GCA17O1 • Nurses

Table of Contents

GCA17O1 • Nurses

How to Receive Credit

NetCE 5 Hour Course #34343 • Pressure Ulcers and Skin Care

34343 • Pressure Ulcers and Skin Care

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF SKIN

3. PRESSURE ULCERS

4. PRESSURE ULCER RISK ASSESSMENT

5. SKIN AND PAIN ASSESSMENTS

6. INDIVIDUALIZED PROGRAM OF SKIN CARE

7. DOCUMENTATION

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #98931 • Irritable Bowel Syndrome

98931 • Irritable Bowel Syndrome

1. INTRODUCTION

2. EPIDEMIOLOGY

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

5. TREATMENT

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #94101 • Low Back Pain

94101 • Low Back Pain

1. INTRODUCTION

2. EPIDEMIOLOGY

3. RISK AND PROGNOSTIC FACTORS

4. CLINICAL COURSE

5. PATHOPHYSIOLOGY

6. ASSESSMENT AND DIAGNOSIS

7. TREATMENT OPTIONS

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

GCA17O1 • Nurses

Maryam Mamou, BSN, RN, CRRN, CWOCN

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

GCA17O1 • Nurses

Expiration Date: 02/28/2022

How to Receive Credit

To complete this Special Offer for continuing education credit please go to http://www.netce.com/specials in your browser.

For assistance with receiving continuing education credit, please contact us at help@netce.com.

34343 • Pressure Ulcers and Skin Care

Maryam Mamou, BSN, RN, CRRN, CWOCN

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

A complete skin assessment and accurate documentation of the assessment findings are critical elements of the nurse's role in patient care. Nursing staff must be able to perform a thorough head-to-toe skin assessment and accurately document their findings. In order to do this, nurses should have a working knowledge of the general characteristics of the skin, its functions, and the changes that occur in the skin throughout an individual's life span. Identifying patients at risk for pressure ulcer development is vitally important, as presence of these wounds greatly increased morbidity and mortality. Use of a risk assessment tool, such as the Braden Risk Assessment, is recommended. Each patient deemed at risk for skin breakdown or with evidence of breakdown should have an individualized program of skin care, including nutritional support and patient and family education among other elements. Ongoing evaluation and documentation of the skincare program and whether or not it is meeting its goals is necessary.

Table of Contents

34343 • Pressure Ulcers and Skin Care

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. GENERAL CHARACTERISTICS OF SKIN

SKIN STRUCTURES

FUNCTIONS OF THE SKIN

SKIN THROUGHOUT THE LIFE SPAN

3. PRESSURE ULCERS

PRESSURE AND SHEAR

FRICTION

MOISTURE

STAGES OF BREAKDOWN

4. PRESSURE ULCER RISK ASSESSMENT

MAJOR RISK FACTORS IN PRESSURE ULCER DEVELOPMENT

RISK ASSESSMENT

5. SKIN AND PAIN ASSESSMENTS

ELEMENTS OF A BASIC SKIN ASSESSMENT

ASSESSING AND DOCUMENTING A PRESSURE ULCER

6. INDIVIDUALIZED PROGRAM OF SKIN CARE

POSITIONING IN BED

POSITIONING WHILE IN CHAIR

CLEANSING AND BATHING

MOISTURIZING THE SKIN

BOWEL AND BLADDER MANAGEMENT

SUPPORT SURFACES

PATIENT/FAMILY EDUCATION

STAFF EDUCATION

NUTRITIONAL SUPPORT

EVALUATION OF THE SKIN PROGRAM

7. DOCUMENTATION

8. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

34343 • Pressure Ulcers and Skin Care

Education Category. Infection Control / Internal Medicine

Release Date. 06/01/2019

Expiration Date. 05/31/2022

Course Overview

A complete skin assessment and accurate documentation of the assessment findings are critical elements of the nurse's role in patient care. Nursing staff must be able to perform a thorough head-to-toe skin assessment and accurately document their findings. In order to do this, nurses should have a working knowledge of the general characteristics of the skin, its functions, and the changes that occur in the skin throughout an individual's life span. Identifying patients at risk for pressure ulcer development is vitally important, as presence of these wounds greatly increased morbidity and mortality. Use of a risk assessment tool, such as the Braden Risk Assessment, is recommended. Each patient deemed at risk for skin breakdown or with evidence of breakdown should have an individualized program of skin care, including nutritional support and patient and family education among other elements. Ongoing evaluation and documentation of the skincare program and whether or not it is meeting its goals is necessary.

Audience

This course is designed for nurses in all practice settings, particularly those caring for patients at high risk for developing pressure ulcers.

Course Objective

The purpose of this course is to provide nurses with the information necessary to accurately identify, treat, and manage skin breakdown (pressure ulcers), thereby improving patient outcomes and quality of life.

Learning Objectives

Upon completion of this course, you should be able to:

1. List the key structures and functions of the skin.

2. Describe skin changes throughout the life span.

3. Identify causative factors contributing to pressure ulcer occurrence.

4. Accurately identify each stage of pressure ulcer development.

5. Identify risk factors leading to the development of pressure ulcers.

6. Outline characteristics of a validated and reliable pressure ulcer risk assessment tool.

7. Complete thorough skin and pain assessments.

8. Outline an individualized program of skin care, including nutritional support, documentation, and patient education.

Faculty

Maryam Mamou, BSN, RN, CRRN, CWOCN, is an Irish-trained RN who has lived and worked in the United States for 20 years. During her career, she has completed a BSN and went on to become a certified rehabilitation nurse, a certified life care planner, and more recently a certified wound ostomy and continence nurse. She is a graduate of the wound ostomy and continence program at Emory University in Atlanta, Georgia, and is nationally certified in these areas.

Ms. Mamou has worked in various rehabilitation settings and has first-hand experience of how pressure ulcers impact patients' recovery and quality of life. She has held positions as staff nurse, unit coordinator, educator, and director of nursing in home health care. She has been involved in developing and implementing several staff education programs in a variety of settings. She was most recently employed as a wound ostomy and continence nurse at East Alabama Medical Center in Opelika, Alabama.

Faculty Disclosure

Contributing faculty, Maryam Mamou, BSN, RN, CRRN, CWOCN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Jane C. Norman, RN, MSN, CNE, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

A complete skin assessment and accurate documentation of the assessment findings are critical elements of the nurse's role in providing care for patients with pressure ulcers. In order to perform a thorough assessment, nurses should have a working knowledge of the general characteristics of the skin, its functions, and the changes that occur in the skin throughout an individual's life span.

Each patient deemed at risk for skin breakdown or with evidence of breakdown should have an individualized program of skin care, including nutritional support and patient and family education, among other elements. Ongoing evaluation and documentation of the skincare program and whether or not it is meeting its goals is necessary.

2. GENERAL CHARACTERISTICS OF SKIN

Skin is the largest organ in the body. In the average person it covers approximately 3,000 square inches [1]. In total, it weighs around six pounds, or up to 15% of the total adult body weight. Intact skin is dry, supple, and has a pH ranging from 4 to 6. It varies in thickness from 0.5 mm in the tympanic membrane to 6 mm on the soles of the feet and the palms of the hands. Frequent bathing and episodes of incontinence remove naturally occurring oils from the skin [2]. However, as an organ the skin is able to withstand limited mechanical and chemical assaults.

SKIN STRUCTURES

Human skin has two primary layers: the epidermis (outer layer) and the dermis (inner layer). The basement membrane separates the two layers. Beneath the dermis is the hypodermis, which is a layer of connective tissue also referred to as the subcutaneous tissue.

Epidermis

The epidermis is a thin layer that regenerates itself every four to six weeks. It contains no blood vessels and receives its blood supply from the inner (dermis) layer. Nerve fibers are located throughout the epidermis. It is divided into five layers—presented in order from the outermost layer inward: stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.

The stratum corneum is composed of dead keratinized cells and is constantly being sloughed off and renewed from below [2]. It has an acid mantle, an oily layer with reduced pH, provided by sebum, the substance secreted by the sebaceous glands onto the skin surface via the hair follicles.

The stratum lucidum, also known as the clear layer, is found in areas where the epidermis is thicker, like the palms of the hands and the soles of the feet [1]. It lies directly below the stratum corneum. The next layer, the stratum granulosum, is composed of one to five layers. It is believed to help with keratin formation.

The stratum spinosum is referred to as the "prickly layer" because of the spine-like shape of the cells [2]. In this layer, skin cells begin to flatten as they are migrating toward the skin surface. The stratum basale, also known as the stratum germinativum, is the innermost layer of the epidermis. It is composed of a single layer of constantly dividing cells that form new cells. These new cells migrate to the stratum corneum [1]. Cellular migration usually takes 28 days, but this rate is affected by aging and chemotherapy.

Rete pegs and rete ridges are interlocking structures that extend down from the epidermis into the dermis. These finger-shaped downward projections on the epidermis interlock with upward projections from the dermis. Rete pegs and ridges ensure that all the skin layers move together.

The epidermis contains many specialized cells that affect patient health and appearance. The cells of the skin that provide immune protection (dendritic or Langerhans cells) are found in the stratum granulosum and the stratum spinosum. Melanocytes are found only in the epidermis and are responsible for differences in skin color. The number of melanocytes is approximately the same in normal skin regardless of skin color, but the amount of the pigment melanin produced varies from person to person and from one area of skin on the body to another.

Basement Membrane

The basement membrane's main function is to anchor the epidermis to the dermis. It contains several protein substances, including collagen, and is the layer that is affected in blister formation [1].

Dermis

The dermis is the most important part of the skin and is often referred to as the "true skin" [3]. It is the thickest layer of the skin, varying in thickness from 0.2 mm to 4 mm. The reticular dermis anchors the skin to the subcutaneous tissue and contains sweat glands, hair follicles, nerves, and blood vessels [1]. The dermis also contains the sebaceous glands, which secrete sebum, a substance rich in oil that lubricates the skin.

The major proteins found in the dermis are collagen and elastin [1]. Collagen gives skin its tensile strength, while elastin provides the skin with elastic recoil. This characteristic prevents the skin from being permanently reshaped. The dermis is divided into two areas: the papillary dermis, which contains capillaries for skin nourishment, and the reticular layer, which is comprised of thick collagen fibers. The dermis also contains Meissner and Vater-Pacini corpuscles, the receptors that sense pain and pressure.

Subcutaneous Tissue

Beneath the dermis lies subcutaneous tissue, which attaches the skin to the underlying structures. Subcutaneous tissue contains adipose tissue, connective tissue, blood vessels, lymphatics, and nerve endings. It is the adipose tissue that provides protection from pressure and shear. Elderly patients who may have inadequate subcutaneous tissue are at high risk for deep tissue injury due to pressure and shear [2].

Muscle and Fascia

Muscle and fascia are highly vascularized tissue that is most sensitive to ischemia. Pressure damage usually originates here [2]. The skin receives its blood supply from vessels that originate in the muscle tissue.

FUNCTIONS OF THE SKIN

The skin protects against mechanical and chemical trauma, pathogens, dehydration, and malignancy [2]. One of the most important functions of the skin is acting as a physical barrier to micro-organisms, protecting the body against infection. The acid mantle present in the epidermis also retards the growth of micro-organisms.

The skin immune system provides protection as well [1]. Macrophages found in the dermis are phagocytic cells that provide defense against pathogens for the skin and for open wounds. These macrophages also promote wound healing.

Mast cells are present in the skin and are the primary cells involved in allergic reactions. They also help protect against parasites.

The skin maintains heat regulation by the process of vasodilation and vasoconstriction, sweating and shivering [2]. Fluid evaporating from the skin allows for cooling to occur. The amount of sweat excreted can range from 100 mL to 2 liters in one hour [2]. As a result, the skin plays an important role in electrolyte balance and hydration.

Nerve endings in the skin provide information about the external environment and protection. Some areas of the skin are more sensitive than others (e.g., the fingertips are more sensitive than the back). Any loss of sensation increases the chances of injury.

The skin is also involved in the metabolism of certain vitamins. Specifically, the effect of ultraviolet B light on sterols in the skin causes synthesis of vitamin D. Certain drugs and some toxic substances (e.g., pesticides) can also be absorbed directly through the skin and into circulation.

Finally, skin provides for expression and body image [2]. Skin plays a vital role in self-esteem and social communication. Skin characteristics have an impact on how an individual communicates both verbally and nonverbally, and how the other person reacts to that individual. It also provides significant social cues regarding health and vitality.

SKIN THROUGHOUT THE LIFE SPAN

Fetal and Neonatal Skin

Fetal skin appears to have increased amounts of hyaluronic acid, which is associated with fetal scarless healing. Studies indicate that intrauterine surgery done late in the second trimester or early in the third trimester usually results in no scars [2].

Neonatal skin is more permeable due to the immature stratum corneum. During the first two weeks of life, topical administration can equal intravenous (IV) administration in terms of absorption [2]. Because infants have thinner skin and nails, epidermal stripping can occur easily.

Adult Skin

Adult skin shows a gradual increase in epidermal turnover time and decreasing dermal thickness. In young adults, epidermal turnover is around 21 days; by 35 years of age, this time doubles [2]. In addition, melanocytes decrease 6% to 8% each decade after 30 years of age. This loss of skin melanocytes is thought to increase the risk of skin cancer [1].

Elderly Skin

In elderly individuals, there is a 50% reduction in the cell turnover rate in the stratum corneum (outer most layer) and a 20% reduction in dermal thickness. Elderly patients experience an overall reduction in dermal vascularization and associated drop in blood flow to the skin. The collagen bundles in the dermis shrink, causing permanent wrinkles to develop [2].

Rete ridges and pegs flatten, resulting in decreased adhesion between the skin layers. The area of contact between the epidermis and the dermis is reduced by 50% [4]. There is increased capillary fragility; slight pressure can cause bruising. A decrease in subcutaneous tissue causes a reduction in thermal insulation and increases the risk of shear/pressure injury. Reduced activity of sweat glands and sebaceous glands can lead to dry skin.

Elderly individuals experience a drop in the number of Langerhans cells, a 50% decrease in the number of mast cells, and up to a 50% decrease in the function of the remaining cells. As a result, there is an increased risk of skin cancer and fungal and other infections [1].

Other age-related changes include decreased absorption, reduction in the skin's ability to synthesize vitamin D, and significantly marked reduction in the ability of the skin to sense pressure, heat, and cold. Decreased cellular competence and activity leads to a reduction in cell repair and the increased possibility of nonhealing wounds [2].

3. PRESSURE ULCERS

In 2016, the National Pressure Advisory Panel (NPUAP) released updated definitions for pressure ulcers and staging classification. In this revision, the term "pressure injury" replaced "pressure ulcer," to alleviate confusion between injury to intact skin and open ulcers. According to the NPUAP, a pressure injury is localized damage to skin and/or underlying soft tissue and usually occurs over a bony prominence. It is the result of prolonged pressure or pressure combined with shear and/or friction. A pressure injury can present as intact skin or an open ulcer. Patients at risk for pressure injury (e.g., immobile patients) are also at risk for friction and shear damage [5]. For the purpose of this course, the term "pressure ulcer" will encompass both injury of intact skin and an open ulcer, unless otherwise noted.

Pressure ulcers usually occur over a bony prominence such as the sacrum, the ischial tuberosity, the trochanter, and the heels, but they can occur anywhere on the body. In some cases, ulcers will develop around a tracheostomy tube or under a cast, splint, or cervical collar [1]. The most common locations for pressure ulcers are the sacrum and the heels because there is less soft tissue present between the bone and the skin in these areas. An estimated 95% of pressure ulcers occur on the lower body; of these, about 65% develop in the pelvic area and 30% in the lower extremities [6]. There is a two to six times greater mortality risk with pressure ulcer development. Many factors impact the level and extent of tissue trauma (Table 1) [7].

Table 1: FACTORS CONTRIBUTING TO THE FORMATION OF PRESSURE ULCERS

Extrinsic Factors

Undue, prolonged pressure

Shear

Friction

Moisture

Abnormal posture

Intrinsic Factors

Altered consciousness

Decreased or absent sensations

Nutritional factors (under- or over-nourished)

Anemia

Edema

Atherosclerosis

Aged-related changes

Acute illness

Sleep

Medications

Cardiovascular changes

Emotional stress

Source: [7]

PRESSURE AND SHEAR

Pressure that results in the development of ulcers is defined as compression of soft tissues between two rigid surfaces. For example, blood vessels, muscle, subcutaneous fat, or skin may be compressed between a bone and an external surface, such as a bed or chair. The end result is ischemia and necrosis. All the tissues between the two points of pressure are affected, but the tissue closest to the bony prominence suffers the greatest damage. It is important to note that low-intensity pressure over a long period of time can create tissue damage, just as high-intensity pressure over a short period of time can result in damage [2]. Application of high pressure for shorter duration not only causes tissue necrosis due to blockage of capillaries but also produces pressure effect on the larger vessels, causing thrombosis (usually venous). Hence, the deleterious effect of high pressure for short duration is much more than that of low pressure for a longer duration. This has been proven by the observation that when the high pressure is relieved, ischemia persists due to effects on the adjacent larger vessels; upon relief of low pressure, the normal hyperemic response compensates for the temporary ischemia and the tissue does not undergo degeneration [7].

Pressure ulcer pathogenesis has still not been clearly defined. Most reports indicate a "bottom-up" progression of tissue damage [2]. Muscle is more sensitive to pressure damage than skin because it is the most metabolically active layer and is at the greatest risk for ischemic injury [7].

The capillary level is the end point of circulation. From the capillaries oxygen and nutrients diffuse into the tissues, and carbon dioxide and waste products are removed. A collapsed capillary bed is nonfunctioning and useless to the tissues. The minimal amount of pressure required to collapse a capillary is referred to as the capillary closing pressure [1]. Studies have shown that an average of 32 mm Hg will collapse the arterial side of the capillary circulation, and 18 mm Hg of pressure will collapse the venous end. However, these values cannot be accepted as the universal; capillary pressures vary among persons, sites, and times [2]. Furthermore, the studies that elicited these values were done on healthy adult males, not debilitated or elderly patients. Other studies have shown that the functional capillary pressure, the pressure needed to the keep the capillary bed open, is around 17 mm Hg.

Shear is the result of gravity pushing down on the body and resistance (friction) between the patient and a surface, such as the bed or the chair, holding the skin in place [2]. For example, when the head of the bed is raised (e.g., high Fowler position), gravity facilitates forward slide, pulling the body down toward the foot of the bed. The skin on the patient's lower back and gluteal area resists the motion and is held in place by the bed's surface while the bones and tissues beneath the area begin to slide. This causes puckering of the skin, stretching and angulation of small vessels, impedance of blood flow, and traction on subcutaneous tissue and muscle. Left unchecked, the net effect may result in ischemic injury to tissues at the fascia layer. When the head of the bed is elevated more than 30 degrees, shear force occurs over the sacrum and coccyx. Shear injury is not usually visible at the skin level, but shear is responsible for much of the damage associated with initiation of pressure ulcers [4]. The areas of the body most vulnerable to shearing forces are shoulder blades, elbows, sacrum, ischial tuberosities, and heels. Signs of shear injury include irregular deep lesions, undermining, and tunneling.

Prevention of Pressure and Shearing

There are several steps that may prevent the damage resulting from pressure and shear. If possible, limit the head of the bed elevation to 30 degrees or less. If the head must be elevated, the patient's knees may be bent ("gatched") with his or her feet flat on the bed. Using lift sheets to reposition patients is also recommended. Support surfaces are often utilized, and a low-resistance, breathable, and waterproof surface helps to eliminate friction. Foam surfaces lock the patient into place and reduce sliding. However, foam is not an appropriate surface to use if maceration (damage due to moisture trapped against the skin) is a problem [2].

When the patient is in a chair in sitting position, he or she should place feet flat on the floor and the back should be in alignment with the back of the chair. Consider using wheelchair or chair cushions that are higher in the front than the back for patients who tend to slide out of their chairs.

FRICTION

Friction occurs when one surface moves across another surface, such as when a patient's skin slides across a bed sheet. This can result in the "sanding away" of the epidermal layer and upper part of the dermis, resulting in abrasions [2,7]. Friction injuries often present as erythema and tenderness followed by skin loss. Friction damage can be seen under restraints, braces, and on the elbows, or with repetitive rubbing or repetitive cleansing. Patients with uncontrollable movements or spasticity are also at high risk for friction injury, often referred to as "sheet burn." Friction injury occurs more frequently when the skin is fragile or macerated, and tissues subjected to friction are more susceptible to pressure ulcer damage, infection, and deeper ulceration [4,7].

Prevention of Friction

As with pressure and shear, there are steps to minimize friction in at-risk patients. The most common involve measures to prevent the patient sliding down in bed (e.g., use of knee gatch on bed). All skin care measures should be gentle, no scrubbing or aggressive rubbing, and heel and elbow protectors should be utilized. Cornstarch may help to reduce the impact of friction.

MOISTURE

Moisture weakens the resilience of the epidermis to external forces. Maceration causes softening of the connective tissue, and a macerated epidermis erodes more easily. Overhydrated skin has decreased tensile strength. Skin can appear "water-logged," with areas of denuded skin and fissure formation. Shear and friction are increased when there is a moderate amount of moisture present, but it has been reported that shear and friction decrease in the presence of high levels of moisture. The role moisture plays in pressure ulcer development is an area of on-going research [8].

Major sources of moisture are incontinence, wound drainage, tube leakage, and sweating. Urinary and fecal incontinence expose the skin to excessive amounts of moisture and chemical irritation. There is a higher risk for skin breakdown with fecal incontinence than urinary incontinence because of the pathogens in stool.

Prevention of Excessive Moisture

Research has shown that when properly assessed and treated, urinary incontinence can be corrected in about 30% of nursing home residents [9]. Depending on the severity of the incontinence, the patient may be initiated in a toileting program. This consists of prompted voiding; specifically, the patient is taken to the bathroom at regular intervals and instructed to use the bathroom.

When this is not feasible (e.g., if a patient is unable to respond to instructions), the patient should be checked for incontinence every two to three hours and repositioned every two hours, with skin checks. Moisture barrier creams/lotions offer good protection for patients with incontinence. A folded, clean pillow case between skin folds may also be used for moisture absorption.

For sweating, barriers are contraindicated, because they retain moisture against the skin. For patients for whom sweating is an issue, use non-caking powder or a non-occlusive moisture barrier [2].

Some patients will benefit from the use of absorptive products. All absorbent products are not equal, and their benefits must be evaluated according to the needs of the patient. Odor control, wicking properties, absorbency, comfort, and cost all must be considered.

The appropriate use of containment devices, such as condom catheters, should also be evaluated. Trauma related to incorrect application of condom catheters is common and correct sizing and application is important.

STAGES OF BREAKDOWN

Staging is an assessment system that classifies pressure ulcers based on anatomic depth of tissue damage. In 2016, the NPUAP updated the definitions of pressure injury stages (Table 2) [5]. As noted, in the 2016 revision to the NPUAP staging system, the term "pressure injury" replaced "pressure ulcer," to alleviate confusion between injury to intact skin (stages 1 and deep tissue injury) and open ulcers (stages 2–4 and unstageable pressure injury). In addition, the following changes were made [5]:

- Arabic numbers replaced Roman numerals in stages 1–4.

- The term "suspected" was removed from the deep tissue injury diagnostic label.

- Two additional pressure injury definitions, Medical Device-Related Pressure Injury and Mucosal Membrane Pressure Injury, were added.

Table 2: NPUAP PRESSURE INJURY STAGES

Stage

Definition

Stage 1

Intact skin with non-blanchable redness. Area may present with changes in sensation, temperature, or firmness, even before visual changes are noted. Darkly pigmented skin may not have visible blanching, but its color may differ from the surrounding areas.

Stage 2

Partial thickness loss of dermis presenting as a shallow open ulcer with a red/pink wound bed, without slough. May also present as an intact or open/ruptured serum-filled blister.

Stage 3

Full thickness tissue loss. Subcutaneous fat may be visible, but bone, tendon, or muscle is not exposed. Slough may be present but does not obscure the depth of tissue loss. May include undermining and tunneling.

Stage 4

Full thickness tissue loss with exposed bone, tendon, or muscle. Slough or eschar may be present on some parts of the wound bed. Often include undermining and tunneling.

Unstageable pressure injury

Full thickness tissue loss in which the base of the ulcer is covered by slough (yellow, tan, gray, green, or brown) and/or eschar (tan, brown, or black) in the wound bed.

Deep tissue pressure injury

Persistent non-blanchable, deep red, purple, or maroon area of discolored, intact or non-intact skin or blood-filled blister. The area may be preceded by tissue that is painful, firm, mushy, boggy, warmer, or cooler as compared to adjacent tissue.

Medical device-related pressure injury

Describes the cause of a pressure injury resulting from and taking shape of a medical device. Use staging system to classify.

Mucosal membrane pressure injury

Injury found on mucous membranes in a location in which a medical device was used. Cannot be staged.

Source: [5]

Staging of a pressure injury can only occur after all necrotic tissue has been removed and it is possible to see the ulcer bed [1]. If this is not possible, the ulcer will be classified as unstageable. Pressure ulcer staging is not used to indicate pressure ulcer healing; a pressure ulcer should never be "down staged" or reverse staged (e.g., a pressure ulcer that is healing does not go from a stage 4 to a stage 3).

In pressure ulcer healing there is no regrowth of lost muscle, subcutaneous fat, or dermis; instead, the wound is filled in with scar tissue. Therefore, reverse staging does not accurately reflect the physiologic changes occurring in the pressure ulcer. When a stage 4 ulcer has healed, it should be classified as a healed stage 4 pressure ulcer [4].

Stage 2 pressure ulcers have a healing time that ranges from 8.7 to 38 days. Stage 3 and stage 4 pressure ulcers can take up to 69 days to heal. Healing rates are lower for stage 3 and stage 4 ulcers than for stage 2 ulcers in all healthcare settings [5]. Irreversible tissue damage can happen in as little as two hours in a patient with low tolerance; however, the ulcer may not become apparent for two to five days [10].

