care in the management of patients with CMI. [ Weak For ]

11. The guideline panel suggests considering a trial of selective serotonin reuptake inhibitor (SSRI), serotonin–

norepinephrine reuptake inhibitor (SNRI), or mirtazapine for the treatment of clinical symptoms of CMI. [ Weak 

For ]

12. The guideline panel suggests against the use of doxycycline for the treatment of patients with clinical 

symptoms of pain-predominant CMI. [ Weak Against ]

13. The guideline panel recommends against the long-term use of opioid medications for the management of 

patients with CMI. [ Strong Against ]
8 | Guideline Summary – 2014 

Recommendations

A. Conduct a Thorough Evaluation of Symptoms

1. The guideline panel recommends that all patients receive a thorough evaluation of symptoms based on clinical 

judgment. [ Strong For ]

2. This guideline panel recommends against the use of any test for which there may be limited additional benefit 

to confirm the diagnosis of CMI. Testing for rare exposures or biologic effects should only be done in the 

presence of supportive history or physical findings. [ Strong Against ]

3. This guideline panel suggests discussing risk factors using principles of health risk communication within a 

therapeutic patient-provider alliance for those patients who wish to further understand factors that could 

contribute to their condition. [ Weak For ]

B. Management Strategies for Care of Patients with CMI 

4. The guideline panel recommends using a collaborative, team-based approach, including a behavioral health 

specialist, for the primary care management of patients with CMI. [ Strong For ]

5. The guideline panel recommends that the healthcare team use shared decision-making principles to develop a 

comprehensive and personalized treatment plan in the care and management of patients with CMI. [ Strong For ]

6. The guideline panel suggests that all providers involved in the care of patients with CMI enhance their 

knowledge of the following critical domains:

a. Communication skills (e.g. active listening, risk communication/perception)

b. Empathy skills

c. Working with interdisciplinary teams

d. The biopsychosocial model

e. Risk factors for CMI and analogous conditions

f. Military cultural competency

g. Deployment related exposures

[ Weak For ]

C. Therapeutic Interventions for Global CMI

7. The guideline panel suggests incorporating appropriate elements of physical activity as part of a comprehensive 

and integrated treatment plan for patients with CMI. [ Strong For ]

8. The guideline panel recommends offering cognitive behavioral therapy, delivered by trained professionals, for 

patients with CMI. [ Strong For ]

9. The guideline panel recommends considering mindfulness-based therapy, reattribution, behavioral medical 

intervention, and/or brief psychodynamic interpersonal psychotherapy, delivered by trained professionals, for 

patients with CMI. [ Weak For ]

10. The guideline panel recommends considering complementary and integrated medicine interventions as a 

component of personalized, proactive patient-driven care in the management of patients with CMI. [ Weak For ]

11. The guideline panel suggests considering a trial of selective serotonin reuptake inhibitor (SSRI), serotonin–

norepinephrine reuptake inhibitor (SNRI), or mirtazapine for the treatment of clinical symptoms of CMI. [ Weak 

For ]

12. The guideline panel suggests against the use of doxycycline for the treatment of patients with clinical 

symptoms of pain-predominant CMI. [ Weak Against ]

13. The guideline panel recommends against the long-term use of opioid medications for the management of 

patients with CMI. [ Strong Against ]
10 | Guideline Summary – 2014 

Table 1. Symptom Efficacy of Selected Pharmacotherapies

Agent Predominant Symptom 

Escitalopram Global 

Fluoxetine Global *

Pain

Sertraline Global *

Venlafaxine 

Venlafaxine Extended-release Global *

Mirtazapine Global *

Duloxetine Pain

Fatigue 

Milnacipran Pain 

Fatigue

Amitriptyline Pain 

Fatigue

Pregabalin Pain 

Paroxetine Controlled-release Pain 

Citalopram Pain 

* Equivocal efficacy; not compared with placebo.

For additional drug information see Table 2

ADDITIONAL RESOURCES

For more information, refer to the VA/DoD Evidence-based Clinical Practice Guideline for the Management of Chronic

Multisymptom Illness, found at: http://www.healthquality.va.gov/

In addition, the following other resources may be helpful:

1. War Related Illness and Injury Study Center– a National VA Post-Deployment Health Resource which provides 

post deployment health expertise to Veterans and their healthcare providers through clinical programs, research, 

education, and risk communication. Find out more here: http://www.warrelatedillness.va.gov/

2. Department of Veterans Affairs Office of Public Health – an office within the Veterans Health Administration 

which serves as the leader and authority in public health. Learn more about it here: http://www.publichealth.

va.gov/

3. Deployment Health Clinical Center – a site designed to provide a gateway to information on deployment health 

and healthcare for healthcare providers, service members, veterans, and their families. Check it out here: http://

www.pdhealth.mil/
10 | Guideline Summary – 2014 

Table 1. Symptom Efficacy of Selected Pharmacotherapies

Agent Predominant Symptom 

Escitalopram Global 

Fluoxetine Global *

Pain

Sertraline Global *

Venlafaxine 

Venlafaxine Extended-release Global *

Mirtazapine Global *

Duloxetine Pain

Fatigue 

Milnacipran Pain 

Fatigue

Amitriptyline Pain 

Fatigue

Pregabalin Pain 

Paroxetine Controlled-release Pain 

Citalopram Pain 

* Equivocal efficacy; not compared with placebo.