Stage 1

Stage 1 pressure injury presents as persistent redness in intact skin. If the area is pressed, it will not lighten in color (non-blanchable) [11]. It usually occurs in a localized area over a bony prominence, and this area can be painful, firm, soft, warmer, or cooler than the surrounding tissue [5]. This area of redness has a clear but possibly irregular boundary [11]. In darker skin tones, blanching may not be visible and the color may differ from the surrounding area [5]. In these instances, it is important to look for the other signs of pressure ulcers, such as pain, change in temperature, and changes in skin texture.

Stage 2

Stage 2 pressure injury presents as shallow, open wounds with partial loss of the dermis. The wound bed is pink/red and without slough. A stage 2 pressure ulcer may also present as a serous fluid-filled blister [5]. Fat and deeper tissues are not visible, and slough and eschar are not present. These injuries are most commonly seen on the sacrum due to moisture and shear, and on the heel due to shear [5]. Skin tears, tape burns, incontinence-associated dermatitis, maceration, or excoriation of the skin should not be classified as stage 2 pressure ulcers [4].

Stage 3

Stage 3 is full thickness tissue loss. Subcutaneous fat may be visible and rolled wound edges are often present, but bone, tendon, and muscle are not exposed. There may be slough in the wound, but it does not obscure observation of the wound bed; if slough or eschar obscures the observation, this is an unstageable pressure injury. Tunneling and undermining may be present [5]. It is important to remember that the depth of stage 3 pressure ulcers will differ from one location to another. For example, the bridge of the nose, ear, occiput, and malleolus do not have a subcutaneous layer, and in these areas a stage 3 pressure ulcer can be shallow [5].

Stage 4

Stage 4 ulcers are characterized by full thickness tissue loss with exposed bone, tendon, or muscle. These ulcers often include undermining and tunneling, and rolled wound edges are often seen [5]. Slough and eschar may be present in part of the wound bed; however, if slough or eschar obscures the observation, this is an unstageable pressure injury [11]. In some cases, stage 4 pressure ulcers can affect supporting structures and may lead to osteomyelitis. As with stage 3 ulcers, the depth of the injury will vary by anatomical location.

Unstageable Pressure Injury

A wound that is unstageable is defined as having full thickness tissue loss in which the base of the ulcer is covered by slough (yellow, tan, gray, green, or brown) and/or eschar (tan, brown, or black) [5]. Until the base of the wound can be visualized, the wound will remain unstageable. A necrotic wound cannot be staged until the necrotic tissue has been debrided, and it is then that a stage 3 or stage 4 ulcer will be revealed [5]. It is also important to remember that it is clinically inaccurate to stage a granulating wound if it is the first assessment, as visualizing the depth of the actual pressure sore is not possible [4]. In addition, if stable eschar on an ischemic limb or the heel(s) is present, it should not be removed [5].

Deep Tissue Pressure Injury

Deep tissue pressure injury, previously suspected deep tissue injury, is a pressure-related injury, much like a bruise, that is characterized by persistent non-blanchable, deep red, maroon, purple discoloration or epidermal separation revealing a dark wound bed or blood-filled blister. Deep tissue pressure injuries can present on either intact or non-intact skin. This type of injury is caused by intense and/or prolonged pressure and/or shear. Deep tissue pressure injury may resolve without tissue loss or may rapidly change to reveal the extent of the tissue injury. If necrotic tissue, subcutaneous tissue, granulation tissue, fascia, muscle, or other underlying structures are visible, this indicates a full thickness pressure injury (Unstageable, stage 3, or stage 4). The NPUAP does not recommend using deep pressure tissue injury to describe vascular, traumatic, neuropathic, or dermatologic conditions [5].

Color is the key to differentiating between deep tissue injury and a stage 1 pressure injury. Purple or maroon areas indicate deep tissue injury; non-blanchable redness is characteristic of stage 1 injuries. Deep tissue injury can become a stage 3 or a stage 4 pressure ulcer even with optimal care [5]. In general, the most common areas of involvement are the heels and sacrum [10]. In some patients, particularly those who are debilitated, deep tissue injury can develop rapidly [11].

Medical Device-Related Pressure Injury

Medical device-related pressure injuries describe injuries or ulcers that result from the use of devices designed and applied for diagnostic or therapeutic purposes. The injury is generally in the shape or pattern of the device and should be staged using the staging system [5].

Mucosal Membrane Pressure Injury

Mucosal membrane pressure injury is found on the mucous membranes. This type of injury is typically attributed to use of a medical device on a mucous membrane, and due to the nature of this type of tissue, these injuries cannot be staged.

4. PRESSURE ULCER RISK ASSESSMENT

Evidence Based Practice Recommendation

The National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance recommend the use of a structured approach to risk assessment that includes assessment of activity/mobility and skin status.

https://www.npuap.org/wp-content/uploads/2014/08/Quick-Reference-Guide-DIGITAL-NPUAP-EPUAP-PPPIA-Jan2016.pdf

Last Accessed: May 1, 2019

Level of Evidence: B (The recommendation is supported by direct scientific evidence from properly designed and implemented clinical series on pressure ulcers in humans, providing statistical results that consistently support the recommendation.)

Identifying patients at risk for pressure ulcers is vitally important as it allows for preventative measures to be initiated. Elements of prevention include identifying individuals at risk for developing pressure ulcers, maintaining skin integrity, treating the underlying causes of the ulcer, relieving pressure, assessing the total state of the patient to correct any deficiencies, and patient/family education.

MAJOR RISK FACTORS IN PRESSURE ULCER DEVELOPMENT

Decreased Mobility

Immobility is possibly the greatest risk factor for pressure ulcer development [4]. According to the United Spinal Association, up to 80% of patients with spinal-cord injuries will develop pressure ulcers during their lifetime and 30% will have more than one pressure ulcer [12]. Patients who have lost the ability to ambulate, either for physical or cognitive reasons, will commonly develop pressure ulcers while chair- or bedridden. The prevention of ulcers in these patients is a vital aspect of ensuring an optimal quality of life.

Contractures

Untreated contractures often lead to pressure ulcer development. Contracted limbs, usually caused by continued hypertonic muscle or tendon stress, can exert pressure on surrounding tissues and adjacent areas. Contracture of a leg or foot can result in pressure ulcer development in that extremity, because it exerts more pressure on the support surface than a normal extremity.

Decreased Sensation

The sensory receptors, cortex, and motor neurons/muscles act as a sort of "pressure ulcer prevention system." These sensations induce individuals to move or shift position when an uncomfortable sensation is experienced. Injury or disease to any component of this system results in a loss of these protective reflexes. Therefore, patients who cannot feel discomfort or cannot sense ischemia are at high risk for pressure ulcer development.

Perfusion Status

Adequate circulation is needed to maintain tissue health by delivering oxygen and nutrients to the cells and removing waste products. Edema reduces tissue perfusion by increasing the distance between the cells and the capillary network. Normal, healthy tissue (in a person with normal sensation and movement) can tolerate short periods of ischemia because tissues require intermittent rather than continuous blood flow [2]. However, extended periods of ischemia can result in tissue damage and, with regard to skin, can lead to pressure ulcers.

Hypotension

Low arterial blood pressure (hypotension), defined as systolic blood pressures less than 100 mm Hg and diastolic pressures less than 60 mm Hg, has been linked to increased risk for pressure ulcer development. In response to hypotension, the body redirects blood flow to the vital internal organs at the expense of the peripheral vascular system, which serves the skin. As the perfusion level drops so does the skin's ability to tolerate external pressure. Capillaries subsequently close at lower levels of interface pressure, and there is an increased risk of damage due to ischemia [1].

Hydration

Normal skin hydration is provided by an intact stratum corneum and sebum secretion. Factors that can decrease skin hydration are overly vigorous or frequent washing, low environmental humidity, and aging. The removal of sebum by frequent cleansing or bathing can cause dehydration. It is important to use moisturizing lotion, particularly immediately after bathing to moisten skin.

Cognition

Loss of cognition is also associated with increased risk for pressure ulcers. Impaired mental status leads to a lack of awareness of discomfort or pressure and may be associated with incontinence. The ability to respond appropriately or to inform others of the need for assistance is often lost completely.

Stress

Stress is a primitive response to injury or anticipated injury. Research has shown that during periods of stress, blood vessels in the peripheral tissues constrict. In a study designed to mimic the body's response to stress, healthy subjects were given an infusion of exogenous epinephrine [1]. The increased levels of epinephrine decreased the levels of subcutaneous tissue oxygen by 45%. Other studies have shown that psychologic stress has a negative impact on healing [1].

Depression

The National Institute of Mental Health estimates that 7.1% of adults in the United States are suffering from depression, and major depression is the leading cause of disability worldwide [13]. Depression is particularly under-recognized in the elderly. Depressed patients have little interest in self-care and nutrition, both of which may predispose an individual to pressure ulcers [4].

Age

Patients older than 65 years of age experience pressure ulcers most frequently [1]. With aging, the skin becomes more fragile. The skin layers adhere less securely to each other and often appear paper thin and almost transparent. There is also evidence of increased dryness, decreased vascularization, and increased vascular fragility.

In elderly individuals, there is a decrease in surface barrier function. The ability of the soft tissue to evenly distribute the mechanical load without compromising blood flow is impaired. There is less subcutaneous tissue to cushion boney prominences. This, in addition to decreased sensory perception, makes elderly skin more vulnerable to pressure, shear, and friction [2]. Research has shown that, in the geriatric population, blood flow in the area of the ischial tuberosity while sitting on an unpadded surface is lower than in younger adults [4].

Although much less common, children can also develop pressure ulcers. Most commonly, these ulcers develop in the occipital region in infants and toddlers and on the sacrum in young children [1].

Obesity

In the United States, approximately 78 million adults 20 years of age and older are obese and 15.5 million are morbidly obese [14,15]. Obesity is defined as a body mass index (BMI) of 30 or greater; severe or morbid obesity is defined as a BMI greater than 40 [14,16].

Factors that contribute to pressure ulcer development in obese individuals include decreased blood supply in adipose tissue, difficulty in turning and repositioning, moisture within skin folds, incontinence, skin-to-skin friction, immobility, and poor nutrition. Obese patients are particularly at risk for "unusual" pressure ulcers resulting from pressure within skin folds. Obese patients may have large panniculi ("aprons"), weighing up to 50 pounds. The abdominal panniculus must be regularly repositioned in order to prevent pressure injury. This may be accomplished by placing the patient in the side-lying position and lifting the panniculus away from the underlying skin surface, which allows air to the area and simultaneously relieves pressure.

Tubes or catheters can also cause pressure by burrowing into skin folds. Poorly fitting beds, chairs, or wheelchairs may also be a source of pressure [17].

Nutrition

Low body weight and impaired nutrition are also concerns. Weight less than 119 pounds or a BMI less than 20 are indicators of increased risk for pressure ulcer development [18].

Recent weight loss, decreased nutritional intake, inadequate dietary protein, and impaired ability to feed oneself have been identified as risk factors for pressure ulcer development. An estimated 50% of elderly patients admitted to the hospital have suboptimal protein nutrition [18]. When there is a sustained deficit of protein as an energy source, skin and soft tissues become more vulnerable to injury. Low protein levels also result in decreased resistance to infection. Older adults also have increased incidence of low calorie intake and low levels of zinc and vitamin B12.

Vitamin A, C, and E deficiencies have been associated with pressure ulcer formation. Vitamin A works in the body to maintain epithelial integrity and is involved in collagen synthesis. It also plays a role in protection against infection. A deficiency of vitamin A can inhibit collagen synthesis, delay re-epithelialization, and decrease cellular cohesion. Vitamin C is also involved in collagen synthesis, immune function, and wound repair. A deficiency of vitamin C can result in capillary fragility. Vitamin E deficiency often decreases the immune function of the skin.

Diabetes

It is estimated that 9.4% of the U.S. population has diabetes [19]. Alone, diabetes increases the risk for pressure ulcer development by 56% [18]. However, approximately 43% of diabetics in the United States are 60 years of age or older, which compounds the risks [20].

Elevated blood sugar levels characteristic of diabetes result in decreased phagocytic ability of neutrophils and diminished wound strength. Patients with diabetes are more prone to infection, and wound healing is slower in this population than in patients without diabetes. Hyperglycemia can also result in protein-energy malnutrition, dehydration, and alteration in microcirculation [1]. Peripheral neuropathy, a common complication associated with diabetes, results in decreased sensation, an established risk factor for pressure ulcers.

Smoking

Nicotine impedes blood flow to the tissues in two ways: it is a potent vasoconstrictor, and it increases the adhesiveness of platelets, resulting in clot formation. Carbon monoxide contained in cigarette smoke prevents oxygen from attaching to the hemoglobin molecule. This significantly reduces the amount of oxygen circulating in the blood stream. The same reaction occurs to some extent in people exposed to secondhand smoke. Studies have shown that cigarette smoking is associated with a higher incidence of pressure ulcer development in spinal cord-injury patients [21]. Patients who smoke also have a higher rate of recurrence of pressure ulcers [4].

Medications

Several medications can affect skin integrity. Normal skin flora can be altered by antibacterials, oral steroids, and hormones. Additionally, analgesics, antihistamines, nonsteroidal anti-inflammatory medications, and chemotherapy can alter inflammatory reactions. Of these, corticosteroids have been studied the most extensively. Corticosteroids interfere with collagen synthesis and epidermal regeneration at a dose of 40–60 mg per day [2].

Other Risk Factors

Areas of advanced pressure ulcers that have healed are more likely to have recurrent breakdown. Therefore, documentation of history of a healed ulcer and its stage, if known, is important. Several other conditions can interfere with systemic and peripheral oxygenations and nutrition, resulting in pressure ulcers. These conditions include:

- Respiratory problems

- Atherosclerosis

- Coronary artery disease

- Peripheral vascular disease

- Congestive heart failure

- Malignancies

- Human immunodeficiency virus/acquired immune deficiency syndrome

- Anemia

- End-stage renal disease

- Thyroid disease

- Terminal illness

- Patient refusal of some aspects of care and treatment

RISK ASSESSMENT

No step is more important in preventing pressure ulcers than understanding a patient's risk. Risk assessment is used to identify:

- Populations at risk

- Level of risk

- Type of risk

A risk assessment is a way of attaching numbers and specifics to identified risk factors. An informal risk assessment cannot take the place of a formal risk assessment, such as the one conducted using the Braden Scale. Research shows that without formal risk assessment, clinicians tend to intervene consistently only at the highest levels of risk [22]. In some studies, repositioning or turning, an important part of pressure ulcer prevention, was prescribed for fewer than 50% of the patients at mild-to-moderate risk for pressure ulcer development [4].

The Braden Scale

The Braden Scale was developed in 1987 by Barbara Braden and Nancy Bergstrom [22]. Since then, it has undergone testing in several clinical settings, and its validity has been established by expert opinion. It is considered one of the most reliable tools for identifying patients at risk for pressure ulcer development, and it is the most widely used. The Braden Scale scores factors that contribute to prolonged pressure and factors that result in diminished tissue tolerance for pressure [22]. There are six items scored in the assessment [22]:

- Sensory perception

- Moisture

- Activity

- Mobility

- Nutrition

- Friction and shear

Each item is scored on a scale between 1 and 4 with the exception of friction and shear, which is scored between 1 and 3. The lower the score, the more severe the impairment or problem in that area. Therefore, the lower the score, the higher the patient's risk for pressure ulcer development. Various studies have shown cut-off scores from 16 to 18 as being at risk [2]. Although cut-off scores vary, usually a score of 13–14 is considered moderate risk, 10–12 indicates high risk, and 9 or less is very high risk.

The Braden Scale should be used for assessment on admission to a care facility or after return from a hospital. Research shows that a repeat assessment done 48 hours to 72 hours after admission further defines pressure ulcer risk. In nursing home populations, the majority of pressure ulcers develop during the first two weeks following admission [1]. In addition, most facilities set their own policies regarding reassessment frequency (e.g., quarterly). However, it is important to note that any change in a patient's condition warrants reassessment.

Braden Scale assessment is completed by licensed personnel familiar with the patient and is shared with all staff caring for the patient; good communication is essential to ensure a meaningful assessment [4]. Licensed and unlicensed staff must have a basic knowledge of Braden scores and how it directs patient care. Accuracy of scoring is very important to determining the appropriate intervention.

5. SKIN AND PAIN ASSESSMENTS

Admission assessment is the foundation for effective prevention and initiation of a management program. All special garments, including shoes, heel and elbow protectors, orthotic devices, restraints, and protective wear, should be removed during a skin inspection. If immobilizers or splints are being used, the physician should be consulted to ensure that they may be safely removed. If they cannot be removed, this should be documented in the patient's record.

It is also important to incorporate a holistic assessment, evaluating the meaning and significance of skin breakdown and wound development to the patient and his or her caregiver. Does the patient view the ulcer as a sign of vulnerability, a loss of independence, or an unavoidable consequence of aging?

There are several goals of completing a skin assessment. Foremost, it is imperative to identify and assess areas of impending or actual skin breakdown and patients at risk for future skin ulcers and immediately begin appropriate management interventions. For patients at high risk for pressure ulcer development, a systemic skin assessment should be conducted at least daily and findings should be documented.

ELEMENTS OF A BASIC SKIN ASSESSMENT

A basic skin assessment includes evaluation of the temperature, color, moisture, turgor, and integrity of the skin. The skin's response to pressure indicates its condition. Pressure to soft tissue interrupts the blood flow to that area and results in pallor to the overlying skin. This pallor indicates tissue ischemia. When the pressure stops, the skin should quickly return to its normal color as blood flow returns [23]. In general, when pressure is relieved from an area, redness will resolve within 30 minutes if there is no tissue damage. Therefore, it is important to recheck areas of redness 30 minutes after pressure is relieved and to document findings.

All aspects of the assessment should be explained to the patient. Many people are shy about exposing their body to strangers, even to clinicians. Conduct the exam in a warm and private room with good lighting. It is vital not to rush or overlook part of the assessment, even if the patient is restless.

Although a head-to-toe assessment is often used, a toe-to-head assessment may result in less likelihood of missing areas of potential or actual breakdown, considering that a thorough inspection of the feet and heels is often overlooked. When completing a toe-to-head skin assessment, start with the tips of the toes, between the toes, soles of the feet, back and sides of the heels, and inner and outer areas of both ankles. Continue up the following assessment sites:

- Right and left lower legs

- Right and left knees' inner and outer surfaces

- Right and left thighs

- Right and left ischial tuberosity

- Right and left hip

- Right and left iliac crest

- Sacrum

- Coccyx

- Lower, mid, and upper back

- Right and left shoulders

- Right and left ears (particularly redness under oxygen tubing)

- Back of the head

ASSESSING AND DOCUMENTING A PRESSURE ULCER

Documentation of a pressure ulcer should include location, stage (per NPUAP definitions), wound description (e.g., size, color, drainage), and pain level. Wound size should always be recorded in centimeters. The length is the longest head-to-toe measurement, while the width is the longest hip-to-hip measurement. The best practice recommendation is to measure the wound at the point of greatest length and the point of greatest width. Wound depth is measured by gently inserting a pre-moistened, sterile cotton swab into the deepest part of the wound. The measurement from the tip of the applicator to the level of the skin surface is recorded as the depth [4].

Undermining and/or tunneling should also be recorded in centimeters. Undermining is defined as tissue destruction underlying the intact skin along the wound margins, meaning the wound margins have separated from the wound. Using the face of the clock as a reference for location, with the patient's head representing 12 o'clock, measure the extent of the undermining clockwise. For example, undermining along the right and bottom borders may be recorded as extending 1.5 cm from 2 o'clock to 7 o'clock [24].

Tunneling refers to channeling that extends from any part of the wound and may pass through subcutaneous tissue and muscle. It may result in dead space and abscess formation. The depth of the tunnel should be measured with a sterile cotton swab and recorded. The direction of the tunnel should be documented using the clock method (e.g., 4 cm at 5 o'clock). If there is more than one sinus tract/tunnel, number each one clockwise [4].

It is also vital to assess and document the appearance of the wound bed. If the wound bed has a mixture of tissue in it, this should be documented by an approximate percentage (e.g., the wound base is 75% granulation tissue and 25% slough). Granulation results in "beefy" red tissue with a shiny, moist granular appearance, while necrotic tissue is gray, brown, black, and moist. Eschars are typically gray to black and dry or leathery in appearance [24]. Slough tissue is yellow/white to gray in color. It may be stringy or thick and appear as a layer over the wound bed [24]. Epithelial tissue will often begin to grow in from the edges over the wound surface. This tissue is generally pink and shiny. As a quick reference color guide, red is associated with normal healing, yellow indicates slough or dead tissue, and black is necrosis [4].

Wound drainage is another important aspect of pressure ulcer assessment. The amount should be noted (scant, moderate, or copious). The color and consistency of the drainage may be serous (clear or light yellow in color, thin, watery), sanguineous (red, thin), serosanguineous (pink to light red, thin, watery), or purulent (creamy yellow, green, white, or tan, thick, opaque). The presence of any associated odor should also be documented. A non-infected wound produces little or no odor. The impact of wound odor can be quite devastating to the patient and his or her family.

The area up to 4 cm from the edge of the wound circumferentially should be assessed. Describe its characteristics, particularly color and integrity. Circumferential redness up to 2 cm is indicative of cellulitis [1]. The skin around the pressure ulcer should be palpated to determine if it is soft or indurated. Indurated (hard) tissue, even in the absence of redness, is an indication of infection.

ASSESSING PAIN

Pressure ulcers can cause considerable pain and suffering. Pressure ulcer pain has been described as ranging from sore to excruciating. In one study of patients with stage 2–4 pressure injuries, 74% of patients rated their pain as mild, discomforting, or distressing; 19% rated their pain as horrible or excruciating [25]. Pain and odor control are a major concern for patients, and studies have shown that patients rank pain control as more important than healing [4]. The level of pressure ulcer pain depends both on the stage of the ulcer and on manipulation of the area (e.g., if a dressing change is done at the time of assessment). The majority of patients report pressure ulcer pain at rest as well as with dressing changes. Pressure ulcer pain may be due to tissue trauma from sustained loads, inflammation, damaged nerve endings, infection, procedures such as debridement, and dressing changes [25].

The gold criterion for assessing pain intensity is self-reporting and the utilization of standard pain intensity instruments. Two of the most widely used pain assessment scales are the numeric pain intensity scale and the Wong-Baker Faces Pain Rating Scale [26]. The numeric pain intensity scale consists of ratings from 0 (no pain) to 10 (worst possible pain). This scale can be used for pain assessment with adults and children older than 7 years of age [27]. Visual presentation of the numeric pain intensity scale is helpful with hearing impaired patients, and the scale has been translated into many languages.

The Wong-Baker Faces Pain Rating Scale consists of six faces ranging from a happy smiling face (no pain), to a crying, frowning face (worst pain). The patient is asked to choose the face that best reflects his or her pain. The Faces Pain Rating Scale is the preferred scale for use with children and may also be used with the geriatric population. It can also be used with cognitively impaired patients and those for whom English is a second language.

After the initial pain assessment has been completed, reassessment should be done at regular intervals. Pain intensity should be rated by the patient, not a healthcare professional. The following questions may be used to help determine patients' pain levels:

- What kind of pain are you experiencing?

- What word(s) would you use to best describe it (e.g., burning, aching, shooting)?

- What makes the pain better?

- What makes it worse?

- Where is the pain located?

- Does the pain radiate?

- Would you describe your pain as none, mild, moderate, severe, or excruciating?

- How would you rate your pain on a scale of 0 to 10, with 0 representing no pain and 10 being the worst imaginable pain?

- What is the pain intensity at its worst, best, and now?

- Is the pain better or worse at any particular time of the day or night?

- When does it start and when does it stop?

Pain Management

The goal of pain management in the patient with pressure ulcer is to eliminate the cause of pain and to provide analgesia. There are several interventions and practice modifications that can prevent or manage pressure ulcer-associated pain.

Evidence Based Practice Recommendation

According to the National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance, adequate pain-control measures, including additional dosing, should be implemented prior to commencing wound care procedures.

https://www.npuap.org/wp-content/uploads/2014/08/Quick-Reference-Guide-DIGITAL-NPUAP-EPUAP-PPPIA-Jan2016.pdf

Last Accessed: May 1, 2019

Level of Evidence: C (The recommendation is supported by indirect evidence and/or expert opinion.)

Skin care and assessments should be performed at a time of day when the patient is less fatigued [11]. All procedures should be thoroughly explained before they are performed. If a patient has questions, this should be addressed, and healthcare professionals should be encouraging and provide positive reinforcement. It is important to avoid trauma (shearing and tear injuries) to fragile skin during transferring, positioning, or holding a patient. If necessary, adjunctive medications may be administered to improve sleep and reduce anxiety, which can contribute to experiences of pain.

Dressing changes are often very painful. An analgesic may be administered 30 minutes before dressing changes, and if possible, the number of daily dressing changes should be kept to a minimum. Tape should always be avoided on fragile skin. If patients are able, they should be allowed to remove their own dressings or set the pace of dressing changes. All patients should be assessed for pain before, during, and after dressing changes, and these findings must be documented [4].

Physical therapy and occupational therapy may be helpful to decrease contractures and muscle spasm. Of course, ensuring proper seating and positioning can improve pain scores as well as decreasing the risk for further pressure injuries.

6. INDIVIDUALIZED PROGRAM OF SKIN CARE

One of the most important steps to prevent pressure ulcers is physically repositioning the patient frequently. Repositioning should be done every one to two hours, depending on the patient's condition [2].

POSITIONING IN BED

Every time the patient is repositioned, look for areas of redness and make sure that the new position does not put weight on these areas. Avoid massaging reddened areas over bony prominences [11]. Donut-shaped supports or ring cushions that encircle the ischemic areas should not be used as they can reduce blood flow to an even wider area of tissue. To the degree that the patient is able, encourage activity. Even a few steps done frequently will help. It is important to maintain current activity level, mobility, and range of motion. When repositioning the patient in bed, it is essential to avoid the 90-degree side-lying position. This position puts intense pressure directly over the trochanter. Instead, use the 30-degree lateral position, utilizing a pillow or foam wedge to maintain the position [11]. Keeping the head of the bed at 30-degrees or less (if medically feasible) will help prevent shear. Place a pillow between the patient's knees or ankles to minimize pressure where one limb lies on top of the other. Lifting devices, such as an overhead trapeze or bed linen, are helpful when moving patients. It is important to minimize dragging during transfers and position changes. Minimize environmental factors leading to skin drying, such as low humidity (less than 40%) and exposure to cold [4]. Posting an individualized turning schedule in patient rooms can be helpful to healthcare professionals and patients.

Heel ulcers are especially painful and are among the most difficult to heal. Heel pressure ulcers can develop infection and, in extreme cases, may lead to amputation of the foot. To prevent the development of pressure ulcers on the heels, place a pillow under the calf to float the heels off the bed. There are also devices available that eliminate pressure on heels and prevent foot drop (e.g., suspension boots). Current guidelines state that heels are to be kept off the bed [2].

POSITIONING WHILE IN CHAIR

Pressure ulcers are a particular concern for patients who spend a significant amount of time in chairs. A patient is more likely to develop pressure ulcers from sitting than from reclining, as sitting puts the patient's weight on the relatively small surface areas of the buttocks, thighs, and soles of the feet. Much of this weight is focused over the small area of tissue covering the ischial tuberosities. It is important for patients who sit in a chair to regularly change position. A dependent patient must have his/her position changed in a chair at least every hour. Patients who are able to move themselves should shift their weight (even slightly) every 15 minutes.

Evidence Based Practice Recommendation

The National Pressure Ulcer Advisory Panel, the European Pressure Ulcer Advisory Panel, and the Pan Pacific Pressure Injury Alliance recommend using wheelchairs and chairs that are wide and strong enough to accommodate obese patients' girth and weight. A pressure redistribution cushion designed for the bariatric individual should be used on seated surfaces, and clinicians should check routinely for "bottoming out" of the cushion.

https://www.npuap.org/wp-content/uploads/2014/08/Quick-Reference-Guide-DIGITAL-NPUAP-EPUAP-PPPIA-Jan2016.pdf

Last Accessed: May 1, 2019

Level of Evidence: C (The recommendation is supported by indirect evidence and/or expert opinion.)

A patient should be properly positioned in a chair for postural alignment, distribution of weight, balance, and stability. Patients should sit with their back erect and against the back of the chair, thighs parallel to the floor, knees comfortably parted, and arms horizontal and supported by the arms of the chair. This position distributes weight evenly over the available body surface area. Slouching can cause shearing and friction and places undue pressure on the sacrum and coccyx. Feet should be kept flat on the floor to protect the heels from pressure and distribute the weight of the legs over the largest available surface area. The thighs and arms should remain parallel to ensure that weight is evenly distributed instead of being focused on the ischial tuberosities and elbows. Parting the knees will prevent the knees and ankles from rubbing together. If a patient uses a footstool, it is vital that his or her knees are not above hip level, because this shifts the weight from the back of the thighs to the ischial tuberosities. This same problem can occur if the chair is too short for the patient.

CLEANSING AND BATHING

Maintaining skin cleanliness and moisturizing frequently can protect skin integrity. The skin should be cleaned with water and a gentle soap, preferably a pH-balanced cleanser. Alkaline products remove skin lipids, which increases water loss and weakens the barrier function of the skin [11]. Avoid hot water for bathing and scrubbing or using harsh cleaning agents. A soft cloth should be used to pat rather than rub the skin dry. Thromboembolic deterrent (TED) stockings should be removed when bathing, and the nurse or physician should be notified of any redness, discoloration, or skin breakdown.

It is important to individualize the frequency of skin cleansing based on the patient's age, skin texture, and dryness or excessive oiliness of the skin. A daily bath may not be needed for all patients.

MOISTURIZING THE SKIN

The epidermis is about 30% water, but through a process called trans-epidermal water loss, skin can lose its natural moisture. Without sufficient moisture, skin can become dry, brittle, and vulnerable to breakdown [2]. Therefore, products should be used to keep the skin supple.

Emollients, such as mineral oil, petrolatum, and lanolin, penetrate into the stratum corneum to increase the lipid component and add softness to the skin. In addition, the oil film on the skin surface prevents water loss and helps to rehydrate the stratum corneum [11].

Moisture barriers such as dimethicone also help to prevent water loss and to retain lipids and water within the skin cells. These products maintain the "brick and mortar" configuration of the skin by replacing lost "mortar" [2].

Humectants, such as glycerin, urea, and Lac-Hydrin, increase the water content of the stratum corneum by pulling water from the environment. Normal hydration of the skin cells maintains normal cell shape and cell function. All moisturizers should be applied to clean, slightly moist skin. Special attention should be paid to bony prominences, heels, ears, and the back of the head.

BOWEL AND BLADDER MANAGEMENT

Urinary and Fecal Incontinence

According to the National Association for Continence, approximately 25 million Americans have transient or chronic incontinence. It is estimated that more than 90% of patients with urinary incontinence fail to seek medical intervention or treatment [28].

At least half of all nursing home residents experience urinary incontinence [28]. For patients who are cooperative and aware of bladder filling, a toilet program should be instituted, including planned voiding every two hours. For patients who are uncooperative or unaware of bladder filling, consider the use of absorptive products or condom catheters for men. It is important to use diapers and underpads that wick moisture away from patients' skin. These patients should be checked for incontinence every two hours. Incontinent patients should be cleaned as soon as possible after soiling using specialized incontinence skin cleansers or soaps.

For patients with fecal incontinence and severe diarrhea, all potential causative factors should be explored and addressed. A rectal pouch may be useful for these patients. In cases of chronic incontinence, an every-other-day suppository or enema may be considered. In addition, barrier ointments help protect the skin from incontinent episodes. If used, apply a thick coat of ointment, wipe off the soiled top layer, and apply another layer. Do not clean off the paste to skin level when bathing or cleaning.

SUPPORT SURFACES

There is a vast array of support surfaces and seating options available, but as helpful as these devices may be, they are no substitute for attentive care. Patients still require individualized turning schedules regardless of the equipment used.

Most support surfaces reduce pressure by conforming to the contours of the body so pressure is redistributed over a larger area rather than concentrated in one location [2]. There are many support options, including mattresses, overlays, and cushions.

Mattresses and Overlays

Most pressure relief mattresses use some form of foam, gel, or water to cushion the patient. Water mattresses and some air mattresses evenly distribute pressure under the patient. Low-air-loss and high-air-loss mattresses are specialized support devices that pass air over the patient's skin and promote evaporation [2].

The most common mattress overlays are foam, air, and gel. Foam overlays should be at least 3 inches thick for the average patient; even thicker is better. Two-inch foam overlays may add comfort, but they are not suitable for patients at risk for pressure ulcers. Standard egg-crate mattresses are used for comfort only [2]. All support surfaces, regardless of the medium, function best with less linen between the patient and the surface. If a patient's weight completely compresses a mattress overlay, it is not effective. To make sure that a mattress is not "bottoming out," slide one hand between the mattress overlay and the mattress. If the patient's body can be felt through the overlay, it should be replaced [8]. The weight limit for most support surfaces is about 350 lbs. Special low-air-loss mattresses are available for patients who weigh more than 350 lbs.

An important factor in air-filled overlays is inflation; they may not be effective in preventing pressure ulcers if they are over-inflated, under-inflated, or punctured. Therefore, inflation must be checked daily.

Patients must be comfortable and able to sleep on the support surface. Some surfaces produce noise that may not be tolerable for some patients.

Cushions

Products designed to help prevent pressure ulcers while sitting fall into two broad categories: those that relieve pressure and those that make repositioning easier.

Seat cushions may be used to distribute weight over the largest possible surface area. These are generally made of foam, gel, air, or a combination [2]. Wheelchair cushions for short-term use are foam, air, water, or gel. The goal of these products is to improve weight distribution cost effectively. Gel and air cushions have been shown to be the most effective [11]. Wheelchair-bound patients who require long-term solutions need cushions that fit the wheelchair, support seating stability, provide high-level pressure reduction, and reduce shear. All cushions should be checked and repaired or replaced on a regular basis.

PATIENT/FAMILY EDUCATION

A vital component of a pressure ulcer prevention program is education. If possible, pressure ulcer prevention should not be a passive process for the patient and his/her family members. Rather, it should be a dialogue in which the patient or family feels comfortable asking questions and discussing problems. Patients should have as much control as possible in the plan of care. Empowerment is very important in maintaining the patient's physical and emotional well-being. The plan of care should be explained thoroughly to cognitively aware patients and their family.

At the same time, it is vital to evaluate the patient's/family's existing knowledge regarding pressure and pressure ulcers. Healthcare professionals should show patients what they can do to facilitate pressure relief (e.g., how to make small position changes while in the chair). If possible, it is often beneficial to teach patients how to do simple range-of-motion exercises. Take time to train the patient as often as is appropriate; not everyone will absorb the information the first time it is heard [4]. It is important not to let noncompliance or a bad attitude from the patient or family discourage the teaching process. The subject should be approached as often as is reasonable. Include the family members and caregivers in the instructions. As well as assisting with care, they can encourage compliance. All efforts at patient and family/caregiver education should be documented, along with the patient's response (both verbal and behavioral).

STAFF EDUCATION

Education of caregivers is also a key factor in the prevention of pressure ulcers and in the successful management of existing pressure ulcers. All healthcare personnel providing care to the patient must appreciate the role that they play in pressure ulcer prevention. Materials should be prepared to meet the educational levels of different members of the interdisciplinary team [29]. Certified nursing assistants (CNAs) are an essential part of the nursing team, and their education regarding pressure ulcer prevention and pressure ulcer healing should not be neglected. Programs specifically geared towards CNAs may be developed and implemented.

NUTRITIONAL SUPPORT

Nutrition is important for maintaining skin integrity. A strong correlation exists between poor nutrition and pressure ulcer development [18]. Despite this fact, nutrition is often overlooked during treatment. It is of vital importance to address the nutritional needs of every individual with pressure ulcers [30].

Malnutrition is defined as undernutrition or overnutrition caused by a deficit or excess of nutrients in the diet. Undernutrition occurs because intake is inadequate or the individual is unable to absorb nutrients. Overnutrition is most commonly seen in obesity. Patients with nutritional compromise should receive nutritional support, with the possible exception of patients in the end of life. Evaluation of hydration status is also an integral part of the overall nutritional picture.

Nutritional Assessment

Weight is the cornerstone in the diagnosis of malnutrition [2]. An unplanned weight loss of more than 10% in the last six months indicates a serious nutritional compromise. Signs of malnutrition include:

- Loss of subcutaneous tissue

- Muscle wasting

- Generalized edema

- Dry, pluckable hair

- Dry, flaky, itchy skin

- Cracks in the mucous membranes

- Delayed wound healing/failure to granulate

Food and fluid intake should be continuously assessed. Pay attention to food preferences and tolerances; it is beneficial to optimize the eating environment by individualizing meal times and patterns as much as possible. Culture and religion often play a significant part in food choices and attitudes toward eating. It is often necessary to consider an interdisciplinary assessment of chewing and swallowing ability and dental problems.

Malnutrition is common in elderly individuals. Older people produce less saliva, which makes swallowing more difficult. Smell and taste diminish with age, and medication can affect taste buds, causing food to become less appealing. Patients' ability to self-feed should also be monitored. The use of finger foods, adaptive utensils, and feeding assistance should be considered if necessary.

Interventions to Promote Nutrition

For patients with inadequate nutrition, strategies must be employed to increase oral intake. The preferred route of nutritional support is oral; whenever possible, the gastrointestinal tract should be used for feeding. It is the easiest and most comfortable way to provide supplementation, and it is also the least expensive and most convenient way. Patients must have diets prescribed with protein and caloric content sufficient to meet metabolic needs. The diet should consider the patient's preferences and special needs (e.g., mechanical soft diets) [4]. Daily multivitamin supplementation may need to be implemented. Mouth care should be performed prior to eating. Additionally, toileting and hand washing should be offered prior to meals.

Provide an environment conducive to eating. Position the patient properly; an upright position is preferred. Make sure the food is at the right temperature for the patient. Do not rush eating, particularly if the patient is elderly and requires more time to be oriented. Many patients benefit from the inclusion of snacks high in calories and protein in the diet (e.g., a peanut butter sandwich with milk). Consider adding powdered milk to yogurt and pudding to maximize caloric intake and protein levels. Commercial nutritional supplements, such as breakfast shakes, are also a common adjunct.

It is vital to maintain patient control as far as medically feasible. Some patients may not like ice in their water, others may prefer soup lukewarm. Patient preferences should be accommodated as much as possible.

Remind the patient to chew food thoroughly. If necessary, liquids may be offered between bites; some patients require this to help swallow their food.

Keeping patients hydrated is vitally important, and healthcare professionals should take all available opportunities to improve patients' hydration if it is medically indicated. Patients at risk of becoming dehydrated should be listed on assignment/report sheets as a reminder to monitor these patients. Fluids should be scheduled between meals at least three times a day. Patient preferences for fluids (e.g., straws, temperature, ice) should be observed and noted. Refill water pitchers frequently and keep them within reach of patients, especially those with restricted mobility. Patients should be offered something to drink at every interaction. Ambulatory patients should be provided with a water bottle. As with nutrition and positioning, it is necessary to educate patients/families about the importance of hydration. When, despite these measures, patients are unable to consume adequate levels of water or nutrients, tube feeding or parenteral feeding should be considered. Patient and family preferences and the overall goals of treatment guide these decisions [18].

EVALUATION OF THE SKIN PROGRAM

Patients at risk for skin breakdown should have a daily inspection at every interaction, including during bathing, dressing, and repositioning. Every time the patient is repositioned, the skin surfaces should be checked. This will help determine if the turning schedule is appropriate for the patient or if it should be modified. Particularly, patients should be assessed to determine if episodes of incontinence are being adequately controlled. Differential diagnosis for fecal incontinence includes infection (e.g., Clostridium difficile), impaction, and dietary deficits. Ongoing evaluation of interventions in use is essential to ensure that they are effective.

Assessment is a team effort and should include all members of the interdisciplinary team, including physicians, nurses and nurse assistants, physical therapists, occupational therapists, dieticians, and social workers. If an intervention is determined to be ineffective, it should be modified or changed completely. Possible modifications of a skincare plan include physical therapy to assess current level of mobility, changing seating surfaces, and correcting inappropriate body alignment when sitting.

7. DOCUMENTATION

Documentation of skin assessments provides information for those involved in the patient's care; it is a communication tool between the disciplines. To determine if an ulcer is improving, documentation of the various states of the ulcer is necessary. This allows for evidence that the ulcer has improved [8]. Therefore, observations and interventions should be presented clearly and concisely. Another purpose of documentation is for a legal record of the assessment, interventions, and outcomes [6]. The individualized interventions for skin care should be documented, with specific details regarding who provided care, how often, what supplies and equipment are needed, and how the care should be undertaken. This information should be readily available to all of the patient's caretakers.

There are several tips to facilitate the complete documentation of pressure ulcers. A good rule for documentation is to keep a record of the initial evaluation, interventions, patient's response, and any follow-up. All changes or complications identified should be noted. It is important to write clearly so anyone reading the chart will understand the language and the terms used.

Efforts to educate patients and/or families should be documented, including instructions given and responses from the patient/family. If a patient refuses or is unwilling to engage in certain interventions, this should become part of the documentation.

8. CONCLUSION

A thorough, holistic assessment of each patient at admission, with factual, concise documentation of findings, is a clear starting point for treating and/or preventing pressure injuries. Daily skin assessments for high-risk patients and informal assessment with every patient contact are recommended to ensure optimal patient care. A reliable tool, such as the Braden Scale, should be utilized to identify patients at high risk for skin breakdown, and the NPUAP guidelines should be used to stage skin breakdown appropriately. The establishment of goals consistent with the values and lifestyle of the patient and his/her family can facilitate greater patient involvement in care and adherence to prescribed interventions. A team approach in deciding appropriate individualized interventions for each patient has proven advantages. Team members should be aware of their roles in implementing the plan of care. Ongoing assessment of the interventions in place and modification/change of the plan of care as needed is the final step in implementing an individualized skincare plan. Of course, this should be supported by timely, accurate documentation.

Works Cited

1. Bryant RA, Nix DP. Acute and Chronic Wounds: Current Management Concepts. 5th ed. St. Louis, MO: Elsevier-Mosby; 2016.

2. Emory University School of Medicine Wound, Ostomy and Continence Nursing Education Center. Skin and Wound Module. 6th ed. Atlanta, GA: Emory University WOCNEC; 2006.

3. Barber P, Parkes J, Blundell D. Further Essentials of Pharmacology for Nurses. Maidenhead: McGraw-Hill International; 2012.

4. Baranoski S, Ayello EA. Wound Care Essentials: Practice Principles. 3rd ed. China: Lippincott Williams & Wilkins; 2012.

5. National Pressure Ulcer Advisory Panel. Press Release. National Pressure Advisory Panel (NPUAP) Announces a Change in Terminology from Pressure Ulcer to Injury and Updates the Stages of Pressure Injury. Available at http://www.npuap.org/national-pressure-ulcer-advisory-panel-npuap-announces-a-change-in-terminology-from-pressure-ulcer-to-pressure-injury- and-updates-the-stages-of-pressure-injury. Last accessed April 10, 2019.

6. Fenstemacher PA, Winn P (eds). Post-Acute and Long Term Medicine: A Pocket Guide. 2nd ed. Geneva: Springer International Publishing; 2016.

7. Agrawal K, Chauhan N. Pressure ulcers: back to the basics. Indian J Plast Surg. 2012;45(2):244-254.

8. Wound, Ostomy, and Continence Nurses Society. Guideline for Prevention and Management of Pressure Ulcers. Mt Laurel, NJ: Wound, Ostomy, and Continence Nurses (WOCN); 2010.

9. Newman DK, Palmer MH. Incontinence and PPS: a new era. Ostomy Wound Manage. 1999;45(12):32-49.

10. Wound, Ostomy and Continence Nurses Society. WOCN Society Response to NPUAP White Papers: Deep Tissue Injury, Stage I Pressure Ulcers, and Stage II Pressure Ulcers. Ninth National NPUAP Conference. February 2005.

11. Medline Industries, Inc. Pressure Ulcer Prevention Program. Mundelein, IL: Medline Industries, Inc.; 2008.

12. United Spinal Association. Health and Wellness after SCI: Skin Breakdown, Pressure Ulcer Prevention with SCI-RRTC. Available at http://www.spinalcord.org/resource-center/askus/index.php?pg=kb.page&id=2396. Last accessed April 10, 2019.

13. National Institute of Mental Health. Major Depression. Available at https://www.nimh.nih.gov/health/statistics/major-depression.shtml. Last accessed April 10, 2019.

14. Hamdy O. Obesity: Epidemiology. Available at https://emedicine.medscape.com/article/123702-overview#a5. Last accessed April 10, 2019.

15. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the US. Int J Obes (Lond). 2013;37(6):889-891.

16. Centers for Disease Control and Prevention. Overweight and Obesity: Defining Adult Overweight and Obesity. Available at https://www.cdc.gov/obesity/adult/defining.html. Last accessed April 10, 2019.

17. Institute for Clinical Systems Improvement. Pressure Ulcer Prevention and Treatment Protocol: Health Care Protocol. Bloomington, MN: Institute for Clinical Systems Improvement; 2012.

18. Stasik L. Hospital-Acquired Pressure Ulcers: Making the Nutrition Connection. Columbus, OH: Abbott Nutrition; 2008.

19. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Diabetes Fast Facts. Available at https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. Last accessed April 10, 2019.

20. Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion: Division of Diabetes Translation. National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States. Available at https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Last accessed April 10, 2019.

21. Smith BM, Guihan M, LaVela SL, Garber SL. Factors predicting pressure ulcers in veterans with spinal cord injuries. Am J Phys Med Rehabil. 2008;87(9):750-757.

22. Bergstrom N, Braden BJ, Laguzza A, Holman V. The Braden Scale for predicting pressure sore risk. Nurs Res. 1987;36(4):205-210.

23. Family Health Media. Pressure Ulcer Prevention: What Caring People Need to Know [DVD]. 2nd ed. Charlottesville, VA: Family Health Media; 2008.

24. Kennedy KL. Gaymar Pictorial Guide to Pressure Ulcer Assessment. 2nd ed. Orchard Park, NY: Gaymar Industries; 2006.

25. Günes UY. A descriptive study of pressure ulcer pain. Ostomy Wound Manage. 2008;54(2):56-61.

26. Wong DL, Hockenberry-Eaton M, Wilson D, Winkelstein ML, Schwartz P. Wong's Essentials of Pediatric Nursing: Wong-Baker Faces Pain Rating Scale. 6th ed. St. Louis, MO: Mosby; 2001.

27. Bergstrom N, Allman R, Alvaraz O, et al. Treatment of Pressure Ulcers: Clinical Guideline Number 15. Publication No. 95-0652. Washington, DC: Agency for Healthcare Policy and Research; 1994.

28. National Association for Continence. Incontinence Conditions From A–Z. Available at https://www.nafc.org/conditions-overview. Last accessed April 10, 2019.

29. Armstrong, Ayello EA, Capitulo KL, et al. New opportunities to improve pressure ulcer prevention and treatment: implications of the CMS inpatient hospital care present on admission indicators/hospital-acquired conditions policy: a consensus paper from the International Expert Wound Care Advisory Panel. Adv Skin Wound Care. 2008;21(10):469-478.

30. Dorner B, Posthauer ME, Thomas D. The Role of Nutrition in Pressure Ulcer Prevention and Treatment: National Pressure Ulcer Advisory Panel White Paper. Available at https://www.npuap.org/wp-content/uploads/2012/03/Nutrition-White-Paper-Website-Version.pdf. Last accessed April 19, 2019.

Evidence-Based Practice Recommendations Citations

1. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance. Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline. Washington, DC: National Pressure Ulcer Advisory Panel; 2014. Available at https://www.npuap.org/wp-content/uploads/2014/08/Quick-Reference-Guide-DIGITAL-NPUAP-EPUAP-PPPIA-Jan2016.pdf. Last accessed May 1, 2019.

98931 • Irritable Bowel Syndrome

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Irritable bowel syndrome (IBS) is common in the general population and has a significant medical and socioeconomic impact. IBS has long been viewed as a functional gastrointestinal (GI) disorder, which means the symptom complex of chronic abdominal pain and altered bowel habits cannot be explained by identifiable structural or biochemical abnormalities. Education on the recent breakthroughs in etiology, pathophysiology, and treatment will empower healthcare providers to optimize treatment of their patients with IBS.

Table of Contents

98931 • Irritable Bowel Syndrome

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

COMMON COMORBID CONDITIONS

NATURAL HISTORY

DISEASE BURDEN

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

CONTRIBUTING FACTORS

BRAIN-GUT AXIS AND PROCESSING

ALTERED PAIN PERCEPTION IN PATIENTS WITH IBS

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

CLINICAL PRESENTATION

CONCEPTUAL AND DIAGNOSTIC ADVANCES

DIAGNOSTIC CRITERIA AND MEASUREMENT SCALES

CLINICAL EVALUATION AND DIAGNOSTIC WORKUP

5. TREATMENT

THE THERAPEUTIC RELATIONSHIP AND TREATMENT ADHERENCE

LIFESTYLE MODIFICATION

PSYCHOLOGIC INTERVENTIONS

ANTIDEPRESSANT MEDICATIONS

DIARRHEA-PREDOMINANT IBS

CONSTIPATION-PREDOMINANT IBS

ABDOMINAL PAIN-PREDOMINANT IBS

SPECIALIST REFERRAL

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

7. CONCLUSION

8. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

98931 • Irritable Bowel Syndrome

Education Category. Infection Control / Internal Medicine

Release Date. 12/01/2019

Expiration Date. 11/30/2022

Course Overview

Irritable bowel syndrome (IBS) is common in the general population and has a significant medical and socioeconomic impact. IBS has long been viewed as a functional gastrointestinal (GI) disorder, which means the symptom complex of chronic abdominal pain and altered bowel habits cannot be explained by identifiable structural or biochemical abnormalities. Education on the recent breakthroughs in etiology, pathophysiology, and treatment will empower healthcare providers to optimize treatment of their patients with IBS.

Audience

This course is designed for physicians, physician assistants, nurses, and other healthcare providers who may improve the identification and care of patients with irritable bowel syndrome.

Course Objective

The purpose of this course is to provide primary care physicians and nurses a review of irritable bowel syndrome, emphasizing pathophysiology, clinical assessment, and principles of care that take into account the biopsychosocial features of this common disorder. The goal is to improve clinical recognition and treatment and to promote management strategies that lead to better patient outcomes.

Learning Objectives

Upon completion of this course, you should be able to:

1. Describe the incidence and prevalence of irritable bowel syndrome (IBS).

2. Identify conditions that are commonly comorbid with IBS.

3. Outline the natural history and disease burden of IBS.

4. Review the pathogenesis and pathophysiology of IBS.

5. Discuss risk factors for the development of IBS and underlying etiology.

6. Describe the assessment of patients with suspected IBS, including presenting signs and symptoms, testing, and clinical diagnostic criteria.