For additional drug information see Table 2

ADDITIONAL RESOURCES

For more information, refer to the VA/DoD Evidence-based Clinical Practice Guideline for the Management of Chronic

Multisymptom Illness, found at: http://www.healthquality.va.gov/

In addition, the following other resources may be helpful:

1. War Related Illness and Injury Study Center– a National VA Post-Deployment Health Resource which provides 

post deployment health expertise to Veterans and their healthcare providers through clinical programs, research, 

education, and risk communication. Find out more here: http://www.warrelatedillness.va.gov/

2. Department of Veterans Affairs Office of Public Health – an office within the Veterans Health Administration 

which serves as the leader and authority in public health. Learn more about it here: http://www.publichealth.

va.gov/

3. Deployment Health Clinical Center – a site designed to provide a gateway to information on deployment health 

and healthcare for healthcare providers, service members, veterans, and their families. Check it out here: http://

www.pdhealth.mil/
12 | Guideline Summary – 2014

Table 2. Pharmacologic Agents for Chronic Multisymptom Illness (cont.)

Agent Dosage in Adults Notable Adverse Effects Comments 

Milnacipran • 100 mg/d (100-200mg/d) in 2 

divided doses;

• Titrate up from 12.5 mg by 12.5– 

50 mg/d per week over 3–4 weeks

• Adequate trial: 12 weeks 

• Dose in patients with severe renal 

impairment (5–29 ml/min): 

50–100 mg/d in 2 divided doses

• Do not ordinarily use in patients 

with substantial alcohol use or 

chronic liver disease. 

• Not recommended in patients 

with end-stage renal disease.

• Nausea

• Headache

• Constipation

• Insomnia

• Dizziness

• Hot flush

• Serotonin 

syndrome

• Suicidal ideation

• Increased blood 

pressure and heart 

rate

• Urinary retention

• Hepatotoxicity

• Withdrawal 

symptoms

• Contraindicated with MAOIs and within 14 

days of starting or stopping MAOIs

• MAOIs contraindicated within 5 days of 

discontinuing milnacipran

• Contraindicated in patients with 

uncontrolled narrow-angle glaucoma

Amitriptyline • 10-50 mg daily 

• Adequate trial: 6-8 weeks

• Use lower doses in the elderly

• Dry mouth

• Fatigue

• Sedation

• Vasovagal 

reaction

• Orthostatic 

hypotension

• Constipation 

• Urinary retention

• QTc prolongation; 

conduction 

abnormalities

• Suicidal ideation

• Contraindicated with MAOIs and within 14 

days of starting or stopping MAOIs

• Contraindicated with cisapride

• Avoid use with QTc prolonging drugs, 

anticholinergics

• Use with caution in patients with cardio- or 

cerebrovascular disease

Pregabalin • 300-450 mg/d divided BID-TID;

• Starting at 150 mg/d and 

increasing by 150 mg/d every 

week

• Adequate trial: 8 weeks

• Adjust dose based on renal function

• Dizziness

• Somnolence

• Headache

• Weight gain

• Angioedema

• Suicidal ideation

• Peripheral edema

• Withdrawal 

symptoms

• Blurred vision; 

visual field 

changes

• Dose of 600 mg/d was studied but showed 

no additional benefit and increased the risk 

of adverse events

Paroxetine 

CR

• 62.5 mg/d (12.5–75 mg/d),

• Starting at 25 mg/d and increasing 

by 12.5 mg/d at intervals of at 

least 1 week

• Adequate trial: 12 weeks 

• Severe renal impairment 

(CrCl <30 ml/min) or severe 

hepatic impairment: Use lower 

starting dose

• Elderly 12.5-50 mg/d

• Drowsiness

• Nausea

• Insomnia

• Headache

• Ejaculatory 

disorder

• Dizziness

• Decreased libido

• Diaphoresis

• Weakness

• Constipation

• Diarrhea

• Dry mouth

• Akathisia

• Suicidal ideation

• Serotonin 

syndrome

• Also available in immediate-release tablets 

(20–60 mg/d)

• Contraindicated with MAOIs and within 14 

days of starting or stopping MAOIs

• Most sedating SSRI

• Potent anticholinergic effects

Citalopram • 20-40 mg/d;

• Titrate up at intervals of at least 

1 week

• Adequate trial: 8-16 weeks

• Elderly (>60 y) and Hepatic 

Impairment: Max 20 mg/d

• Nausea

• Dry mouth

• Somnolence

• Insomnia

• Hyperhidrosis

• Suicidal ideation

• Serotonin 

syndrome

• QTc prolongation

• Contraindicated with MAOIs and within 14 

days of starting or stopping MAOIs

• Avoid using citalopram with other QTc 

prolonging drugs

Refer to current Product Information for additional prescribing information. 

For relative usage and timing of therapies refer to the full clinical practice guideline for management of CMI at: http://www.healthquality.va.gov/

† Associated with risk of torsade de pointes in the presence of other risk factors for QTc prolongation (e.g. high dose, hypokalemia, hypomagnesemia, 

drug interaction or congenital long QT).
http://www.healthquality.va.gov

https://www.qmo.amedd.army.mil