7. Identify conditions that should be included in the differential diagnosis of IBS.

8. Discuss the role of laboratory studies and alarm features in reaching a diagnosis of IBS.

9. Evaluate the role of nonpharmacologic therapies for the treatment of IBS.

10. Compare and contrast available pharmaco- therapies for the treatment of the various IBS subtypes.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

1. INTRODUCTION

Until recently, irritable bowel syndrome (IBS) was considered a diagnosis of exclusion. The pathophysiology was poorly understood, patient outcomes were usually unsatisfactory, and clinicians considered IBS difficult and frustrating to manage [1]. The conceptual and empirical framework to inform the clinical care of patients with IBS took a large step forward in 2016, when the Rome Foundation published the Rome IV diagnostic criteria for IBS. These criteria incorporate the many scientific and clinical advances made since the release of the previous version (Rome III) in 2006. This was part of a larger project to overhaul and update scientific advances and clinical guidance to optimize the diagnosis and treatment of functional gastrointestinal (GI) disorders [2]. In addition, 18 review papers that detail the latest understanding of functional GI disorders were published by members of the Rome Foundation in 2016.

IBS is characterized by recurrent abdominal pain associated with disordered bowel habits (constipation, diarrhea, or a mix of constipation and diarrhea); abdominal bloating/distention is typically present. The symptoms must not have a definable organic, metabolic, or drug-induced basis [3]. IBS and other functional GI disorders are now understood as disorders of the gut-brain axis that arise through complex, bidirectional interactions of biopsychosocial factors.

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

IBS often has an insidious onset with intermittent exacerbation of symptoms so nonspecific and familiar that patients frequently feel no need to seek medical attention. Thus, there usually is a significant lag period between onset, first physician visit, and the eventual IBS diagnosis, which renders the true incidence and prevalence of IBS difficult to establish [4]. However, some prevalence estimates are available.

General Population

The lifetime prevalence of IBS in adult North American and European populations is 10% to 20%, but only 5% to 7% have been diagnosed. IBS shows highest prevalence in South America (21%) and lowest prevalence in Southeast Asia (7%) [5,6].

Clinical Populations

IBS is the most frequently diagnosed GI condition, accounting for 41% of patients with functional GI disorders [5,6,7]. Among clinical populations, IBS accounts for 12% of all patients seen in primary care and 28% in gastroenterology clinics [7]. In the United States, patients with IBS are evenly distributed among three common presenting clinical patterns: IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), and mixed IBS (IBS-M); in Europe, most patients reportedly have either IBS-C or IBS-M [5,6].

Of all persons with IBS symptoms, only a subset seek primary care medical attention, estimated at 10% to 70% in European countries and around 30% in the United States. In a 2017 online survey of 1,924 participants with a history of gastrointestinal symptoms, 43% of individuals who met the criteria for IBS-D had not received a formal diagnosis of the disorder [9]. Patients with IBS-D tend to seek medical attention at higher rates than those with IBS-C or IBS-M. Those seeking medical care report greater levels of pain and anxiety and greater impact on quality of life. In contrast, GI symptom severity does not differ greatly between the two groups [4,8,10].

Sex

The global prevalence of IBS is 14% in women and 8.9% in men, meaning the rate is 67% greater in women than men. This difference in reported sex-specific prevalence may be influenced in part by stigma associated with the diagnosis or by differing attitudes and behaviors that influence the decision to seek medical care rather than merely a variation in susceptibility and severity of underlying pathology [4,11]. Alternatively, female sex hormone physiology may alter regulatory mechanisms of the brain-gut axis more easily and thus promote IBS pathophysiology [12].

In the United States, Canada, and Israel, IBS symptoms are 1.5 to 2 times more prevalent in women than men, while the female/male distribution is closer to even in Asia. Abdominal pain and constipation are more common symptom complaints in women, with diarrhea more common in men [5,11].

Age

A meta-analysis of 81 epidemiologic studies found that IBS prevalence decreases with age. The prevalence rate in patients younger than 40 years of age is 11.0%, with decreased rates in each subsequent decade (9.6% for persons in their 40s, 7.8% for persons in their 50s, and 7.3% for persons in their 60s). The lowest IBS prevalence rates are among persons 50 years of age and older [13,14].

Challenges to Obtaining Accurate IBS Epidemiology Data

Prevalence estimates for IBS are impacted by stigma associated with seeking health care for IBS symptoms or receiving a functional GI disorder diagnosis. Lower reported prevalence is likely in areas where greater stigma is perceived or where symptoms are so common as to be viewed as variations of normal. For example, diarrhea (from all causes) is common in Mexico and may not be viewed as an illness that requires healthcare contact [15]. The reported prevalence of IBS is likely to be higher in communities with higher perceived stress, lower perceived quality of life, greater potential gain from receiving a diagnosis, or fewer barriers to health care access [4,16,17].

The absence of a criterion-standard case definition or standardized diagnostic criteria over time has created difficulty in defining IBS cases for epidemiologic studies. Widely used ancillary data in other disorders are limited in IBS. Relatively few patients are hospitalized for IBS or diagnosed during admission, and IBS is not a cause of death that would show on death certificates [4]. Prescription data are only recently relevant as more medications have received U.S. Food and Drug Administration (FDA) approval for IBS.

COMMON COMORBID CONDITIONS

IBS is associated with numerous comorbidities. Most cluster into functional somatic syndromes (e.g., fibromyalgia, chronic fatigue syndrome, chronic pelvic pain), other GI disorders (e.g., gastroesophageal reflux disease, dyspepsia), and psychiatric disorders (e.g., major depression, anxiety, somatization). These syndromes overlap on multiple dimensions [5,18].

Panic disorder is highly comorbid with IBS, and the prevalence of IBS symptom characteristics in patients with panic disorder is 25% to 44% [12]. A strong association is also found between IBS and generalized anxiety disorder, and patients with comorbid IBS and generalized anxiety disorder have greater functional impairment and depressive symptoms. Post-traumatic stress disorder (PTSD) is also prevalent, and as many as 36% of patients with IBS meet the criteria for lifetime diagnosis for PTSD. Major depressive disorder is the most frequent psychiatric comorbidity in IBS. Patients with major depressive disorder showed a 27% to 47% prevalence of IBS, although patients with major depressive disorder in remission did not differ from healthy controls in terms of IBS symptoms [12].

IBS severity and abdominal pain intensity vary directly with the degree of anxiety and depression [19]. Significantly greater levels of anxiety have been found in patients with IBS-D than in patients with IBS-C or IBS-M; patients with IBS-D also show significantly greater incidence of depression [18].

A higher percentage of patients with IBS and anxiety or depression had extra-intestinal physical symptoms than patients without anxiety (44.8% versus 16.8%, respectively) or depression (57.0% versus 21.5%, respectively) [20,21].

Patients with IBS are much more likely to have psychiatric conditions than persons without IBS. Many patients with IBS receive anxiolytics and antidepressants, and one study found that 62% of patients had received these agents prior to being diagnosed with IBS. A greater percentage of patients with severe IBS have at least one psychiatric disorder compared with patients with mild or moderate IBS (94.4% versus 35.7% and 76.1%, respectively) [21,22,23].

IBS, fibromyalgia, chronic fatigue syndrome, temporomandibular joint (TMJ) disorder, and vulvodynia syndrome are characterized by distressing symptoms of pain and fatigue in the absence of clinically obvious pathology. These conditions have been termed "central sensitivity syndromes." Neuroimaging studies using evoked sensory paradigms have revealed a common sensory augmentation to both painful and nonpainful stimulation, a transformative observation for these syndromes historically considered entirely hysterical or feigned in origin. Whether amplified pain is causal to these syndromes, a predisposing factor, an endophenotype, or an epiphenomenon cannot be discerned without additional research [24].

Roughly 50% of all patients with IBS also experience fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic pelvic pain, chronic headache, or TMJ dysfunction. Symptoms of these functional somatic syndromes considerably overlap with IBS and with each other, and functional somatic syndromes occur almost twice as often in patients with IBS than in the general population [25,26]. In a survey of patients with IBS, 69% reported fatigue, 48% experienced sleep problems, and 37% complained of recurrent or chronic back pain [20,27]. Low back pain was found to be more common in patients with IBS-C than IBS-D [21].

The symptoms of IBS are more severe in patients with somatic comorbidities than in those with IBS alone. More than 50% of patients with IBS also have depression or anxiety and, as a group experience more severe somatic symptoms than patients without these psychiatric conditions [4,28,29]. Many physical symptoms affect the overall well-being of patients with IBS (including psychologic health) and should not be overlooked or marginalized [21].

At the time of IBS diagnosis, the likelihood of an organic lesion being found on colonoscopy in patients lacking alarm symptoms is no higher than in healthy controls, and even most patients with alarm symptoms have no organic pathology [4,30]. In contrast to endoscopy findings at diagnosis, the subsequent risk of developing inflammatory bowel disease was found to be 9 to 16 times greater in patients diagnosed with IBS than the general population, with an average two- to three-year interval between onset of IBS and the inflammatory bowel disease diagnosis. These data implicate some overlap in pathogenesis for IBS and inflammatory bowel disease [31].

Colorectal cancer incidence is around 1% in the first year of IBS diagnosis. While initially higher than in the general population, the incidence of colorectal cancer among patients with IBS returns to population levels after one year [4,32].

NATURAL HISTORY

Symptom Patterns

For most patients with IBS, the symptoms of IBS are intermittent and over time show considerable fluctuation in frequency and duration. In the first three months after diagnosis, patients experience an average of four distinct symptom episodes per month, with the longest episode averaging five days, and most patients experience symptoms more than 50% of the days. One year after initial diagnosis, 30% to 45% of patients report they now have prolonged symptom-free periods. In the second year of follow-up, some patients experience symptom resolution, while others develop new symptoms and rate of symptomatic IBS episodes remains stable. After 10 years, 50% to 70% of patients report persistent symptoms [33,34,35].

Long-term follow-up data from clinical IBS populations indicate that 2% to 18% of patients worsened, 30% to 50% remained unchanged, and 12% to 38% improved over time. Poor outcomes were associated with previous surgery, longer disease duration, higher somatic scores, and higher baseline levels of anxiety or depression [5,36].

Up to 67% of patients with IBS experience functional dyspepsia. Among patients who report IBS symptom resolution, 45% subsequently develop other functional GI disorders [25,37,38]. Even if all GI symptoms resolve, many patients with IBS develop symptoms of other functional disorders. Patients with lower quality of life and higher levels of anxiety are most susceptible to comorbid functional disorders. Converging evidence suggests IBS is one expression of an underlying predisposition for functional disease [4,25,39,40,41].

Patients may also experience migration between predominant symptoms and IBS subtypes over time. Most commonly, IBS-C or IBS-D switches to IBS-M; switching between IBS-C and IBS-D is less common. A possible confounding factor in natural history studies of IBS is the effect of treatment, which can result in difficulty discerning symptom variation due to medical intervention versus true natural history [5,42].

With the passage of time, overlapping symptoms and adjustments in the prevailing diagnostic subtype within a given patient are very common. In one study of 432 primary care patients with IBS-C or functional constipation followed over 12 months, roughly 33% had a change in dominant diagnosis from functional constipation to IBS-C or from IBS-C to functional constipation [43,44]. In female patients with IBS initially classified as constipation, diarrhea, or mixed subtypes, roughly 25% had the same subtype at 12-month follow-up, while 75% made at least one transition into another subtype [45].

Evidence of lower IBS prevalence in older age groups suggests symptom resolution over time, which is contradicted by natural history studies showing symptom chronicity. One explanation is that the diagnosis changes, rather than resolves. As discussed, patients with IBS are more likely to experience other functional syndromes. In addition, "symptom shifting" occurs in some patients, characterized by resolution of functional bowel symptoms followed by development of extra-intestinal functional symptoms [4].

Mortality

Although patients with IBS have a significantly reduced quality of life, greater risk of depression and suicidal ideation, and higher frequency of invasive procedures and surgery, community-based studies have not associated IBS with increased mortality risk [4,46].

DISEASE BURDEN

Like other chronic functional disorders, the overall burden of IBS is high and medical treatments for IBS have been suboptimal. Patients with IBS exhibit high rates of psychopathology, low quality of life, and increased suicidal ideation. These patients also miss more days of work, are less productive at work, and use many healthcare resources [47].

IBS significantly diminishes emotional, physical, and occupational functioning and health-related quality of life. IBS accounts for 3.1 million ambulatory care visits and 5.9 million prescriptions annually in the United States, with total direct and indirect annual expenditures exceeding $20 billion [5,48].

IBS is usually diagnosed and managed in outpatient settings. In 2010, IBS accounted for 0.03% of U.S. hospital discharges, with a mean inpatient stay of 3.7 days costing a mean $21,153 [49].

The impact of IBS subtypes on quality of life was studied in 542 patients with IBS in the United States using the IBS Quality of Life (IBS-QOL) questionnaire. The overall and subscale scores attained from the IBS-QOL range from 0–100, with higher scores suggesting better quality of life. Overall IBS-QOL scores of patients with IBS-D (61.6) and IBS-M (63.0) were lower than those of patients with IBS-C (74.5). Patients with IBS-D scored lower than those with IBS-C on food avoidance (45.0 vs. 61.1) and interference with activity (59.6 vs. 82.3). Compared with patients with IBS-C, patients with IBS-M had greater interference in activities (61.6 vs. 82.3) and impact on relationships (73.3 vs. 84.7). Patients with IBS-M scored lower than IBS-C on food avoidance (47.2 vs. 61.1) and concern over negative social reaction (66.1 vs. 80.0) [50].

Patients with IBS-D or IBS-M are more likely to avoid culprit foods perceived to be symptom triggers than patients with IBS-C. IBS had a significantly greater negative impact on relationships in patients with IBS-M than in those with IBS-C, and more than 50% reported workplace embarrassment. Interpersonal problems were more pronounced in patients with IBS-D. This study indicates that clinicians should pay special attention to food avoidance and negative effects on relationships, daily activities, and social reaction in patients with IBS-D and IBS-M, as these domains influence significantly the quality of life [50].

Bloating is perhaps the most bothersome IBS symptom to patients. Bloating often leads to seeking medical care and adversely affects energy level, food intake, and physical functioning [51]. A large population-based study in Japan found abdominal bloating to be the most bothersome symptom in patients with IBS-C. The levels of anxiety and distress in daily life were associated with severity of abdominal pain, discomfort, and bloating, and abdominal bloating was more likely to occur after a meal, at work/school, and during times of stress [52].

A study assessed past-week impairments in work productivity and daily activities in American patients with IBS-C. Among those working, the average rate of past-week absenteeism was 10.6%. In addition, 37.4% reported presenteeism, 39.3% overall work productivity loss, and 45.7% daily activity impairment due to general health problems over the past week. The economic cost from lost productivity due to IBS-C is estimated at about $155 per employed patient/week, suggesting IBS-C-related impairment is a significant burden for patients and employers [53].

Perceived stigma is an important consideration in the patient with IBS. Patients with symptoms of IBS or other functional disorders present for medical care with painful, embarrassing, and life-limiting symptoms that lack objective confirmation on routine diagnostic exam and laboratory workup. Moreover, the common inclusion of IBS and fibromyalgia in psychiatric diagnostic classification systems as somatoform disorders (e.g., psychologic distress manifesting as physical symptoms) adds to the consternation. Lacking a consistent and valid illness concept or suitable term for the disorder, some caregivers may be tempted to label the patient with dismissive terms like "difficult patient," "frequent attender," or "heart-sink patient." This type of labeling may result in patient reluctance to seek medical care [54].

3. ETIOLOGY, PATHOGENESIS, AND PATHOPHYSIOLOGY

GI syndromes/symptoms may be classified into three general diagnostic categories: organic, motility, or functional disorders [2,15]. Organic (or structural) disorders are characterized by macro- or micro-level pathology of organs or structures and include esophagitis and inflammatory bowel disease. Motility disorders are characterized by pathology of organ (motility) function. Examples of motility disorders are gastroparesis and intestinal pseudo-obstruction.

Functional GI disorders are idiopathic disorders of gut-brain interaction and, unlike organic and motility disorders, diagnosis involves identification of symptom clusters. These disorders may be further categorized as functional bowel, functional esophageal, IBS, noncardiac chest pain, functional gastroduodenal, and other disorders.

IBS is a functional bowel disorder, as are functional constipation, functional diarrhea, and functional abdominal bloating/distension. More precisely termed "disorders of gut-brain interaction," functional GI disorders develop from complex, bidirectional interactions of biopsychosocial factors. These environmental, psychologic, and biologic factors interact to drive the genesis, clinical expression, and chronicity of functional GI disorders (Table 1) [2,15].

Table 1: FACTORS AFFECTING THE DEVELOPMENT, EXPRESSION, AND CHRONICITY OF FUNCTIONAL GI DISORDERS

Genetic and environmental factors

Genetic polymorphism

Early life experiences

Parental beliefs and behaviors

Social learning, support, stress

Trauma

Infection

Psychologic factors

Psychopathology (anxiety, depression)

Cognitive-affective processes:

- Health anxiety and somatization

- GI-specific anxiety

- Attentional bias/symptom hypervigilance

- Catastrophizing

CNS structure and function

Structural brain abnormalities

Functional network connectivity

Emotional and cognitive modulation of visceral afferent signals

Fear conditioning

Gut physiology

Gut permeability

Motility

Sensation

Altered bacterial flora

Inflammation and immune dysfunction

Source: [2,15]

Psychosocial factors such as early life events, trauma, social learning, and/or psychiatric and psychologic disorders influence the brain and gut, which interact bidirectionally via the autonomic nervous system and hypothalamic-pituitary-adrenal (HPA) axis through brain-gut mediation. The integrated effects of altered physiology and psychosocial status shape the illness experience and clinical outcome, which in turn influences the severity of the disorder [55].

IBS pathophysiology is complex and multifactorial. Genetic, environmental, and psychosocial factors increase the risk of developing IBS. Factors that trigger IBS onset or exacerbation include gastroenteritis, food intolerances, chronic stress, and surgery. Pathophysiologic mechanisms vary but commonly include altered colonic motility, visceral hyperalgesia, increased intestinal permeability, immune activation, altered microbiota, and disturbances in central nervous system (CNS) function [3].

CONTRIBUTING FACTORS

Familial and Environmental Factors

Childhood Social Learning

Childhood functional GI disorders aggregate in families. Research into genetic factors is ongoing, but what children learn from parents is considered a greater contributor to the risk for developing functional GI disorders. One important contributor is the learning principle of positive reinforcement or reward. Children whose mothers reinforce illness behavior experience more severe stomachaches and more school absences than other children. In children with functional abdominal pain, cognitive-behavioral therapy (CBT) that targets coping strategies and parent and child beliefs about, and responses to, children's pain complaints leads to greater decreases in pain and GI symptoms than an educational intervention. This effect is mediated by changes in parents' cognitions about their child's pain [39,55,56].

A strong association is found between parental psychologic status, especially anxiety, depression, and somatization, and children's abdominal symptoms [57]. This association may occur through modeling, whereby children observe and learn to display the behaviors they observe—in this context, heightened attention to or catastrophizing about somatic sensations. This effect of parental traits on children's symptoms can also occur through reinforcement. Parents with certain traits or beliefs (e.g., excessive worry about pain) might pay more attention to and reward somatic complaints. Parental catastrophizing about their own pain reinforces these types of responses to abdominal pain in their children, which encourages illness behavior and predicts child functional disability [55,58,59].

Childhood and Adult Stressors

Early life trauma is associated with increased risk for IBS and other functional GI disorders, major psychiatric disorders, ischemic heart disease, diabetes, asthma, and other medical disorders in adulthood [60]. Patients with IBS report a high prevalence of adverse life events in general, and childhood physical punishment, emotional abuse, and sexual abuse in particular. This psychosocial history is related to greater functional GI disorder severity and worse clinical outcomes, such as psychologic distress and impaired daily functioning. These effects increase health care seeking and explain the higher prevalence of abuse histories in patients with IBS seen in specialty clinics than in primary care; those with mild IBS symptoms and psychosocial histories may not seek medical care. High frequencies of childhood abuse (approaching 50%) are also found in patients with chronic functional somatic syndromes such as chronic pelvic pain, headaches, and fibromyalgia [61,62,63].

Functional GI disorder onset frequently coincides with experiencing a highly threatening event, such as the breakup of an intimate relationship. Stressful life events are associated with symptom exacerbation and frequent health care-seeking in adults with IBS. Chronic life stress is the greatest predictor of IBS symptom severity one to two years after diagnosis and negatively affects functional GI disorder treatment outcomes. Presence of a single stressor within 6 months of initiating IBS treatment predicts poor outcomes and higher symptom intensity at 16-month follow-up [55,64].

Social Support

Quality of social support is related to many aspects of IBS. Patients have reported that finding social support helps them overcome IBS. Perceived social support adequacy is linked to IBS symptom severity, possibly through reducing stress levels. Negative social relationships with frequent conflict and adverse interactions consistently show a greater impact on poor IBS outcomes than the mere lack of social support. A supportive patient-practitioner relationship improves symptoms and quality of life in patients with IBS, showing the clinically valuable role of social support [55,65,66].

Psychologic Factors and Psychiatric Disorders

Psychologic distress is an important risk factor for developing functional GI disorders. The presence of psychologic comorbidity may perpetuate or exacerbate symptoms and negatively affects the clinician-patient relationship and treatment outcomes. Comorbid anxiety or depression strongly predicts postinfectious IBS and functional dyspepsia and is also associated with severity of symptoms and quality of life impairment. The absence of co-occurring psychiatric comorbidity does not exclude contribution to functional GI disorder from dysfunctional cognitive and affective processes.

Mood Disorders

The overlap between major depressive disorder and functional GI disorder is about 30% in primary care and slightly higher in specialist care. Depression can influence the number of functional GI symptoms and diagnoses. Suicidal ideation is present in 15% to 38% of patients with IBS and is linked to hopelessness surrounding symptom severity, interference with life, and an unsatisfactory response to treatment. Comorbid major depressive disorder is linked to poor outcomes, including high health care utilization and cost, functional impairment, poor quality of life, and poor treatment engagement and outcomes [67,68,69].

Anxiety Disorders

With a prevalence of 30% to 50%, anxiety disorders are the most common psychiatric comorbidity in patients with functional GI disorders. Anxiety can initiate or perpetuate functional GI disorder symptoms by amplifying autonomic arousal (in response to stress) or interfering with GI sensitivity and motor function. Common pathways might exist between vulnerability to anxiety disorders and functional GI disorders, especially through anxiety sensitivity, bodily vigilance, and discomfort intolerance [67,70].

Somatization, Somatic Symptom Disorder, and Functional Somatic Syndromes

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), somatic symptom disorder replaced the abandoned term "somatization," which described patients who responded to psychosocial stress by experiencing, communicating, and seeking medical help for physical symptoms unconfirmed by pathologic findings. The number of symptom complaints was emphasized [55,71].

In the DSM-5, somatic symptoms may or may not be medically unexplained but are distressing, disabling, and associated with excessive and disproportionate thoughts, feelings, or behaviors persisting longer than six months. This approach shifts the experience of medically unexplained symptoms from subconscious manifestations of psychologic distress to the abnormal cognitive-affective processes surrounding the symptoms [55,72,73].

Somatization is associated with GI processes such as gastric sensitivity and emptying, symptom severity, and impaired quality of life. It is linked to higher health care use and predicts poor treatment response and discontinuing medication from side effects. Somatization remains extensively used in the medical literature to describe syndromes, often with prominent pain, that lack apparent physiologic cause following standard diagnostic workups. Assessing somatization through severity of the multiple somatic symptoms remains clinically useful [73,74,75].

Somatization was considered the basis for frequent extra-intestinal symptoms in patients with IBS and the high co-occurrence between functional GI disorder and other functional somatic syndromes. The overlap is extensive; 67% of patients with functional GI disorders also have a positive history for conditions such as interstitial cystitis, chronic pelvic pain, headaches, fibromyalgia, or other functional somatic syndromes, independent of psychiatric comorbidity [55,76,77].

Cognitive-Affective Processes

The psychologic constructs of health anxiety, GI symptom-specific anxiety, attentional bias/symptom hypervigilance, and catastrophizing are linked to functional GI disorders independent of psychiatric comorbidity (Table 2). These are important treatment targets for CBT [55].

Table 2: COGNITIVE-AFFECTIVE PROCESSES INFLUENCING THE SYMPTOM EXPERIENCE IN FUNCTIONAL GI DISORDERS (FGIDs)

Term

Definition

Association with FGID

Outcomes

Management

Illness anxiety

Global tendency to worry about current and future bodily symptoms, formerly referred to as hypochondriasis

Low insight

Extensive research into what is wrong

Not easily reassured

Lack of acceptance

Rick factor for the development of FGID

Chronicity

Social dysfunction

Occupational difficulties

High health costs

Negative physician-patient relationship

Poor treatment response

Responsive to CBT

Symptom-specific anxiety

Worry/hypervigilance around the likelihood/presence of specific symptoms and the contexts in which they occur

Belief that normal gut sensations are harmful or will lead to negative consequences

Promotes GI symptoms

Drives health care use

Negatively impacts treatment response

Aerophagia improved with distraction

May be differentially responsive to interoceptive exposure-based therapy

Hypervigilance/

attentional bias

Altered attention toward, and increased engagement with, symptoms and reminder of symptoms

Patients with IBS: Higher recall of pain words and GI words compared with healthy controls

Patients with NCCP: Hypervigilance toward cardiopulmonary sensations

Dismiss signs of improvement

Ignore information suggesting FGID is not serious

Responsive to CBT

Catastrophizing

Individual magnifies the seriousness of symptoms and consequences while simultaneously viewing him/herself as helpless

Symptom amplification

Increased pain

Inhibits pain inhibition

Negatively affects interpersonal relationships

Leads to increased worry, suffering, disability

High symptom reporting

Reduced quality of life

Can impact patient self-report

Burdens provider

Improves with CBT

Mediates outcome

CBT = cognitive-behavioral therapy, NCCP = noncardiac chest pain.

Source: Reprinted from Van Oudenhove L, Levy RL, Crowell MD, et al. Biopsychosocial aspects of functional GI disorders: how central and environmental processes contribute to the development and expression of functional GI disorders. Gastroenterology. 2016;150(6):1355-1367, with permission from Elsevier.

GI symptom-specific anxiety is an important perpetuating factor that describes threatening interpretation and out-of-proportion behavioral response to GI sensations. This anxiety is characterized by worry and hypervigilance around GI sensations common to normal bodily functions (e.g., hunger, satiety, gas) as well as to symptoms of an existing GI condition (e.g., abdominal pain, diarrhea, urgency). Worry and hypervigilance generalize into fear about when sensations/symptoms will occur and about the social contexts where this could happen. Avoidance or behaviors disproportional to symptoms follows [55,78].

As an example, a person with IBS who has not eaten all day becomes aware her stomach is rumbling. This is interpreted to mean that the need to defecate may be imminent, triggering anxiety about whether and how this can be managed, as she is in public with friends. The anxiety increases when no restroom is visible, and the person leaves her friends for fear they would not understand [55].

Other Factors

Genetic Predisposition

Variations in the gene that encodes serotonin reuptake transport system have been found in patients with IBS. It is believed that polymorphism of the 5-HT2A receptor gene may be associated with the development of IBS [79].

Acute Infectious Gastroenteritis

The prevalence of IBS is increased six- to seven-fold in persons who have experienced a prior infectious gastroenteritis or enterocolitis, and postinfectious IBS accounts for 5% to 25% of all cases of IBS [80]. IBS develops in 3% to 30% of patients following acute gastroenteritis, illustrating an acute pathogen and host interaction that predisposes to development of chronic IBS [5,81]. Factors with the greatest risk for postinfectious IBS are elongating toxin and longer duration of the initial illness [82,83]. Other predisposing factors include:

- Female sex

- Younger age

- Toxicity/severity of infecting strain

- Cigarette smoking

- Mucosal inflammation

- Immune function

- Microbiome

- Concurrent depression or anxiety

- GI infection severity

- Antibiotic treatment

Psychopathology increases the risk of developing postinfectious IBS by enhancing susceptibility to infectious gastroenteritis [5,84]. Mucosal inflammation and abnormal gut-host microbial interactions also promote postinfectious IBS. Mucosal immune activation and immune cell proliferation may amplify peripheral sensory signaling to result in visceral hypersensitivity, a primary IBS pain mechanism [5,84].

Patients with postinfectious IBS are important to identify because roughly 50% will experience spontaneous remission within six to eight years of the initial infection. This disease course differs from the chronic relapsing nature of typical IBS [5,85].

Acute gastroenteritis is now known to cause marked disruptions in the gut microbiota by pathogen overgrowth and substantial reduction in the diversity of normal flora. In the past, gut equilibrium was assumed to normalize after the infection cleared. However, research indicates individuals recovering from Campylobacter jejuni enteritis (a common cause of food poisoning) are as likely to show continued alteration in microflora (with potential progression to IBS-D) as they are full recovery of gut equilibrium [86,87].

Alterations in the Intestinal Microbiome

Gut dysbiosis is defined as an imbalanced or maladapted, but stable, gut ecosystem that has reduced capacity for protection and is associated with disease [88]. Gut dysbiosis has potentially significant consequences in psychiatric disorders, cognitive disorders, and chronic visceral pain (due to brain-gut mediation). The intestinal flora of patients with IBS differs from healthy persons, and intestinal flora profiles also differ among IBS subtypes [89]. Deficiency in Bifidobacterium has been associated with greater abdominal pain and bloating in patients with IBS. As such, treatment with probiotics has shown some promise in alleviating symptoms in IBS. In one study, probiotic administration was found to alter central processing of emotional stimuli and resting brain connectivity in sensory and affective brain circuits. The hypothesis of a microbiome gut-brain axis is emerging, and there is a possibility that gut microbiota will represent a therapeutic target in the treatment of IBS [55,90,91].

Bile Acids and Bowel Dysfunction

Secretory diarrhea results from colonic perfusion of bile acids due to inadequate ileal reabsorption (less than 95%). Excess bile acids entering the colon increase gut permeability, activate adenylate cyclase, stimulate colonic secretion, and increase stool water and colonic motility. Decreased circulating fibroblast growth factor 19 (FGF19) leads to excessive bile acid production and can be primary or secondary to ileal resection or ileitis. Around 10% of patients with IBS-D have severe bile acids malabsorption—defined as less than 5% retention at seven days. In the United Kingdom, bile acid diarrhea accounts for nearly 25% of patients with IBS referred to specialist care for diarrhea [87,92].

Bile salt overproduction can be identified by reduced seven-day retention of the synthetic radiolabeled bile acid selenium-75 homocholic acid taurine (SeHCAT), but access to SeHCAT is limited. Another approach measures fasting FGF19 using an enzyme-linked immunosorbent assay (ELISA). FGF19 <145 pg/mL predicts reduced SeHCAT retention [87].

The cause of low FGF19 levels is not fully known, but bile acid malabsorption can begin acutely after an ileitis episode, common with Salmonella spp. or C. jejuni gastroenteritis. Sudden onset and high-volume nocturnal diarrhea are characteristic features [87].

The prevalence and role of ileal malabsorption of bile acids in diarrhea-like symptoms has historically been underestimated in IBS-D. Identification can lead to specific treatment with bile acid sequestrants [15,93].

Diet

Many patients identify food as an IBS symptom trigger. The contribution of true food allergies to IBS is small, but food intolerances are common in patients with IBS. Gluten (present in wheat products) is increasingly recognized as an important symptom trigger in patients with IBS and inducer of IBS-like symptoms in persons without IBS diagnosis. Non-celiac gluten sensitivity is an emerging syndrome provoked by gluten ingestion in patients in whom celiac disease and wheat allergy are ruled out. Other triggers of non-celiac gluten sensitivity pathogenesis include wheat proteins (i.e., amylase and trypsin inhibitors) and FODMAPs (fermentable oligo-, di-, monosaccharides, and polyols) [94,95]. Emerging evidence supports gluten-free and low-FODMAPs diets for patients with IBS. FODMAPs are poorly absorbed carbohydrates that can induce osmotic effects, result in increased fermentation in the small bowel or colon, and trigger symptom exacerbation in patients with IBS with abnormal gut function or sensitivity [5,94].

Dietary constituents also influence the impact of intraluminal factors on gut function. Among these are microflora alterations in short-chain fatty acids; the effects of enteroendocrine cell products (i.e., granins) on nervous, endocrine, and immune cells; and the ratio of secondary to primary bile acids that impact gut transit rates [15,96].

A six-week placebo-controlled, double-blinded trial in patients with IBS with gluten sensitivity histories found poorly controlled IBS symptoms in 68% randomized to diets with gluten versus 40% receiving a gluten-free diet. In patients receiving a gluten-free diet, double-blinded gluten re-challenge worsened pain, bloating, stool consistency, and fatigue [97]. A study of patients with IBS-D reported that gluten administration led to altered gut permeability and increased stool frequency and immune activation [98].

While these data suggest that symptom exacerbation after ingesting wheat is primarily caused by gluten, wheat also contains fructans and other proteins that may trigger symptoms in patients with IBS [5]. A clinical trial of 920 patients with IBS found that 33% of subjects experienced worsened symptoms of increased abdominal pain and distension after receiving wheat (not limited to gluten), but not after placebo [99].

BRAIN-GUT AXIS AND PROCESSING

Bidirectional interactions involving multiple components of the (peripheral) GI system (microbiome, altered mucosal inflammation, visceral hypersensitivity) and the CNS (emotional arousal, sensorimotor function, salience and executive function, central autonomic function) contribute to the development of IBS. Neurophysiologic mechanisms in the brain-gut axis link psychologic processes, psychiatric comorbidity, and IBS symptoms [2,100].

In the brain-gut axis, homeostatic information about visceral physiologic status is continuously signaled to the brain through afferent neural and humoral "gut-brain" pathways. Most gut-brain signals are not consciously perceived under normal conditions. Visceral pain results from the perception of strong gut-brain signaling, triggered by noxious stimuli to warn of potential threat to homeostasis that requires a response [55,100].

Visceral afferent signals are relayed to the brain and then processed, modulated, and integrated through the afferent network, emotional arousal, and cortical modulatory neurocircuits [55]. Emotional arousal and cortical modulation circuits project "top-down" to brainstem areas, which send descending projection neurons to dorsal horns of the spinal cord, where pain transmission is modulated. This circuitry is termed the descending pain modulation system (DPMS) [55].

ALTERED PAIN PERCEPTION IN PATIENTS WITH IBS

The hallmark symptom of IBS in the Rome IV criteria is chronic visceral pain and/or discomfort, and patient perception of visceral pain in IBS is disproportionate to the intensity of visceral afferent inputs, which is the result of complex psychobiologic processes [55].

Visceral hypersensitivity (also referred to as sensitization) describes lowered thresholds for visceral pain and occurs in the majority of patients with IBS. In these patients, lower pain thresholds are reflected by an exaggerated pain response to normally modest GI discomfort and/or painful response to stimuli that are not normally pain- or discomfort-inducing (e.g., normal bowel function). Visceral sensitivity is amplified in patients with IBS [15].

Psychologic processes and psychosocial factors substantially influence visceral hypersensitivity. In patients with IBS, hypervigilance (defined as a heightened psychologic tendency to focus on and report pain) is considered a greater contributor to lowered pain thresholds than actual increased neurosensory sensitivity. Anxiety and depression levels are directly related to pain severity in patients with IBS [101,102,103,104].

As discussed, extra-intestinal chronic pain conditions are highly prevalent in IBS, and widespread hypersensitivity and extra-intestinal pain syndromes suggest CNS involvement and central sensitization. Descending neural modulatory circuits from the brain can inhibit or facilitate ascending nociceptive transmission, influenced by cognitive processes and mood. Changes in DPMS function are thought to influence pain perception [105]. Dysregulated cortical modulation of descending pain regulatory pathways can amplify sensitivity to noxious and innocuous stimuli [106].

Neural pathways play a major role in modulating visceral pain experience and other IBS symptoms. Spinothalamic tracts localize and differentiate visceral stimuli, while spinoreticular pathways influence the reflexive, affective, and motivational aspects of sensation and pain [81]. Pain modulatory system dysfunction promotes visceral hypersensitivity, and studies of IBS have shown abnormalities in pain signal processing and modulation that include functional and structural abnormalities in sensory, emotional arousal, and prefrontal cortical modulatory regions [55,106].

Altered Brain Network Function

Colorectal distension in patients with IBS activates brain stress response areas but deactivates brain areas that modulate stress response [80,107,108]. This pattern reflects up-regulated connectivity in emotional arousal circuitry; the increased sympathetic arousal, anxiety, and vigilance often observed in patients with IBS; and the association between IBS symptoms and functional alteration in multiple brain networks [55].

When anticipating experimentally induced visceral pain, anticipatory response in the locus coeruleus predicts subjective perception and brain response to the actual painful stimulus. Sensory filtering is degraded by anxiety-related dysfunction of the descending pain modulation system [107,109].

Altered Brain Structure

Alterations in brain structure have been demonstrated in patients with IBS. The role of structural brain changes in IBS and other functional pain disorders is not clear, because these changes may represent pre-existing vulnerability factors or consequences of long-term exposure to the pain [106].

Female patients with IBS have shown increased cortical thickness in the somatosensory cortex and decreased cortical thickness in pain processing regions, including the insula and anterior cingulate cortex. IBS symptom severity is negatively correlated with cingulate thickness, suggesting a role for loss of neural density in symptom generation [106,110,111].

Patients with IBS have also shown decreased gray matter volumes in widespread regions, with early life trauma contributing to these decreases [106]. Decreased gray matter density in prefrontal and posterior parietal cortex areas is consistent with the close relationship between IBS and mood disorders. Pain catastrophizing negatively correlates with the degree of cortical thickness in the prefrontal cortex [112,113,114].

Abnormal structure of brain white matter tracts have been found in multiple areas in patients with IBS. These white matter changes are associated with symptom severity, trait anxiety, and catastrophizing [115,116,117].

4. CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

CLINICAL PRESENTATION

Abdominal Pain

Descriptions of pain associated with IBS often change, but the pain is typically described as cramping discomfort that is diffuse or variable in location, without radiation. The most common site of pain is the lower abdomen, specifically the left lower quadrant. Many patients experience periodic exacerbations that vary in intensity from mild to severe; others describe acute episodes of sharp pain, often superimposed on a more constant dull ache. Meals may precipitate or aggravate the pain. Some patients report that pain is worsened by defecation, others that the pain is relieved by defecation. On occasion, the combination of enhanced colonic peristalsis and trapped gas in the splenic flexure may produce severe left upper quadrant abdominal pain or referred pain to the chest that mimics that of cardiac ischemia. Termed splenic flexure syndrome, balloon inflation in the splenic flexure will provoke this pain and should be considered in selected patients in order to differentiate it from more serious causes of chest or left upper quadrant abdominal pain [118].

Altered Bowel Habits

Altered bowel habits may be described as diarrhea, constipation, or alternating diarrhea and constipation. Some patients have periods of relatively normal bowel habits alternating with episodic periods of either diarrhea or constipation. Patients with predominant constipation may describe painful or infrequent defecation, non-response to laxatives and often associated with the passage of hard, pellet-like or narrow stools. Diarrhea is usually described as small volumes of loose stool preceded by urgency or frequent defecation. Postprandial urgency is common. [118]. Stools may also be white or clear (mucosa).

Abdominal Distention

Patients with IBS frequently report increased amounts of bloating and intestinal gas, but confirmation by quantitative measurements is elusive. People with IBS can experience expanding, and measurable, abdominal circumference throughout the day. Intolerance of otherwise normal amounts of abdominal distention is common [118].

Other Common Symptoms and Complaints

Dyspepsia, heartburn, nausea, vomiting, sexual dysfunction (including dyspareunia and poor libido), and urinary frequency and urgency frequently occur in patients presenting with IBS complaints. Fibromyalgia commonly co-occurs. Careful questioning can reveal stressor-related symptoms; if disclosed, ask further about avoidance of stressors [118].

Perimenstrual Symptom Exacerbation

Many women of reproductive age experience cyclical changes in GI symptoms (including alteration in bowel habits) during their menstrual cycle. Female patients with IBS often experience worsened GI symptoms of abdominal pain, bloating, or diarrhea during menses, possibly due to elevated prostaglandin levels during menses that enhance perception of viscera-somatic stimuli and increases nausea, abdominal distension, and pain [119].

Fatigue

Despite receiving little attention in the medical literature, fatigue is a frequent symptom in patients with IBS and is associated with poor quality of life. A study of 160 patients with IBS found a multidimensional and negative impact from fatigue on daily life [120]. Fatigue may interfere with patients' ability to perform physical activities, work, domestic work, and interact socially. Poor stamina is the most prominent feature, and strategies to limit the bodily consequences of tiredness are common. Severe fatigue is associated with more severe IBS symptoms, anxiety, and depression. Fatigue is a distressing symptom in a sizeable proportion of patients with IBS and should be assessed and, if confirmed, targeted for intervention [120].

CONCEPTUAL AND DIAGNOSTIC ADVANCES

Over time, the definitions of IBS and functional GI disorders have been shaped by societal perspectives of illness and disease, available scientific evidence, and clinician training and bias. Even today, some consider functional GI disorders to be "less legitimate" than pathologically based disorders, and patients with functional GI disorders may be stigmatized for having functional symptoms. This is a carry-over from the influence of dualistic principles that dichotomized organic disorders from functional disorders, which were often considered psychiatric or undefined. However, the definition has changed from the absence of organic disease, to a stress-related or psychiatric disorder, a motility disorder, a disorder of GI functioning, and finally to a disorder of gut-brain interaction [2].

The Rome Foundation was founded in the 1980s to promote global recognition of functional GI disorders, advance scientific understanding of functional GI disorder pathophysiology, optimize clinical management for patients with functional GI disorders, and develop educational resources to achieve these goals. The Foundation is comprised of scientists and clinicians from around the world with expertise in diverse areas relevant to functional GI disorders [121].

The Rome III criteria incorporated scientific data
on IBS diagnosis and treatment. Rome III defined IBS as recurrent abdominal pain or discomfort three or more days per month in the preceding three months, associated with two or more of the following: symptom improvement with defecation, symptom onset coupled
with altered stool frequency, or symptom onset
coupled with altered stool form [122,123].

Over the past decade, the need to revise Rome III became increasingly apparent. Knowledge of IBS pathophysiology continued evolving, and many clinicians found Rome III criteria unhelpful and lacking in real-world clinical applicability. For example, Rome III did not recommend basic laboratory testing and ignored the fact that, for many patients, abdominal pain worsened rather than improved with defecation. Some Rome III criteria were seen as vague or incorrect [122].

In 2016, the Rome IV guidelines were published to address these criticisms and improve guidance to healthcare providers based on latest scientific and clinical evidence. Important changes in Rome IV IBS diagnostic criteria include [2,3]:

- The term "abdominal discomfort" was removed because it was determined to be imprecise and difficult to translate.

- The required frequency and presence of abdominal pain was increased to reflect research that identified pain as a cardinal symptom of IBS.

- Rome IV recognizes that IBS is often associated with irregular bowel habits of constipation, diarrhea, a mix or alternation of each, and that common symptoms include bloating and distension.

- As IBS is a chronic condition, Rome IV requires symptom persistence for six or more months for diagnosis.

- Rome IV now acknowledges the role of diagnostic tests to exclude other common conditions with similar symptoms to IBS, such as celiac disease, lactose intolerance, and inflammatory bowel disease.

- Replacing the term "functional" was found impractical due to its pervasive use in healthcare nosology, so this term was limited to the extent possible.

By clarifying language, updating the definition, and including the option of laboratory testing, the new criteria are intended to make IBS easier to diagnose. The emphasis on abdominal pain validates clinician reports of this symptom as the essential element of IBS. Rome IV should also help differentiate IBS from intermittent abdominal spasms or cramps and chronic constipation or diarrhea [3,122]. The revised Rome IV IBS criteria are part of a larger project by the Rome Foundation to overhaul and update scientific data, educational information, and clinical guidance to optimize the diagnosis and treatment of functional GI disorders.

Functional bowel disorders, a functional GI disorder subgroup, describe a spectrum of chronic GI disorders characterized by predominant signs or symptoms of abdominal pain, bloating, distention, and/or bowel habit abnormalities (i.e., constipation, diarrhea, or mixed constipation and diarrhea) [3]. These disorders are distinguished from other GI disorders based on chronicity (more than six months of symptoms at the time of presentation), current activity (symptoms present within the last three months), frequency (symptoms present, on average, one or more days per week), and absence of obvious anatomic or physiologic abnormalities identified by routine diagnostic workup. Functional bowel disorders include IBS, functional constipation, functional diarrhea, functional abdominal bloating/distention, unspecified functional bowel disorder, and opioid-induced constipation, a new entry that differs from other functional bowel disorders by etiology but resembles functional constipation in clinical presentation [3].

Importantly, these disorders significantly overlap and should be viewed as a continuum instead of discrete diagnostic entities. Given the extent of overlap, differentiation of functional bowel disorders may not always be possible [3].

Importance of a Formal IBS Diagnosis

There are data to suggest that among persons with IBS-D symptoms, a formal diagnosis may have important implications for quality of care [9]. Patients with a formal diagnosis of IBS are more likely to have a sustained clinician-patient relationship that facilitates dialog, promotes patient education, and provides access to evidence-based therapies. As a group, these patients are better informed regarding IBS pathophysiology and more attuned to the role of aggravating factors, such as diet, stress, and the state of the intestinal microbiota.

DIAGNOSTIC CRITERIA AND MEASUREMENT SCALES

Evidence Based Practice Recommendation

The National Collaborating Centre for Nursing and Supportive Care recommends that healthcare professionals should consider assessment for IBS if the person reports having had any of the following symptoms for at least six months: abdominal pain or discomfort, bloating, and/or change in bowel habit.

https://www.nice.org.uk/guidance/cg61

Last Accessed: November 14, 2019

Level of Evidence: Consensus Statement/Expert Opinion

As noted, IBS is a functional bowel disorder with recurrent abdominal pain associated with defecation or a change in bowel habits. Disordered bowel habits and symptoms of abdominal bloating/distention are typically present. The formal diagnosis requires evidence of chronicity, defined as symptom onset and duration of at least six months and active symptoms present during the previous three months [3].

For all IBS subtypes, the key requirement is that symptoms must not have an organic, metabolic, or drug-induced origin. A symptom-focused patient history and careful physical examination are mandatory to rule out intestinal or extra-intestinal diseases, symptom-inducing medications, and alarm symptoms that prompt further diagnostic exploration [44].

The Rome IV IBS diagnostic criteria are [3]:

- Recurrent abdominal pain occurring, on average, one or more days per week

- The abdominal pain is associated with two or more of the following criteria:

- Related to defecation

- Associated with a change in frequency of stool

- Associated with a change in form (appearance) of stool

Diagnosis is made with criteria fulfilled the last three months and symptom duration at least six months.

Bristol Stool Form Scale

The Bristol Stool Form Scale (BSFS) illustrates and describes the appearance of seven different stool types that correspond to intestinal transit time ranging from severe constipation (Types 1 and 2) to diarrhea (Type 7). Patients can use the BSFS to record frequency and subtype of their stools [124]:

- Type 1: Separate hard lumps, like nuts (hard to pass)

- Type 2: Sausage-shaped but lumpy

- Type 3: Like a sausage with cracks in the surface

- Type 4: Like a sausage or snake, smooth and soft

- Type 5: Soft blobs with clear-cut edges

- Type 6: Fluffy pieces with ragged edges, a mushy stool

- Type 7: Entirely liquid, no solid pieces

Diagnostic Criteria for IBS Subtypes

IBS is subtyped by predominant bowel habit change, but only after all medications to treat bowel habit abnormalities are discontinued. The BSFS can be used to categorize IBS into subtypes based on stool characteristics (Table 3). Predominant bowel habits are based on stool form on days with at least one abnormal bowel movement[3,44].

Table 3: DIAGNOSTIC CRITERIA FOR IBS SUBTYPES

Subtype

BSFS Criteria

Alternative

IBS with predominant constipation (IBS-C)

>25% of bowel movements with BSFS types 1 or 2 AND <25% of bowel movements with BSFS types 6 or 7

Patient reports that abnormal bowel movements are usually constipation (BSFS type 1 or 2).

IBS with predominant diarrhea (IBS-D)

>25% of bowel movements with BSFS types 6 or 7 AND <25% of bowel movements with BSFS types 1 or 2

Patient reports that abnormal bowel movements are usually diarrhea (BSFS type 6 or 7).

Mixed-type IBS (IBS-M), in which constipation and diarrhea alternate

>25% of bowel movements with BSFS types 1 or 2 AND >25% of bowel movements with BSFS types 6 or 7

Patient reports that abnormal bowel movements are usually both constipation and diarrhea.

IBS unclassified (IBS-U)

—

Patients who meet diagnostic criteria for IBS but whose bowel habits cannot be accurately categorized into one of the other three groups.

BSFS = Bristol Stool Form Scale.

Source: [3,44]

Diagnostic Criteria for Related Functional Bowel Disorders

Functional bowel disorders are diagnosed when criteria are fulfilled for the last three months, with symptom onset more than six months before diagnosis [3].

Functional Constipation

In order for a diagnosis of functional constipation to be made, two or more of the following must be present [3]:

- Straining during >25% of defecations

- Lumpy or hard stools (BSFS 1 or 2) in >25% of defecations

- Sensation of incomplete evacuation in >25% of defecations

- Sensation of anorectal obstruction/blockage in >25% of defecations

- Manual maneuvers to facilitate >25% of defecations (e.g., digital evacuation, support of the pelvic floor)

- Fewer than three spontaneous bowel movements per week

In patients with functional constipation, loose stools are rarely present without laxative use. Although symptoms may be similar, these patients do not meet the full criteria for IBS-C.

Functional Diarrhea

Functional diarrhea is characterized by loose or watery stools (>25% of stools) without predominant abdominal pain or bothersome bloating. These patients do not meet the criteria for IBS-D.

Functional Abdominal Bloating/Distension

Functional abdominal bloating (FAB) or distention (FAD) represent two different sets of signs and symptoms but are combined by Rome IV into the diagnostic entity of FAB/FAD. In patients with FAB/FAD, mild abdominal pain related to bloating and/or minor bowel movement abnormalities may be present. Symptoms of recurrent abdominal fullness, pressure, a sensation of trapped gas, and/or measurable increase in abdominal girth must be present. Abdominal bloating and/or distention predominates over other symptoms, occurring, on average, at least one day per week. These patients do not meet the diagnostic criteria for IBS, functional constipation, functional diarrhea, or postprandial distress syndrome.

CLINICAL EVALUATION AND DIAGNOSTIC WORKUP

The diagnosis of IBS relies on a thorough patient history, physical examination, and limited laboratory testing. While not necessary for diagnosis, a brief psychosocial assessment should be performed in all patients. In most patients who fulfill Rome IV diagnostic criteria and for whom alarm features are absent, the need for diagnostic testing should be minimal; performing a battery of tests in all patients suspected of IBS is not warranted. However, focused diagnostic testing may be required to differentiate IBS from several conditions with mimicking symptoms when ambiguity is present. IBS mimics include inflammatory bowel disease, celiac disease, lactose and fructose intolerance, and microscopic colitis [3].

Clinical History

Abdominal pain is a hallmark of IBS; the absence of abdominal pain precludes the diagnosis of IBS. Pain can be present anywhere throughout the abdomen, although it is more common in the lower abdomen [3].

A history of disordered bowel habits (i.e., constipation, diarrhea, or both) should be identified, along with their temporal association with episodes of abdominal pain. Unpredictable bowel pattern (i.e., three or more different stool form types/week) reinforces the diagnosis of IBS-D. An increasing number of consecutive days without a bowel movement suggests a diagnosis of IBS-C.

Ask patients for specific information regarding bowel habits and stool characteristics, as this informs subtyping of their IBS. A diagnosis of unclassified IBS (IBS-U) is reserved for patients meeting IBS diagnostic criteria whose bowel habits cannot be accurately grouped into one of the three main subtypes; this group is uncommon. Difficulty in accurate subtyping can result from frequent changes in diet or medications or an inability to stop medications that affect GI transit. Subtyping should be based on the patient's reported predominant bowel habit on days with abnormal bowel movements. As noted, the BSFS should be used to record stool consistency [124].

Diagnosing patients with IBS-D or IBS-C is usually straightforward, but IBS-M can be more complex. A detailed history helps determine whether mixed bowel patterns originate from the underlying disease state or are a consequence of medical intervention. All prescription and over-the-counter medications and supplements with known influence on IBS symptoms should be considered. A stool diary helps identify patterns in the erratic bowel habits of many patients with IBS. Patients with IBS-M often report protracted periods when bowel movement is absent or appears with small, hard stools; this is followed by periods of multiple stools of variable consistency interpreted by patients as diarrhea. In most cases, this reflects IBS-C, and radiographic demonstration of fecal loading helps confirm clinical suspicion [5].

Non-Specific Symptoms

Common non-specific symptoms in IBS include abnormal stool frequency, abnormal stool form (BSFS types 1/2 or 6/7), excessive straining during defecation, urgency to defecate, feelings of incomplete evacuation, and mucus with bowel movements. Abdominal bloating is present in most patients with IBS and abdominal distention may be reported, but neither is required for an IBS diagnosis [3].

Patients with IBS frequently report that symptoms are induced or worsened by meals, although these symptoms are not specific to IBS. Many other functional GI (e.g., dyspepsia) and non-GI (e.g., migraine headaches, fibromyalgia, interstitial cystitis, dyspareunia) disorder symptoms are reported in patients with IBS; their presence supports an IBS diagnosis [3].

Physical Examination

A physical examination should be performed for every patient evaluated for IBS. This reassures the patient and helps exclude organic etiology. Physical examination frequently reveals tenderness in the left lower quadrant over a palpable sigmoid colon. A rectal examination is warranted to rule out rectal disease and abnormal function of the anorectal sphincter (e.g., paradoxical pelvic-floor contraction during a defecation attempt), which may contribute to symptoms of constipation [125]. The presence of ascites, hepatosplenomegaly, or abdominal mass warrants further evaluation. An anorectal examination is mandatory to identify anorectal causes of bleeding, evaluate anorectal tone and squeeze pressure, and identify dyssynergic defecation [3].

Differential Diagnosis

Several diseases should be considered in patients with IBS symptoms, including celiac disease, inflammatory bowel disease, giardiasis, and dyssynergic defecation. When detailed history taking, physical examination, and/or routine laboratory testing results make it crucial to rule out a disease that requires diagnostic tests or functional studies not available in primary care, referral to a specialist is indicated.

Celiac Disease

Patients with IBS symptoms have a fourfold increased risk of biopsy-proven celiac disease [5]. However, the prevalence of celiac disease in patients with IBS symptoms varies by region, with European studies, but not American studies, demonstrating a higher prevalence of the disease. Routine celiac disease screening in patients with IBS becomes cost-effective with prevalence ≥1%. Given the potential long-term consequences of a missed celiac disease diagnosis, clinicians caring for patients with IBS should have a low threshold of suspicion, especially in patients with IBS-D [5,126].

Serologic tests for celiac disease should be performed in patients with IBS-D or IBS-M who fail empiric therapy. Upper GI endoscopy with duodenal biopsies should be performed if serologic tests for celiac disease are positive or clinical suspicion is high; duodenal biopsies can also identify tropical sprue, another mimic of IBS.

Microscopic Colitis

A small subgroup of patients with suspected IBS-D have microscopic colitis. Risk factors for microscopic colitis include age older than 50 years, nocturnal stools, weight loss, shorter duration of diarrhea, recent introduction of new medications, and comorbid autoimmune disease. When colonoscopy is performed in patients with suspected IBS-D, random colon biopsies should be obtained to rule out microscopic colitis [5,126].

Inflammatory Bowel Disease

Inflammatory bowel diseases, like Crohn disease, can mimic IBS symptoms during acute inflammatory flares. Nerve and muscle changes can persist following acute inflammation, even in remission. The underlying mechanisms may include altered gut permeability and persistent low-level immune activation, shown by cecal biopsies from patients with inflammatory bowel disease in apparent remission with ongoing IBS symptoms. Other mechanisms may include persisting alterations in enteric nerves and serotonin signaling. This information can help identify patients with inflammatory bowel disease and persistent IBS symptoms who may respond better to dietary restriction and other IBS treatments than to escalated immunosuppression [87,127,128].

Because even low-grade chronic inflammation can alter gut permeability and sensitize visceral afferent neurons, leading to aberrant motility and visceral sensitization, inflammatory bowel disease should be considered in all patients with IBS symptoms. IBS criteria are met by more than 33% of patients with inflammatory bowel disease, but the proportion of patients with inflammatory bowel disease and overlapping IBS symptoms with alarm features is unclear [5].

The pragmatic question is how often inflammatory bowel disease is ultimately identified in patients with typical IBS symptoms who lack alarm features. A prospective U.S. study of more than 900 non-constipated patients with IBS and healthy controls receiving colonoscopy found inflammatory bowel disease in less than 1% of patients with IBS and none in the controls. This argues against routine colonoscopy in patients with typical IBS symptoms who lack concerning features. Noninvasive biomarkers may be more cost-effective than colonoscopy for inflammatory bowel disease screening [5,129].

Fecal calprotectin, a biochemical assay for intestinal inflammation, is a cost-effective choice in inflammatory bowel disease screening, although 33% of patients with inflammatory bowel disease and IBS-like symptoms show negative results. C-reactive protein levels of <0.5 mg/dL or fecal calprotectin levels of <40 mcg/g confer a ≥1% risk of inflammatory bowel disease in patients with typical IBS symptoms [5,130]. However, inflammatory bowel disease was found to develop two to three years after initial IBS diagnosis at rates far exceeding population norms, despite negative colonoscopy findings [31].

If inflammatory markers are mildly elevated but the probability of inflammatory bowel disease is low, testing should be repeated before performing colonoscopy (unless other indications for colonoscopy are present). Inflammatory markers are not useful in patients with constipation-predominant symptoms.

Giardiasis

Giardia is a relatively common enteric parasitic infection that causes subacute-to-chronic watery diarrhea often accompanied by bloating, urgency, and excess flatulence. Infection is acquired from contaminated water sources in geographic regions scattered throughout the United States. Fluctuating symptoms and chronicity are common, leading to psychologic stress and social disruptions not unlike that experienced by patients with IBS. Examination of stool for the parasite has variable sensitivity, but stool tests that rely on detection of Giardia antigen or subunit ribosomal RNA are highly sensitive and specific. This is a curable cause of GI symptoms, as the condition can be easily and effectively treated.

Bile Acids Diarrhea

As noted, perfusion of bile acids into the colon stimulates water and electrolyte secretion and accelerates transit. Evidence of bile acid malabsorption may be present in up to 33% of patients with IBS-D symptoms. Clinicians can empirically assess for bile acid malabsorption by initiating a bile acid sequestrant trial. Several tests can identify such malabsorption but are not widely available in the United States [5,92].

Dyssynergic Defecation

Dyssynergic defecation is an under-recognized, constipation-associated condition characterized by an inability to coordinate abdominal wall, anal sphincter, and pelvic floor muscles for normal defecation. Symptoms are non-specific and include abdominal pain, discomfort, and bloating. Intervention with biofeedback can improve bowel and abdominal symptoms. Thus, patients with medically refractory IBS-C symptoms should be referred to a specialist for evaluation of dyssynergia by digital rectal examination, anorectal manometry, balloon expulsion testing, or anorectal imaging [131,132,133].

Laboratory Studies

There is no specific laboratory test that defines the presence of IBS; laboratory evaluation is used selectively to screen for other disorders in the differential diagnosis, principally in patients with IBS-D. In 2019, the American Gastroenterological Association (AGA) published a guideline to aid clinicians in choosing appropriate laboratory tests to exclude other diagnoses in the patient with functional diarrhea and IBS-D [209]. This guideline is applicable for the typical patient with chronic "watery" diarrhea of at least six weeks' duration, and is not intended to guide the evaluation of patients with a more complicated clinical profile, such as bloody diarrhea, recent foreign travel to regions endemic for enteric pathogens, or family history of inflammatory bowel disease or cancer. The AGA recommendations for laboratory testing in patients presenting with chronic diarrhea (IBS-D) are [209]:

- Either fecal calprotectin or fecal lactoferrin to screen for inflammatory bowel disease (threshold value: 50 mcg/g for calprotectin to optimize sensitivity)

- Giardia antigen test or polymerase chain reaction to screen for giardiasis

- Testing for celiac disease with IgA tissue transglutaminase and a second test to detect celiac disease in patients with IgA deficiency

- Consider testing for bile acid diarrhea (or an empiric trial of a bile acid binder)

The AGA suggests against the use of erythrocyte sedimentation rate or C-reactive protein to screen for inflammatory bowel disease and against testing for ova and parasites (other than Giardia) if there is no travel history or recent immigration from high-risk areas [209].

On initial evaluation, most patients with IBS should have a complete blood count to rule out anemia or screen for systemic signs of infection. In the absence of alarm symptoms or suspicion of abnormalities that other laboratory testing can confirm, no other testing is needed for diagnosis. However, the presence of alarm criteria requires further testing specific to the index alarm finding—colonoscopy in most cases [3,44].

Colonoscopy is indicated in the presence of alarm symptoms, family history of colorectal cancer, or persistent diarrhea that has failed empiric therapy. Biopsies of different segments of the colon may be required in patients with chronic diarrhea to rule out microscopic colitis. Colorectal cancer screening colonoscopy is indicated in patients 50 years of age or older (or 45 years of age or older in African Americans) in the absence of warning signs based on national recommendations.

With failure of empiric therapy, other diagnostic options in limited use include [3]:

- Scintigraphic evaluation (75SeHCAT test)

- Postprandial serum C4 (7a-hydroxy-4-cholesten-3-one)

- FGF19

Breath tests to rule out carbohydrate malabsorption may be useful in some patients with IBS symptoms and persistent diarrhea.

Alarm Features

Concerning features that may suggest organic disease require assessment. Although the presence of these features may identify patients with organic disease, most will have negative evaluation findings, and concerning features are valuable for their negative (not positive) predictive value. IBS can be confidently diagnosed in patients who meet symptom-based criteria and lack concerning features, because extensive diagnostic testing is infrequently positive. However, the perspective of IBS as a diagnosis of exclusion remains widespread, and many healthcare professionals are uncomfortable relying solely on symptom-based criteria for its diagnosis [5,134].

Alarm criteria requiring further testing to rule out organicity include [3,44]:

- Personal or family history of colorectal cancer, intestinal polyposis, inflammatory bowel disease, or celiac disease

- Symptom onset after 50 years of age

- Recent changes in bowel movement habit

Additional signs and symptoms that may suggest organicity are:

- Nocturnal symptoms

- Fever

- Anemia

- Unintended weight loss not explained by other causes

- Fecal blood in the absence of documented bleeding hemorrhoids or anal fissures

- Severe abdominal pain

- Palpable abdominal mass, visceromegalias, or abnormal digital rectal examination on physical exam

Psychosocial Assessment

As discussed, psychosocial factors influence physiologic functioning of the GI tract (including motility, sensitivity, and barrier function), mediate pain experience and symptom behavior of the patient, and impact treatment selection and clinical outcome [15]. This makes psychosocial assessment a vital part of the evaluation of patients with IBS symptoms.

Primary care clinicians and gastroenterologists can use psychosocial screening to identify patients at risk for refractory symptoms, poor treatment response, or low quality of life. When overt psychopathology or moderate-to-severe symptoms are absent, visceral-specific anxiety, catastrophizing, somatization, and quality of life can be assessed to determine if comprehensive evaluation by a health psychologist or psychiatrist is indicated [55].

Clinicians should consider a brief psychosocial assessment for each patient with functional GI disorder, with the precondition that a satisfactory patient-clinician relationship is established earlier in the evaluation. A few specific questions on key psychosocial processes can be woven into routine history taking. If a patient asks about the relevance of this inquiry, a truthful response is, "I always ask my patients these questions as part of my initial assessment—it helps me determine the best way to help. The items may or may not apply to you." This psychosocial assessment will only be satisfactory if the patient is able to speak freely, which requires privacy, a lack of judgment or stigma, and sufficient time. Sensitive areas of discussion include abuse history, depressed mood, possible suicidal thoughts, and the nature of intimate relationships. These may require a second appointment for a full assessment.

The clinician should provide feedback about results of the overall evaluation and discuss treatment options, which can include medical and psychosocial approaches [55]. Consider referring patients with severe symptoms, previous treatment failure, poor treatment adherence, or marked disability to a clinician with special training in psychosocial assessment [55].

Changes in Symptom Severity, Frequency, or Treatment Response

When a plausible explanation for a change in symptoms or treatment response in patients with an established IBS diagnosis is lacking, it is important to assess for an underlying causal condition. Following a new physical examination, time since the last diagnostic workup should be considered. Changes in epidemiologic characteristics of the family should be assessed and recorded. IBS can include phases where symptom severity changes, and patients may perceive they have an inadequately explored organic disease. With these considerations, additional diagnostic testing should generally be limited to the presence of alarm symptoms or signs [44].

5. TREATMENT

Treatment of IBS should be directed at the dominant symptom type and severity [3]. In this section, interventions for all IBS subtypes (e.g., lifestyle, psychologic interventions, dietary, antidepressants) are discussed first, followed by therapeutic options specific to dominant symptom type (i.e., constipation, diarrhea, abdominal pain).

THE THERAPEUTIC RELATIONSHIP AND TREATMENT ADHERENCE

IBS treatment begins by explaining the condition, providing reassurance of the benign natural history, and educating the patient about the benefits and safety of diagnostic tests and treatment options [3]. Clinical experience suggests that providing the patient with a plausible disease model (e.g., "brain-gut disorder") and accepting patient symptoms and distress as real instead of dismissing them as "psychosomatic" helps to establish a positive therapeutic relationship. An approach that acknowledges the disease, educates the patient about the disease, and reassures the patient may improve treatment outcomes [125].

Steps to Enhance the Therapeutic Relationship

Healthcare professionals who repeatedly perform unnecessary diagnostic studies to rule out pathologic disease, dismiss patient concerns, or do not collaborate effectively in patient care can promote a vicious cycle of symptom anxiety and health care seeking [2]. Effective provider-patient relationships can improve patient satisfaction, treatment adherence, symptom reduction, and other health outcomes. General guidelines can help optimize this relationship with patients with IBS [2]. Patient satisfaction is based on a perception of healthcare providers' humaneness, technical competence, interest in psychosocial factors, and provision of relevant health information; over-emphasis on biomedical issues can have a negative effect. In addition to verbal communication, engagement involves nonverbal communication such as good eye contact, affirmative nods, a gentle tone of voice, close interpersonal distance, and creation of a partner-like interaction.

It is important to conduct the patient history using a nondirective, nonjudgmental, patient-centered approach. This involves active listening and asking questions based on the patient's thoughts, feelings, and experiences, instead of a preset agenda of questions. A good first step is to inquire regarding the reason for the appointment. Immediate reasons for a patient's visit may include [135]:

- New or exacerbating factors (e.g., dietary change, concurrent medical disorder, side effects of new medication)

- Personal concern about a serious disease (e.g., recent family death)

- Personal or family stressors (e.g., recent or anniversary of death or other major loss, abuse event, or history)

- Worsening or development of psychiatric comorbidity (e.g., depression, anxiety)

- Impairment in daily function (e.g., recent inability to work or socialize)

- A hidden agenda (e.g., opioid or laxative abuse, pending litigation, disability claims)

The next step is a careful physical examination and investigation. Although this obviously assists in diagnosis and assessment of new complaints, a well-conducted physical examination itself has therapeutic value [136].

In the course of clinical assessment, it is important to pay attention to patient concerns and understanding of their illness and to provide an explanation of the disorder that takes into consideration the patient's own perspective and beliefs about their condition. When plausible, one should point out the link between stressors and symptoms consistent with patient's views. Many patients are unable or unwilling to associate stressors with illness, but most understand the impact of illness-related stress on their emotional state.

Patients should be given therapeutic options and be involved in treatment decision-making. When possible, treatment recommendations should be consistent with patient interests. Identifying and responding realistically to the patient's expectations for improvement can strengthen rapport. However, it is also important to set consistent limits, especially as related to pain management and opioid use.

Finally, patients should be reassured that care will continue and that they should expect an ongoing relationship. It can help to let patients know that many treatment options can be explored to help control IBS.

Steps to Enhance Therapy Adherence

Adherence is essential for the effectiveness of prescribed therapy, including dietary measures, lifestyle changes, and pharmacotherapy. A therapy regimen alone is often insufficient unless the patient understands and accepts the approach and agrees to follow it. This highlights the importance of a trust-based therapeutic relationship that promotes cooperation and empowers patient participation in decision-making and responsibility for self-care [44].

In addition to consideration of best-available therapeutic options, the following measures can facilitate patient engagement and adherence [44]:

- Prescribing therapeutic regimens with the least number of effective daily doses

- Providing simple, easy-to-understand written information and reminders

- Providing adherence "diaries" to the patient

- Including information on the pathophysiology of the condition (according to education level) in patient education

- Including family members and caregivers who can positively reinforce patient behavior

The importance of regularity should be stressed for constipation management. Some patients only use medication intermittently for exacerbations, which is less effective. Other patients avoid laxatives altogether due to false beliefs that laxatives induce dependence or may be ultimately dangerous.

LIFESTYLE MODIFICATION

Limited data suggest that IBS symptoms may be improved by lifestyle modifications that include exercise, stress reduction, and good sleep habits [3]. Greater evidence supports dietary interventions.

Increased physical activity in patients with IBS has been found to improve GI symptoms and help protect against symptom deterioration [137]. In one study, exercise for 12 weeks significantly improved symptoms and extra-intestinal manifestations of IBS in 102 patients, while another 12-week exercise trial significantly improved constipation but not other IBS symptoms [137,138]. In adolescent patients with IBS, one hour of yoga daily for four weeks significantly improved symptoms [139].

Evidence Based Practice Recommendation

The National Collaborating Centre for Nursing and Supportive Care recommends drinking at least eight cups of fluid per day, especially water or other non-caffeinated drinks (e.g., herbal teas). Tea and coffee should be limited to three cups per day.

https://www.nice.org.uk/guidance/cg61

Last Accessed: November 14, 2019

Level of Evidence: Consensus Statement/Expert Opinion

Other recommendations that may improve IBS symptoms include [118]:

- Judicious water intake (particularly for patients with IBS-C)

- Caffeine avoidance

- Legume avoidance

Poor quality of sleep is relatively common in patients with IBS, and studies have shown that sleep difficulties predict next-day exacerbations, fatigue, and depressed mood [140]. Researchers have suggested autonomic nervous system dysregulation may be a common factor underlying both IBS symptoms and sleep disturbances. As such, patients should try to get enough sleep (at least seven to eight hours per night) and should keep good sleep hygiene (e.g., avoidance of electronics in the bedroom, going to sleep and rising at the same time every day).

Perceived high stress levels can also increase the risk for IBS exacerbations and increased symptoms [141]. Avoidance of high-stress situations, when possible, is recommended. However, psychologic interventions may also help provide effective stress-coping strategies.

Dietary Interventions

Dietary and Supplemental Fiber

Dietary fiber supplementation has long been the foundation of treatment in all patients with IBS, and IBS guidelines have consistently recommended dietary fiber by increasing fiber-rich foods or adding soluble fiber (usually Psyllium seed, but polycarbophil compounds may produce less flatulence) [44,118].

While evidence indicates that poorly fermentable, soluble fiber has modest benefits in reducing global IBS symptoms in patients with IBS-C with mild constipation, insoluble fiber may worsen abdominal pain and distension and has little benefit in patients with IBS-D. Wheat bran, in particular, can exacerbate problems of abdominal distention, abdominal pain, and flatulence and should be avoided [3,5,44]. If fiber is indicated, initiate soluble fiber at a very low dose and gradually increase to total daily intake of 20–30 g [5].

Gluten Restriction

Dietary restriction of gluten may improve symptoms in some patients with IBS. Two small prospective studies in patients with IBS, in which celiac disease was carefully excluded, demonstrated global symptom improvement [97,98].

Dietary FODMAP Restriction

Numerous short-chain carbohydrates, including lactose, fructose, and polyols, can provoke IBS symptoms [84,143,144]. These short-chain fermentable carbohydrates are collectively termed FODMAPs, and there is direct evidence (using magnetic resonance imaging) that some FODMAPs may induce IBS symptoms via increased small bowel water content or increased colonic gas production [84,143,144].

FODMAPs promote poor absorption in the small bowel and rapid fermentation in the colon. FODMAP is an acronym for [87]:

- Fermentable

- Oligosaccharides (e.g., fructo-oligosaccharides, galacto-oligosaccharides, fructans, raffinose, inulin)

- Disaccharides (e.g., lactose, sucrose)

- Monosaccharides (e.g., fructose)

- AND

- Polyhydric alcohols (e.g., sorbitol, mannitol, xylitol, maltitol)

The most common sources of FODMAPs in the western diet are wheat, onions, fruit in which fructose exceeds glucose (e.g., apples, pears), and processed food. Dairy products are important in those with lactose malabsorption.

True lactose intolerance may induce IBS-like symptoms, but only with relatively high lactose loads (20 g) that are easily avoidable. Psychologic factors have a major influence on symptomatic responses to lactose intake [145,146].

Fructose is a monosaccharide abundantly present in many processed foods. The small bowel has a relatively limited absorptive capacity that particularly affects free fructose—the fraction in excess of the glucose that facilitates fructose absorption. High fructose loading can induce symptoms even in healthy individuals.

Polyols such as sorbitol, mannitol, and xylitol are naturally present in many fruits and vegetables and are added as artificial sweeteners to processed food products and pharmaceuticals. Polyols tend to induce bowel discharges from their stimulant effect on intestinal motility.

Dietary FODMAP restriction is associated with reduced fermentation and significant symptom improvement in some patients with IBS. In a randomized, controlled, single-blind cross-over trial, patients with IBS who had not previously tried dietary manipulation reported significant reduction in overall GI symptom scores compared with those on a standard Australian diet [87]. The complexity of the FODMAP diet makes implementation difficult, but this may be overcome by excluding only the major sources of FODMAPs (e.g., wheat, onions, dairy), avoiding processed food, and not focusing on items with small specific contribution [87]. Adding a gluten-free diet to patients with IBS already on a low FODMAP diet does not appear to offer additional benefit [147,148,149].

Probiotics

Manipulation of intestinal microbiota has promise as a potential therapy for gut dysbiosis to ameliorate symptoms of IBS and restore health. The concept of probiotics is more than 100 years old, and modern research methods are establishing empiric support for the perceived benefits of probiotic bacteria, which mainly include Lactobacillus and Bifidobacterium species [150].

Probiotics are live bacteria, selected on the basis of ability to survive in the GI tract, adhere to intestinal epithelium, and modulate intestinal flora. Probiotics promote gut health, prevent infection from intestinal pathogens, and prevent bacterial translocation by inhibiting potentially pathogenic bacteria, modulating or stimulating immune response, promoting immune cell proliferation, enhancing phagocyte activity, and increasing production of immunoglobulin A [44,151].

The therapeutic effects for patients with IBS may occur through multiple mechanisms. Bifidobacterium infantis 35624 led to significant improvements in abdominal pain/discomfort, bloating/distention, and/or bowel movement difficulty (vs. placebo) in two randomized controlled trials of patients with IBS [152,153]. A 2016 meta-analysis that included 43 clinical trials using different products found probiotics to offer benefits for global IBS symptoms, pain, bloating, and flatulence. However, the overall usefulness of these findings has been limited by use of different IBS diagnostic criteria and symptom measurement methods in published randomized controlled trials [154].

Prebiotics/Symbiotics

Prebiotics are food products that promote proliferation of bifidobacteria and other species potentially associated with anti-inflammatory effects (e.g., oligofructose, inulin, galacto-oligosaccharides, lactulose, breast milk oligosaccharides). Prebiotics do not seem particularly effective in IBS, possibly due to fermentation products that may themselves stimulate IBS symptoms. Trials for prebiotics are few in number, and no definite conclusions can be drawn [84].

Symbiotics aim to simultaneously produce synergic pro- and prebiotic effects, but evidence has not substantiated their theoretical benefits in IBS. Further evidence is required to establish the role of prebiotics or synbiotics in IBS [84].

PSYCHOLOGIC INTERVENTIONS

As discussed, psychologic factors can amplify pain perception and experience, and strong empirical evidence confirms that pain experience is powerfully influenced by pain catastrophizing, fear avoidance behavior, self-efficacy, lack of perceived control, and passive pain coping. Other psychosocial research has found that depression and anxiety mediate the effect of pain on impaired function and that trauma history can negatively influence pain experience, pain and stress coping, and the clinician-patient relationship. This all supports the utility of psychologic interventions in IBS management [62,155,156].

Psychologic interventions address the cognitive-affective and psychosocial variables that interact with, reinforce, and perpetuate the physiologic factors that are involved in symptom expression, symptom severity, and impact of the disease on other health outcomes (e.g., quality of life, health care use) [55].

Cognitive-Behavioral Therapy

CBT refers to a family of psychologic treatments rather than a specific technique. CBT is derived from behavior theories that focus on learning processes and cognitive theories that emphasize faulty cognitions or thinking processes. These same learning processes are used to help patients gain control and reduce symptoms of IBS. Cognitive theory views external events, cognitions, and behavior as interactive and bidirectional, with primary emphasis on how patients process information about their environment, self, and the future. Cognitive factors, especially the way people interpret or think about stressful events, can intensify the impact of events on patient response. Emotional, physiologic, and behavioral responses to life events will be problematic to the extent that thought processes are faulty. Clinically modifying patient thinking can change behavior and emotional and physical well-being. Cognitive changes can occur by teaching patients to systematically identify cognitive errors generated by automatic thinking, or by providing experiential learning that systematically exposes patients to the situations that cause discomfort [55,157].

Unlike traditional, insight-oriented "talk therapy," which identifies the root causes of a problem, CBT focuses on teaching people how to control their current problems by identifying the thoughts and behaviors that are maintaining them. CBT requires active patient participation during and between sessions and patient responsibility for learning symptom self-management skills. With IBS, CBT can include a combination of techniques such as self-monitoring, cognitive restructuring, problem solving, exposure, and relaxation methods [55].

Self-Monitoring

Self-monitoring is the ongoing, real-time recording of problem behaviors. In IBS, the focus of self-monitoring is internal and external triggers and the thoughts, somatic sensations, and feelings that usually accompany flare-ups. Self-monitoring provides clinically relevant information with which to structure treatment and serves as a useful therapeutic strategy by increasing patient awareness of triggers and contributing factors [55].

Cognitive Strategies

Cognitive strategies are designed to modify thinking errors that bias information processing (e.g., tendencies to overestimate risk and magnitude of threat or underestimate one's ability to cope with adversity). These self-defeating beliefs are clinically important because they are believed to moderate excessive stress experiences. Negative beliefs are identified, and the patient works with the healthcare provider to challenge and dispute them. This involves examining the accuracy of beliefs in light of available evidence and replacing biased beliefs with more logical and constructive cognitions [55].

Problem Solving

Problem solving refers to an ability to define problems, identify solutions, and verify their effectiveness once implemented. The intervention is rooted in the problem-solving model of stress, which acknowledges that a causal relationship exists between health and stressors. Using this model, the health or mental health professional teaches patients how to effectively apply the steps of problem solving to actively cope with stress [55,158].

Relaxation Procedures

Various relaxation techniques are effective in managing IBS symptoms, and relaxation procedures have long been a staple of psychologic treatments for functional GI disorders. These techniques, including progressive muscle relaxation, breath work, and meditation, are designed to directly modify autonomic arousal believed to aggravate GI symptoms [159].

Progressive muscle relaxation training involves systematically tensing and relaxing selected muscle groups throughout the body, from forehead to feet. This exercise helps patients dampen physiologic arousal and achieve a sense of mastery of physiologic self-control over previously uncontrollable and unpredictable symptoms [55,160].

In breathing retraining, the patient is taught to take slow, deep breaths and focus on bodily sensations during exhalation. This technique is based on the idea that patients with stress-related physical ailments develop inefficient respiratory patterns (e.g., shallow chest breathing), which, if chronic, can intensify physiologic arousal and increase somatic complaints [55,161].

Meditation is a self-directed practice that can emphasize focused breathing and mindfulness. Mindfulness is defined as purposefully paying attention in the moment without judgement. This nonjudgmental acceptance of thought processes allows the practitioner to achieve a state of calmness, physical relaxation, and psychologic balance. In mindfulness meditation for IBS, the patient disengages him/herself from the ruminative thoughts considered core aspects of pain and suffering by developing a nonreactive, objective, present-focused approach to internal experiences and external events as they occur [55,162]. Small studies have indicated that engagement in a mindfulness-based stress reduction program can ameliorate IBS symptoms, reduce stress, and improve patients' quality of life, with continued improvements evident after six months [163].

Hypnosis

In hypnosis, a therapist typically induces a trance-like state of deep relaxation and/or concentration using strategically worded verbal cues suggestive of changes in sensations, perceptions, thoughts, or behavior. Most hypnotic suggestions are designed to elicit feelings of improved relaxation, calmness, and well-being. Hypnotic suggestions in IBS are "gut directed," meaning suggestions are conveyed that are incompatible with aversive visceral sensation. Hypnosis might include a suggestion to feel a sense of warmth and comfort spreading throughout the abdominal area [55,164]. Hypnosis has shown some benefit in decreasing IBS symptoms in adults [165].

Exposure Therapy

Exposure therapy is designed to reduce catastrophic beliefs about IBS symptoms, hypervigilance for IBS symptoms, fear of IBS symptoms, and/or excessive avoidance of unpleasant visceral sensations or situations by helping patients confront maladaptive thoughts and beliefs in a systematic manner. Exposure can include interoceptive cue exposure (i.e., the patient repeatedly provokes unpleasant sensations) or situational/in vivo exposure (i.e., feared situations or activities are confronted). Through exposure treatments, patients learn the stimuli that led to fear and avoidance are neither dangerous nor intolerable and that fear will subside without resorting to avoidance, a behavior that reinforces fear and hypervigilance in the long-term [166,167]. In an experimental study of 13 patients with IBS, 70% improved on measures of GI symptoms, pain catastrophizing, and quality of life following 12 sessions of exposure therapy [168].

Efficacy of Psychologic Treatments

Periodic meta-analyses conducted over the past two decades have consistently demonstrated that psychologic therapies, as a class of treatments, are at least moderately effective for relieving symptoms of IBS when compared with a pooled group of control conditions. The Internet has been used as a treatment delivery platform to give a larger proportion of patients with functional GI disorder access to, and engagement in, therapy than would have been feasible through clinic-based treatment alone [169,170,171].

A 2016 meta-analysis investigated the duration of sustained benefit gained from psychologic therapy in reducing GI symptoms in patients with IBS. Forty-one trials recording data from 2,290 subjects (1,183 assigned to therapy, 1,107 assigned to a control condition) were analyzed. Compared with a mixed group of control conditions, psychologic therapies had a medium size effect on reducing GI symptom severity immediately after treatment. On average, subjects receiving psychotherapy had greater post-therapy reduction in GI symptoms than individuals assigned to a control condition. After short-term follow-up (1 to 6 months after treatment) and long-term follow-up (6 to 12 months after treatment), this beneficial effect remained significant and medium in magnitude [172].

For the most part, the efficacy of psychologic therapies for IBS has been demonstrated from studies conducted as freestanding clinical trials; less clear is the effectiveness of psychotherapy approaches within the context of general clinical practice. To assess this further, a systematic review was made of the types and effects of psychologic treatments for IBS conducted in gastroenterology clinic settings. In an analysis of seven eligible studies comparing psychologic treatments to controls, IBS symptoms improved significantly among patients in cognitive and behavioral therapies, mindfulness-based stress reduction, guided affective imagery, and emotional awareness training [210].

ANTIDEPRESSANT MEDICATIONS

Although antidepressants are used extensively in the treatment of IBS and other functional GI disorders, the accumulated clinical experience, lack of other effective treatment options, and evidence from other functional somatic syndromes such as fibromyalgia make these agents viable options for treating pain and improving quality of life in patients with IBS. In general, antidepressant medications should be reserved for patients with moderate-to-severe symptoms with significant impairment of quality of life for which other first-line treatments have not been sufficiently effective [173,174].

Choice of Agent

The choice of antidepressant agent is determined by the patient's predominant symptoms, disease severity, presence of comorbid anxiety or depression, prior experience with medications in the same class, and patient and prescriber preference. The three broad antidepressant classes most often used in IBS are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-noradrenalin reuptake inhibitors (SNRIs) [55].

Tricyclic Antidepressants

TCAs such as amitriptyline, imipramine, desipramine, doxepin, and trimipramine are the most widely used psychotropic agents for treating neuropathic (e.g., postherpetic neuralgia, diabetic neuropathy) and functional (e.g., fibromyalgia) pain syndromes. Their analgesic effect is thought to be independent of antidepressant mechanisms and effects because TCAs can benefit patients with diverse pain syndromes in whom psychopathology is modest or absent and because they are often effective for pain at low (sub-psychiatric) doses [106,175,176].

In general, TCAs are the first antidepressant choice for pain in non-constipated patients with IBS due to their dual mechanism of action (serotonin and norepinephrine reuptake inhibition). Nortriptyline or desipramine is better tolerated than amitriptyline or imipramine due to fewer anti-histaminergic and anti-cholinergic effects. The usual starting dose is 25–50 mg at night and can be titrated up as needed up to about 150 mg/day, while carefully monitoring side effects and/or blood levels. Typically, lower doses than the full antidepressant dose are effective for visceral pain if no psychiatric comorbidity is present [55].

In one study, amitriptyline 10 mg/day in patients with IBS-D significantly improved overall IBS symptoms, reduced frequency of loose stool and feelings of incomplete defecation, and led to complete response (remission) in some [165,177].

SSRIs

Evidence Based Practice Recommendation

The American Gastroenterological Association (AGA) suggests against using selective serotonin reuptake inhibitors for patients with IBS.

https://www.gastrojournal.org/article/S0016-5085

Last Accessed: November 14, 2019

Strength of Recommendation/Level of Evidence: Conditional recommendation/low-quality evidence

SSRIs are less effective for pain and are less commonly prescribed as monotherapy for IBS. Review papers have arrived at different conclusions concerning SSRI utility in IBS treatment, with some authors concluding no convincing evidence has been reported for functional GI disorders and others reporting beneficial effects for overall IBS symptoms [3,93,165].

However, SSRIs are considered useful in patients with high levels of anxiety that contribute directly to IBS exacerbations and symptom severity. SSRIs and SNRIs have a more narrow therapeutic range, and therefore, the doses used for the treatment of pain are closer to the doses used for mood and anxiety disorders. Starting doses are usually within the lower range of the psychiatric dose (e.g., citalopram 20 mg or duloxetine 30 mg) and titrated up as needed [173,174,178].

A systematic review of SSRIs found benefits over placebo for overall IBS symptoms. Several clinical characteristics, including the predominant stool complaint, presence of insomnia, or comorbid anxiety, can influence antidepressant selection for individual patients with IBS [165].

SNRIs and Other Psychotropics

For SNRIs, especially venlafaxine, higher doses (≥225 mg) are usually required to attain effective analgesia because the noradrenergic mechanism of action is only evident at these doses. If nausea and weight loss are concerns, the addition of a low dose (15–30 mg) of mirtazapine can be helpful.

Atypical antipsychotics, such as quetiapine, are only recommended for patients with severe, refractory IBS, especially if severe anxiety and sleep disturbances are also present and the patient has failed to respond to other centrally acting agents. A low starting dose of 25–50 mg is recommended and can be titrated up as required [173,174].

Augmentation of Therapy

Augmentation, or the use of a combination of drugs from different classes in submaximal doses instead of one drug at a maximal dose, is common in psychiatry and is increasingly used in the treatment of functional GI disorders. Examples of augmentation include adding buspirone to an SSRI, TCA, or SNRI to enhance therapeutic effect, or adding a low-dose antipsychotic (e.g., quetiapine) to a TCA or SNRI to reduce pain and anxiety and improve sleep. If there is a component of abdominal wall pain associated with the GI pain, pregabalin or gabapentin can be added to a TCA or SNRI [173,174].

Combination Antidepressant and Psychologic Treatment

Combining antidepressants with psychologic therapy can be an effective augmentation strategy. Antidepressants can improve pain and vegetative depression symptoms, and psychologic therapy improves higher cortical functioning, including coping, reappraising maladaptive cognitions, and adapting to previous losses and trauma. Psychotherapy can optimize medication adherence, while antidepressants can sufficiently increase physical and psychic energy to improve the level of engagement in therapy. The difference in effect size with combined treatment can exceed 50% compared to either treatment alone [106,179,180,181].

Although drugs work faster and are readily available, psychologic treatments have several advantages. They are safe and effective, their effects persist beyond the duration of the treatment, and they may be more cost-effective. Potential barriers to the use of psychologic approaches in the treatment of IBS are a longer treatment duration, the need for patient motivation, and limited availability and access to a mental health professionals trained in IBS treatment [55,182].

Adherence

Careful patient selection, initiation at a low dose with gradual escalation, monitoring for side effects, and a good patient-clinician relationship are important for medication adherence and, by extension, therapeutic response. In particular, eliciting and addressing any potential concerns/barriers to taking psychotropic medications for IBS, discussing potential side effects, setting realistic expectations, and involving the patient in decision making result in improved adherence [55,174].

DIARRHEA-PREDOMINANT IBS

Chronic diarrhea in IBS is usually associated with a non-infectious cause, and symptomatic drug therapy is indicated when definitive treatment is unavailable. Pharmacologic agents for IBS-D are diverse in mechanism of action, and prescribing these agents requires proper diagnosis and differential diagnosis in order to ensure effectiveness [183].

Mu Opioid Receptor Agonists

Loperamide is a synthetic, peripheral-acting mu opioid receptor agonist with limited ability to penetrate the blood-brain barrier (and therefore limited abuse potential). It decreases peristaltic activity, inhibits secretion, increases water and ion absorption, reduces colonic transit, and increases resting anal sphincter tone. This results in reduced fluid and electrolyte loss and improved stool consistency [93,183]. Loperamide is available over the counter.

Diphenoxylate is another mu opioid receptor agonist, but unlike loperamide, it can cross the blood-brain barrier and is therefore combined with atropine to reduce abuse potential. Both of these agents are effective in reducing diarrhea in general, but research for the treatment of IBS-D is not well developed [93].

Several small randomized controlled trials of loperamide in IBS-D have shown reduced bowel frequency and improvements in stool consistency, urgency, and subjective overall response. Pain outcomes were mixed, with reduced pain intensity or increased nightly abdominal pain both reported in separate trials [3,183]. However, loperamide may improve quality of life by allowing the planning of trips and socializing, which anxious patients with IBS-D often avoid for fear of fecal urgency or even incontinence [87].

Adverse effects with loperamide or diphenoxylate are rare, but include bladder dysfunction, glaucoma, and tachycardia. These may be more likely with diphenoxylate due to the atropine constituent [93].

Bile Acid Binders (Sequestrants)

As discussed, the underlying pathophysiology in some patients with IBS-D is bile acid perfusion into the colon, and bile acid sequestrants are used as treatment for these patients. Cholestyramine is the agent generally considered first-line treatment for IBS-D with bile acid diarrhea [3,183]. Other options include colesevelam and colestipol. Cholestyramine granules are often poorly tolerated due to poor taste and adherence to the teeth [93].

Nonabsorbable Antibiotics

Antibiotics have traditionally been used as adjunctive IBS treatment. However, they are associated with systemic side effects, and there are concerns of promoting antibiotic-resistant microbes [184].

Rifaximin is a synthetic antibiotic derived from rifamycin and has anti-microbial activity against Gram-positive, Gram-negative, aerobic, and anaerobic bacteria. It is not absorbed by the intestinal mucosa, allowing intraluminal activity without systemic circulation and effects [185]. Rifaximin targets the GI tract to reduce gas-producing bacteria and alter the predominant bacterial species; it may also reduce mucosal inflammation and visceral hypersensitivity [93].

Evidence Based Practice Recommendation

The AGA suggests using rifaximin (over no drug treatment) in patients with IBS-D.

https://www.gastrojournal.org/article/S0016-5085(14)01089-0/pdf

Last Accessed: December 11, 2018

Strength of Recommendation/Level of Evidence: Conditional recommendation/moderate-quality evidence

In 2015, rifaximin was approved by the FDA for the treatment of IBS-D in adults [93]. Clinical trials have demonstrated that rifaximin improved IBS-associated symptoms of bloating, flatulence, stool consistency, and abdominal pain. The drug showed a side-effect profile similar to placebo. Some patients experience relief of IBS symptoms after a course of rifaximin, while others require retreatment at the same dosage [184,186]. Improvement in symptoms relative to placebo showed a gradual reduction over time, but significant improvement persisted for 10 weeks after the treatment course [3]. The usual dosage is 550 mg three times per day for 14 days [93].

Clinical experience suggests that many rifaximin responders eventually develop recurrent IBS symptoms. Data from re-treatment patients suggest that second and third courses produce efficacy similar to the initial course. The role of other antibiotics in IBS treatment remains unknown, but antimicrobial resistance with repeated courses of systemically absorbed antibiotics is a concern [5]. Overall, rifaximin appears to be safe and beneficial as a management option for IBS-D, although optimal dosing and treatment duration and potential resistance require further study [184,186].

5-HT3 Receptor Antagonists

Serotonin (5-HT) plays an important physiologic and pathophysiologic role in regulating GI function [187]. As such, 5-HT3 receptor antagonists (5-HT3RAs) can be effective treatment for IBS-D by slowing transit, reducing bowel frequency, normalizing stool consistency, and reducing urgency—a key symptom that impairs quality of life in patients with IBS-D [87].

Randomized controlled trials have found the potent, selective 5-HT3RAs alosetron and cilansetron may be effective in the treatment of IBS-D. However, alosetron was voluntarily withdrawn due to postmarketing reports of ischemic colitis (a potentially serious class-wide adverse event) and complications of constipation, while cilansetron was never marketed [187]. Alosetron was subsequently reintroduced to market and is currently available for women with severe IBS-D refractory to conventional therapy under an FDA Risk Evaluation and Mitigation Strategy program [188]. Alosetron is effective at relieving pain and reducing stool frequency and rectal urgency in women with IBS-D [3].

The 5-HT3RA ramosetron has also been studied as IBS-D therapy but has not received FDA approval. Ramosetron reduces defecation induced by corticotropin-releasing hormone and inhibited colonic nociception in preclinical studies. In randomized controlled trials of patients with IBS-D, ramosetron increased patient rates of global IBS symptom relief. In trials limited to male patients with IBS-D, ramosetron was as effective as mebeverine (an agent approved outside the United States) in improving stool consistency, relieving abdominal pain/discomfort, and improving health-related quality of life. Ramosetron shows a lower incidence of constipation versus other 5-HT3RAs and has not been associated with ischemic colitis [187]. In data stratified by sex, women reported significant relief of IBS symptoms only after two months, while men reported significant relief of IBS symptoms at all time points. Reasons for these differences are unknown [21].

The much less potent 5-HT3RA ondansetron (4 mg/day, range 2–6 mg/day) has also been found highly effective at improving stool consistency, reducing stool frequency, and reducing urgency. In one study, 70% with ondansetron (versus 16% with placebo) reported adequate IBS-D symptom relief. Worth noting is that ondansetron has been used for more than two decades without reports of ischemic colitis and has an excellent safety record; these features are important for IBS therapy selection [87].

Eluxadoline

Eluxadoline was approved in 2015 for IBS-D treatment in adults. This drug has therapeutic activity as a mixed mu-opioid receptor agonist and delta-opioid receptor antagonist, a novel mechanism of action developed to control GI function and decrease GI pain while mitigating the constipating effects of unopposed mu receptor agonist activity [21,87].

FDA approval of eluxadoline was based on two multi-center, multi-national randomized controlled trials with 2,426 patients with IBS-D receiving twice-daily eluxadoline (75 mg or 100 mg) or placebo for 26 weeks. Therapeutic response was defined as concurrent improvement in diarrhea (using the BSFS) and abdominal pain. In both trials, the proportion of patients with reduced abdominal pain and improved stool consistency was significantly higher with eluxadoline than placebo, at both doses. Eluxadoline reduced IBS-D symptoms in men and women, and efficacy was sustained over six months with the 100-mg, twice daily dose. The most common adverse events were nausea (8%), constipation (8%), and abdominal pain (5.0%) [189,190].

A small but definite risk (0.3%) of acute pancreatitis resulted from sphincter of Oddi spasm; all patients who developed this adverse effect had a history of cholecystectomy or significant ethanol consumption. Eluxadoline should be used at the lower dose with careful monitoring in these patients, who should also receive education of the risk [3,87].

Mast Cell Stabilizers

In patients with IBS-D, jejunal mucosal biopsies have shown mast cell activation and hyperplasia, providing the theoretical basis for possible benefits with mast cell stabilizers [191]. Disodium cromoglycate and ketotifen act primarily by stabilizing the plasma membrane of mast cells and have been evaluated in the treatment of IBS-D [93].

In a six-month trial of disodium cromoglycate for IBS-D, jejunal biopsies showed reduced release of tryptase and reduced expression of toll-like receptor 2 and 4, and patients showed clinical improvement of bowel function [192]. In an earlier trial of patients with IBS-D with food intolerance, disodium cromoglycate (250 mg, four times per day) plus exclusion diet was associated with prolonged symptomatic benefit compared with exclusion diet alone [193,194].

Ketotifen is a mast cell stabilizer with antihistamine properties that showed substantial improvement in patients with IBS despite no effect on mast cell parameters [195]. Further research suggests the effects mediated by histamine-blocking properties, and ketotifen may also be used in the treatment of abdominal pain-predominant IBS.

Muscarinic Type 3 Receptor Antagonists

Muscarinic type 3 (M3) receptor antagonists have beneficial effects in chronic diarrhea that include delayed small bowel and colonic transit, reduced rectal sensitivity, and reduced enterocyte secretion [93]. Preliminary evidence suggests greatest benefit with otilonium in IBS-D, with benefits shown in increased sensory thresholds to colonic volume and pressure, and reduction in abdominal pain [93,196]. Otilonium is investigational in the United States.

Glutamine

Patients with IBS-D have increased gut permeability, and symptomatic patients with IBS have decreased intestinal glutamine synthetase levels. In a preliminary report of a placebo-controlled trial of 10 g glutamine three times per day in 61 patients, the glutamine arm was associated with improved abdominal pain, bloating, and diarrhea and restored intestinal permeability [93,197].

Summary

During clinical development, rifaximin and eluxadoline demonstrated significant improvement in IBS-D endpoints versus placebo. In the absence of comparative randomized controlled trials, direct comparisons of alosetron, rifaximin, and eluxadoline efficacy cannot be made, but general efficacy estimates suggest similar and responses using outcome measures of adequate relief and combined improvements in abdominal pain/stool form. Clinical use of these agents is suggested to follow a sequential scheme that considers patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles [198].

CONSTIPATION-PREDOMINANT IBS

Constipation is one of the most common functional bowel disorder symptoms encountered in primary care and specialty practices. IBS-C and other disorders of chronic constipation are associated with significant medical costs and a negative impact on quality of life [199].

Laxatives

Osmotic laxatives contain nonabsorbable ions or molecules that retain water in the bowel lumen. Polyethylene glycol (PEG), lactulose, and magnesium salts are most commonly used. Osmotic laxatives are generally useful to treat constipation but can promote or worsen abdominal pain and distension in IBS and are not recommended [44].

Stimulant laxatives promote water and electrolyte secretion in the colon or induce colonic peristalsis. They include diphenylmethanes (phenolphthalein, bisacodyl, sodium picosulfate) and anthraquinones (Senna, bearberry, Aloe vera). While useful for constipation, they can worsen abdominal pain and distension in patients with IBS [44]. In patients with IBS-C, a randomized controlled trial of PEG vs. placebo found stool frequency, stool consistency, and straining were improved, but abdominal pain and bloating were unimproved during the four-week study [142].

Secretagogues

Secretagogues act through different pharmacologic mechanisms to stimulate chloride release into the intestinal lumen, which stimulates intestinal fluid secretion to counteract constipation symptoms in IBS-C [200]. The most commonly used agents are lubiprostone and linaclotide.

Lubiprostone

Lubiprostone is a prostaglandin-derived fatty acid that activates intraluminal chloride channels and chloride ion secretion. This leads to a passive influx of water and sodium, which increases intestinal peristalsis and colonic laxation and decreases intestinal stool transit time. Lubiprostone does not affect pain thresholds during rectal distension [5,87].

In patients with IBS-C, lubiprostone has proven effective in reducing constipation symptoms, but reduction of abdominal pain is much more modest (7% greater than placebo) and generally develops after one month of therapy. Side effects mostly involve mild-to-moderate nausea and diarrhea, and lubiprostone should be taken with food to limit dose-dependent nausea [3,5].

Lubiprostone is approved for the treatment of chronic constipation and opioid-induced constipation for men and women at 24 mcg twice daily, and for IBS-C in women at 8 mcg twice daily. No dosage adjustment is required in patients with impaired renal function [44]. Additional research may expand its clinical use [87,199].

Linaclotide

Linaclotide binds and activates guanylate cyclase C (GC-C) receptors expressed locally on the luminal surface of intestinal epithelium. GC-C receptor activation increases cyclic guanosine monophosphate concentrations, which activates the cystic fibrosis transmembrane conductance regulator to stimulate secretion of chloride and bicarbonate into the intestinal lumen. This leads to increased intestinal fluid and accelerated stool transit [87,189].

Evidence Based Practice Recommendation

The AGA recommends using linaclotide (over no drug treatment) in patients with IBS-C.

https://www.gastrojournal.org/article/S0016-5085

Last Accessed: November 14, 2019

Strength of Recommendation/Level of Evidence: Strong recommendation/high-quality evidence

In patients with IBS-C, randomized controlled trials have shown highly similar results across studies. Improvements in constipation, abdominal pain, discomfort or bloating, and stool consistency were 15% to 30% greater compared with placebo. These benefits persisted for 26 weeks. Diarrhea, the most commonly reported adverse event, occurred in 19.7% of participants and led to drug discontinuation in 4.5%. Efficacy and safety were similar in elderly and middle-aged adults [44,87,186]. Patients should take linaclotide (290 mcg) 30 to 60 minutes before breakfast to minimize the chance of diarrhea [5].

While lubiprostone and linaclotide led to improvements in stool frequency, constipation severity, and abdominal pain/discomfort in IBS-C, the relatively low response rates, higher costs, and adverse effects generally limit these agents to second-line therapy in IBS-C [201].

5-HT4 Receptor Agonists

5-HT4 receptors are expressed on enteric neurons and in cardiac tissue. 5-HT4 receptor agonists (5-HT4RAs) facilitate fast excitatory cholinergic synaptic transmission between enteric neurons, which stimulates GI motility and secretion [93]. Prucalopride, mosapride, and three other 5-HT4RAs (velusetrag, naronapride, and YKP10811) are in development for IBS-C treatment. These drugs have greater cardiovascular safety compared with older 5-HT4RAs due to higher specificity at intestinal 5-HT4 receptors and low intrinsic activity in cardiac muscle. These agents are expected to show efficacy in IBS-C, but this awaits confirmation by large randomized controlled trials [93].

ABDOMINAL PAIN-PREDOMINANT IBS

Antispasmodics (Spasmolytics)

Abnormal contraction of smooth muscle within the colon and the GI tract underlies pain and other IBS symptoms in some patients, providing the rationale for using agents that relax smooth muscle [21]. Spasmolytics fall into three groups based on mechanism of action [44,202]:

- Calcium channel blockers (e.g., alverine, otilonium, pinaverium bromide)

- Direct smooth muscle relaxants (e.g., mebeverine)

- Antimuscarinic/anticholinergic agents (e.g., hyoscine, cimetropium bromide, dicyclomine hydrochloride)

A review of 23 randomized controlled trials using various antispasmodics found that these agents improved IBS symptoms to a greater extent than placebo, but efficacy of individual antispasmodics varied. Only otilonium (investigational), hyoscine bromide, cimetropium bromide, pinaverium bromide, and dicyclomine showed significant improvements beyond placebo [196,203].

Antispasmodic drugs with anticholinergic or calcium-channel blocking mechanisms are used for relieving diarrheal symptoms, abdominal pain and distension, and spasms in all IBS subtypes. However, anticholinergic agents may be better tolerated in patients with IBS-D [5,183]. Otilonium and hyoscine have the best evidence of efficacy, and otilonium bromide is the most effective agent in preventing IBS symptom recurrence. Some patients with IBS have an exaggerated gastrocolic reflex that is in part cholinergic-mediated, and spasmolytics may be best suited for postprandial abdominal cramping and loose stools in these patients [5].

The most commonly reported adverse effects associated with spasmolytics include dry mouth, dizziness, and blurred vision; serious adverse events are rare. Spasmolytics with greater anticholinergic activity are more likely to induce blurred vision, urinary retention, constipation, and dry mouth. Anticholinergics should be avoided in the elderly and in patients with a history of acute myocardial infarction or hypertension. Use during pregnancy and breastfeeding is not recommended [5,44].

Peppermint Oil

Peppermint oil possesses a calcium-channel blocking mechanism and is classified as an antispasmodic [5]. The spasmolytic properties of peppermint oil may modulate pain by attenuating visceral hypersensitivity [44]. Two systematic reviews found peppermint oil superior to placebo in the management of IBS pain [203,204]. A 2014 review evaluated five trials enrolling a total of 482 patients and showed a statistically significant positive effect of peppermint oil over placebo [203].

Although peppermint oil is typically well tolerated, with no significant side effects reported with standard doses (250–750 mg two to three times/day), some patients may experience reflux symptoms, and allergic reactions, heartburn, and headache have been described [5]. Peppermint oil is available over the counter, and enteric-coated capsules are preferred [44].

Linaclotide

Linaclotide (290 mcg daily) demonstrated improvement in abdominal pain in two large, phase 3 studies in IBS-C, with one trial extending treatment out to 26 weeks [93].

Antidepressants

As discussed, antidepressants are commonly used to treat pain symptoms associated with chronic functional GI disorders, including IBS. In a Cochrane review, the TCAs desipramine (25–100 mg at bedtime) and amitriptyline (10–50 mg at bedtime) demonstrated some global improvements of abdominal pain [93].

Pregabalin

Pregabalin, an a2d ligand that inhibits release of a number of excitatory neurotransmitters, may alleviate visceral pain in patients with IBS [106,205]. Pregabalin increases distension sensory thresholds to normal levels in patients with IBS with rectal hypersensitivity. Studies are in progress to evaluate efficacy in centrally mediated abdominal pain syndrome (formerly termed functional abdominal pain syndrome) [93].

Histamine H1 Receptor Antagonists

Ketotifen

Ketotifen is a mast cell stabilizer with antihistamine properties. An eight-week randomized controlled trial showed evidence of improved pain, bloating, flatulence, diarrhea, quality of life, sleep, and sexual functioning in patients with IBS-D, despite lack of reduction in mast cell mediators [195]. The underlying mechanism of action was identified as histamine H1 receptor antagonism, which helped prompt further study of H1 receptor antagonists in patients with IBS [206].

Ebastine

Evidence suggests disordered GI motility, psychosocial distress, and visceral hypersensitivity converge on common pathways, including transient receptor potential cation channel subfamily V (TRPV). TRPV expressed on sensory neurons throughout the gut produces pain when activated by inflammatory mediators [207].

Researchers examined colorectal biopsies of patients with IBS and found greater TRPV-4 metabolite levels, which correlated with abdominal pain and bloating severity, and significantly greater nervous tissue and nerve growth mediators [207]. From these discoveries and results of ketotifen in the treatment of IBS, the histamine H1 receptor antagonist ebastine was studied for possible effects on visceral pain and hypersensitivity in 56 patients with IBS, randomized to ebastine (20 mg/day) or placebo. Over 12 weeks, a significant reduction of abdominal pain was found with ebastine compared to placebo and to baseline. Significantly more patients treated with ebastine (vs. placebo) had at least considerable relief of symptoms (46% vs. 12%) and lower mean abdominal pain scores (0–100 scale: ebastine 38, placebo 62). Quality of life was significantly improved on all IBS-QOL subscales in the ebastine group compared with baseline and placebo [206,207].

Hypersensitive and normosensitive subgroups did not differ in ebastine response. Visceral pain response, as measured by rectal distension, had no association with clinical response, showing barostat findings as an invalid outcome measure. Most importantly, this study suggests H1-receptor blockade may represent an effective treatment for IBS abdominal pain regardless of subtype. This is encouraging given the lack of targeted treatments for visceral hypersensitivity and abdominal pain in IBS [206,207].

Fecal Microbial Transplantation

Fecal microbiota transplants have been used in the last decade for severe cases of Clostridium difficile infection, with success rates greater than 90%. Fecal microbiota transplants may be a therapeutic option for severe refractory IBS or inflammatory bowel disease, but current FDA regulations limit use to the treatment of severe C. difficile infection [208].

In a randomized, double-blind placebo-controlled trial involving 52 adult patients with moderate-to-severe IBS, fecal microbiota transplantation successfully altered gut flora in patients with IBS, but patients in the placebo group experienced greater symptom relief after three months than did patients in the treatment group [211]. The authors concluded that altering gut microbiota is not an effective means of obtaining symptom improvement in patients with IBS. A 2019 literature review and meta-analysis, conducted to evaluate the combined outcome of improvement in global IBS syndrome, found no significant difference at 12 weeks in fecal microbiota transplantation versus placebo [212].

Concerns over introducing pathologic organisms must be addressed before fecal microbiota transplant is approved in clinical management of inflammatory bowel disease. An example is the case of a female patient with C. difficile infection who received fecal microbiota transplant from an obese person and subsequently became obese herself [208].

SPECIALIST REFERRAL

Specialist referral from primary care should be considered for patients with IBS who do not respond or are intolerant to management with dietary and lifestyle changes, common laxatives, spasmolytics, or antidepressants [44]. Referral is also indicated if defecation dysfunction is suspected, there is unexplained worsening in clinical status, or there is an unambiguous need for a second expert opinion.

6. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such an important aspect of the care of patients with IBS, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient or caregiver understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. (In many cases, the terms "interpreting" and "translating" are used interchangeably, but interpreting is specifically associated with oral communication while translating refers to written text.) Frequently, this may be easier said than done, as there may be institutional and/or patient barriers.

Depending upon the patient's language, an interpreter may be difficult to locate. Or, an organization may not have the funds to bring in an interpreter. Also, bringing in an interpreter creates a triangular relationship with a host of communication dynamics that must be negotiated. Many view interpreters merely as neutral individuals who communicate information back and forth. However, another perspective is that the interpreter is an active agent, negotiating between two cultures and assisting in promoting culturally competent communication and practice. In this more active role, the interpreter's behavior is also influenced by a host of cultural variables such as gender, class, religion, educational differences, and power/authority perceptions of the patient. Consequently, an intricate, triangular relationship develops between all three parties. Another factor affecting the communication process is the fact that many interpreters are not adequately trained in the art of interpretation in mental health and general health settings, as there are many technical and unfamiliar terms. An ideal interpreter goes beyond being merely proficient in the needed language/dialect. Interpreters who are professionally trained have covered aspects of ethics, impartiality, accuracy, and completeness. They are also well-versed in interpreting both the overt and latent content of information without changing any meanings and without interjecting their own biases and opinions. Furthermore, knowledge about cross-cultural communication and all the subtle nuances of the dynamics of communicating in a mental health or general health setting is vital.

On the patients' side, they may be wary about utilizing interpreters for a host of reasons. They may find it difficult to express themselves through an interpreter. If an interpreter is from the same community as the patient, the patient may have concerns about sharing private information with an individual who is known in the community and the extent to which the information disclosed would remain confidential. In some cases, raising the issue of obtaining an interpreter causes the patient to feel insulted that their language proficiency has been questioned. Finally, if an interpreter is from a conflicting ethnic group, the patient may refuse having interpreter services. The ideal situation is to have a well-trained interpreter who is familiar with health and mental health concepts.

If an interpreter is required, the practitioner must acknowledge that an interpreter is more than a body serving as a vehicle to transmit information verbatim from one party to another. Instead, the interpreter should be regarded as part of a collaborative team, bringing to the table a specific set of skills and expertise. Several important guidelines should be adhered to in order to foster a beneficial working relationship and a positive atmosphere.

A briefing time between the practitioner and interpreter held prior to the meeting with the patient is crucial. The interpreter should understand the goal of the session, issues that will be discussed, specific terminology that may be used to allow for advance preparation, preferred translation formats, and sensitive topics that might arise. It is important for the patient, interpreter, and practitioner to be seated in such a way that the practitioner can see both the interpreter and patient. Some experts recommend that the interpreter sit next to the patient, both parties facing the practitioner.

The practitioner should always address the patient directly. For example, the practitioner should query the patient, "How do you feel?" versus asking the interpreter, "How does she feel?" The practitioner should also always refer to the patient as "Mr./Mrs. D" rather than "he" or "she." This avoids objectifying the patient.

At the start of the session, the practitioner should clearly identify his/her role and the interpreter's role. This will prevent the patient from developing a primary relationship or alliance with the interpreter, turning to the interpreter as the one who sets the intervention. The practitioner should also be attuned to the age, gender, class, and/or ethnic differences between the patient and the interpreter. For example, if the patient is an older Asian male immigrant and the interpreter is a young Asian woman, the practitioner should be sensitive to whether the patient is uncomfortable given the fact he may be more accustomed to patriarchal authority structures. At the conclusion of the session, it is advisable to have a debriefing time between the practitioner and the interpreter to review the session.

In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding diagnostic procedures, treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered.

7. CONCLUSION

IBS is common in the general population and has a significant medical and socioeconomic impact. Standard management of IBS has involved psychologic support, dietary measures, and pharmacotherapy directed at symptoms. IBS has long been considered a notoriously difficult condition to manage, because the pathophysiology has been poorly understood. Advances in the understanding of the disease's etiology and pathophysiology are informing the use of novel treatment approaches. This course has reviewed current concepts of pathogenesis, diagnosis, and treatment to provide clinicians with the information necessary to appropriately diagnose and treat IBS and improve patients' quality of life.

8. RESOURCES

American College of Gastroenterology

https://gi.org

American Gastroenterological Association

https://www.gastro.org

International Foundation for Functional Gastrointestinal Disorders

https://www.iffgd.org

https://www.aboutibs.org

National Institute of Diabetes and Digestive and Kidney Diseases

https://www.niddk.nih.gov/health-information/digestive-diseases/irritable-bowel-syndrome

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

https://naspghan.org

The Rome Foundation

https://theromefoundation.org

Society of Gastroenterology Nurses and Associates

https://www.sgna.org

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Evidence-Based Practice Recommendations Citations

1. National Collaborating Centre for Nursing and Supportive Care. Irritable Bowel Syndrome in Adults: Diagnosis and Management of Irritable Bowel Syndrome in Primary Care. London: National Institute for Health and Care Excellence; 2017. Available at https://www.nice.org.uk/guidance/cg61. Last accessed November 14, 2019.

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94101 • Low Back Pain

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Back pain in general, and low back pain (LBP) in particular, is highly prevalent, associated with substantial economic expenditures (mainly health care) and losses (e.g., absenteeism, lost productivity). It can incur serious and prolonged patient suffering, diminished quality of life, and disability. LBP is the chronic pain syndrome responsible for the greatest clinical, social, economic, and public health burden. By completing this course, physicians, nurses, and other primary care providers will achieve a greater understanding of the pathophysiology and differential diagnosis of back pain conditions, the distinction between acute and chronic back pain and its management implications, and knowledge of appropriate treatment options that are guided by advances in pain neuroscience. Also gained from this course is the understanding of advances in the conceptualization and treatment of chronic LBP that challenge long-held assumptions and paradigms.

Table of Contents

94101 • Low Back Pain

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

PERSONAL IMPACT

ECONOMIC AND SOCIETAL COSTS

3. RISK AND PROGNOSTIC FACTORS

RISK FACTORS FOR DEVELOPING BACK PAIN

RISK FACTORS FOR PROGRESSION OF ACUTE LBP TO CHRONIC LBP

IATROGENIC RISK FACTORS

PROGNOSTIC FACTORS OF UNSATISFACTORY TREATMENT RESPONSE

4. CLINICAL COURSE

5. PATHOPHYSIOLOGY

PAIN PHYSIOLOGY

CHRONIC LOW BACK PAIN

PATHOANATOMIC BASIS OF COMMON LBP CONDITIONS

6. ASSESSMENT AND DIAGNOSIS

HISTORY AND PHYSICAL EXAM

DIAGNOSTIC IMAGING AND TESTING

LABORATORY TESTS

ENHANCING ASSESSMENT AND DIAGNOSIS

7. TREATMENT OPTIONS

TREATMENT OF ACUTE AND SUB-ACUTE LBP

TREATMENT OF CHRONIC LBP

NON-DRUG THERAPIES

COMPLEMENTARY AND ALTERNATIVE THERAPIES

PHARMACOTHERAPIES

INTERVENTIONAL PAIN MEDICINE THERAPIES

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

LIMITATIONS IN PAIN THERAPY RESEARCH

DECLINING AVAILABILITY OF MULTIDISCIPLINARY PAIN PROGRAMS

THE RISE OF INTERVENTIONAL PAIN MEDICINE

FINANCIAL AND MONETARY INFLUENCES

HEALTHCARE PROVIDER EDUCATION

PATIENT SATISFACTION RATINGS

COMMUNICATION WITH NON-ENGLISH-PROFICIENT PATIENTS

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94101 • Low Back Pain

Education Category. Infection Control / Internal Medicine

Release Date. 08/01/2019

Expiration Date. 07/31/2022

Course Overview

Back pain in general, and low back pain (LBP) in particular, is highly prevalent, associated with substantial economic expenditures (mainly health care) and losses (e.g., absenteeism, lost productivity). It can incur serious and prolonged patient suffering, diminished quality of life, and disability. LBP is the chronic pain syndrome responsible for the greatest clinical, social, economic, and public health burden. By completing this course, physicians, nurses, and other primary care providers will achieve a greater understanding of the pathophysiology and differential diagnosis of back pain conditions, the distinction between acute and chronic back pain and its management implications, and knowledge of appropriate treatment options that are guided by advances in pain neuroscience. Also gained from this course is the understanding of advances in the conceptualization and treatment of chronic LBP that challenge long-held assumptions and paradigms.

Audience

This course is designed for physicians, physician assistants, nurses, and other healthcare professionals involved in the care of patients with back pain.

Course Objective

The purpose of this course is to provide healthcare professionals with a greater understanding of the pathophysiology and differential diagnosis of low back pain conditions so they may effectively treat or manage low back pain, resulting in improved patient health, quality of life, and satisfaction.

Learning Objectives

Upon completion of this course, you should be able to:

1. Outline the epidemiology of back pain, including economic and societal costs.

2. Identify modifiable and nonmodifiable risk factors for back pain.

3. Review prognostic factors for unsatisfactory treatment response or progression to chronic low back pain.

4. Describe the clinical course of low back pain.

5. Describe the pathophysiology of the different types of back pain.

6. Outline the assessment and diagnosis of low back pain, including "red flags" evident on the initial assessment.

7. Assess approaches to enhancing the assessment of low back pain.

8. Compare available approaches for the management of acute and chronic low back pain.

9. Describe non-drug therapies that may be helpful for low back pain.

10. Discuss the use of complementary and alternative modalities for the treatment of low back pain.

11. Review the available oral pharmacotherapies for the treatment of low back pain.

12. Compare and contrast topical medications for the management of low back pain.

13. Evaluate the efficacy of spinal surgery to manage low back pain.

14. Assess the indications and potential benefits of epidural injections for the management of low back pain.

15. Identify barriers to the effective care of chronic back pain.

Faculty

Mark Rose, BS, MA, LP, is a licensed psychologist in the State of Minnesota with a private consulting practice and a medical research analyst with a biomedical communications firm. Earlier healthcare technology assessment work led to medical device and pharmaceutical sector experience in new product development involving cancer ablative devices and pain therapeutics. Along with substantial experience in addiction research, Mr. Rose has contributed to the authorship of numerous papers on CNS, oncology, and other medical disorders. He is the lead author of papers published in peer-reviewed addiction, psychiatry, and pain medicine journals and has written books on prescription opioids and alcoholism published by the Hazelden Foundation. He also serves as an Expert Advisor and Expert Witness to law firms that represent disability claimants or criminal defendants on cases related to chronic pain, psychiatric/substance use disorders, and acute pharmacologic/toxicologic effects. Mr. Rose is on the Board of Directors of the Minneapolis-based International Institute of Anti-Aging Medicine and is a member of several professional organizations.

Faculty Disclosure

Contributing faculty, Mark Rose, BS, MA, LP, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John M. Leonard, MD

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

The Director of Development and Academic Affairs has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

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1. INTRODUCTION

When it occurs, back pain is most often localized to the lower back, and chronic back pain is almost always chronic low back pain (LBP). Although acute-onset LBP is a common problem that usually resolves within four to six weeks, many patients develop a persistent, disabling pain syndrome with a diminishing prognosis for return to normal function. When LBP continues beyond 12 weeks, the prospect for subsequent remission is poor and progression to chronic LBP is likely. Chronic LBP imposes a great burden: for patients, pain and disability; for society and the healthcare system, an enormous expense in direct and indirect costs.

The status of care for patients with LBP is far from adequate and is fraught with a multiplicity of barriers (patient, professional, and system based) to the delivery of more satisfactory, cost-effective care. In primary care settings, low adherence to clinical practice guidelines for LBP is prevalent, most commonly involving neglect in assessing serious pathologic causes of LBP, overuse of diagnostic imaging, inappropriate advice concerning sick leave and activity, underuse of evidence-supported therapy, and overuse of approaches deemed ineffective. Interestingly, physician knowledge, experience, and interest in LBP has not been found to correlate with effective treatment decisions or adherence to practice guidelines [1,2].

Objective, comprehensive clinical practice guidelines become outdated when important studies are subsequently published, leaving clinicians with deficient and incomplete guidance. Despite research breakthroughs and diverse therapeutic options, only a minority of patients experience substantial treatment benefit. Many remain in pain, and inadequate pain relief is common even with careful, sequential trials of evidence-based pharmacotherapies recommended in practice guidelines [3,4]. A potential cause may be the over-reliance on randomized controlled trial outcomes to determine the direction of patient care. While these trials control for many factors that confound outcomes in uncontrolled trials, the restrictive inclusion criteria and inflexible dosing and titration can limit their clinical applicability or underestimate treatment benefit from attrition of patients who would otherwise respond well to a tailored approach. Patients with chronic LBP are typically complex in clinical presentation and more often resemble patients excluded from randomized controlled trials [5].

Patients with refractory chronic LBP can be desperate for treatment that relieves their pain. Numerous therapies for chronic LBP are available, but many lack sufficient safety and efficacy evaluation. This is where clinician-patient dialogue and shared decision-making are important. The clinician reviews the known risks, benefits, and gaps in evidence, and the patient shares his/her expectations and preferences [4]. In short, the tyranny of data should be tempered by clinical judgment [5].

The objective of this course is to provide clinicians with information to more effectively care for patients with back pain. Discussion will include clinical practice guideline recommendations for LBP, evidence that expands or challenges this guidance, assessment and treatment approaches not addressed by practice guidelines, obstacles to more effective care of patients with back pain, and methods to help identify research that is clinically useful. In this course, the term chronic LBP, in the absence of qualifiers, refers to pain of nonspecific etiology.

2. EPIDEMIOLOGY

LBP is a highly prevalent condition associated with substantial economic expenditures and losses. It can incur serious and prolonged patient suffering, diminished quality of life, and disability. LBP is the chronic pain syndrome responsible for the greatest clinical, social, economic, and public health burden [6,393].

INCIDENCE AND PREVALENCE

A 2009 population survey of U.S. adults measured the prevalence of pain for a prior three-month time interval. Respondents who reported recent pain were asked to rate their functional impairment from the pain. Of common causes of pain, LBP showed highest prevalence and life impairment in its sufferers (Table 1) [12].

Table 1: EXTENT OF PAIN-RELATED DISABILITY AMONG ADULTS WITH PAIN IN THE LAST THREE MONTHS, UNITED STATES

Type of Pain

Experienced in the Past Three Months

Difficulty with Basic Actionsa

Complex Activity Limitationb

Low back pain

28.1%

51.6%

55.0%

Severe headache or migraine

16.1%

31.0%

33.5%

Neck pain

15.1%

30.2%

34.4%

Knee pain

19.5%

37.3%

38.6%

Shoulder pain

9.0%

17.7%

21.4%

Finger pain

7.6%

14.3%

16.3%

Hip pain

7.1%

15.0%

18.4%

aBasic actions are defined as movement, emotion, seeing, hearing, or cognition.

bComplex activities are defined as self-care, social activities, or school/work.

Source: [12]

In 2017, 28% of adults reported LBP in the past three months. The prevalence was slightly greater for women (30.2%) than men (25.7%) and among those with lower educational attainment (33.3%), defined as non-high school graduates, compared with those with a Bachelor's degree or higher (23.5%) [8]. Persons older than 75 years of age were more likely to report past-three-month LBP (33.5%), though there is almost identical reporting among adults 65 to 74 years of age and 45 to 64 years of age (32.7% and 32.6%, respectively). This is followed by adults 18 to 44 years of age, of whom 23.8%reported LBP. Lower family income (33.7% in ≤$35,000, 24.1% in ≥$100,000) and poverty status (35.6% in poor, 26.3% in non-poor) also appear to be factors, likely related (at least in part) to the type of work typical of the group [8].

Genetic or ethnic factors may influence the prevalence of some known causes of LBP. For example, the prevalence rate of lumbar spondylolisthesis is 25% in Inuit Eskimo, 6% in white, and 2% to 3% in black populations. Reasons for the high prevalence in Inuits are not known but may be genetically mediated [9].

Data on changes in LBP prevalence over time are somewhat conflicting, and causality is difficult to establish. Data from the Department of Veterans Affairs health system showed an annualized increase in LBP prevalence of roughly 5% per year, larger than the increases in depression, diabetes, and hypertension [10,394]. National claims data indicate that the proportion of physician office visits for LBP increased from 12% in 1998 to 18.1% in 2013. It is likely the claims figures under-report population incidence because many people do not seek medical care for LBP, but the data are a valid indicator of population-level change [11,396].

PERSONAL IMPACT

Worldwide, LBP is the single greatest cause of disability and years lived with disability, and in the United States, roughly 1% to 2% of the adult population is disabled by chronic LBP. LBP is the most common reason cited for curtailment of activity by young adults and for sick leave from work in all age groups [11,395].

ECONOMIC AND SOCIETAL COSTS

Accurate cost estimates incurred by LBP are difficult to calculate because expenditures for pain and other conditions are intertwined. What is known is the economic impact of LBP in the United States is substantial and likely to increase in the future. The full 2010 cost impact of chronic pain ranged from $560 to $635 billion, with pain care accounting for $261 to $300 billion and lost productivity from pain ranging from $299 to $335 billion [12]. The annual cost of disability from all causes was an estimated $300 billion, with back pain and arthritis the two leading causes of disability [13]. In 2013, low back and neck pain accounted for the third highest amount of healthcare spending, costing an estimated $67.5 to $94.1 billion. Healthcare spending for low back and neck pain has increased by $57.2 billion since 1993 [397].

An estimated 12% to 15% of annual healthcare provider visits in the United States are related to LBP [14]. The estimated 8% of patients whose LBP is chronic and debilitating account for 50% of direct medical expenditures for back pain, estimated at $85 billion [11,15]. Together with costs from decreased wages and lost productivity, the total is $100 to $200 billion [16].

While the healthcare costs for LBP are substantial, they may account for as little as 15% of total costs, with up to 85% coming from indirect costs. Sizeable contribution to indirect costs comes from lost productivity, which includes absenteeism from work, impaired productivity at work (presenteeism), and employer cost of hiring a replacement. Other costs include workers' compensation, disability benefits, lost earnings, litigation, and early retirement [17].

Between 1999 and 2010, there was a 106% increase in primary care physician referrals of patients with LBP to specialist physicians. This is important because such referrals contribute to increases in costly and often ineffective interventional and surgical treatment [18].

Between 2000 and 2009, interventional pain medicine procedures for back pain in the Medicare population increased more than 200% from 1,469,495 to 4,645,679 annually [19,393]. However, follow-up has shown that between 2009 and 2016 there was a more modest increase of 18.6%, with 5,509,306 procedures in 2016 [393]. From 1997 to 2005, medical costs for spinal pain treatment increased 65%, and the dominant contributor to cost increases was interventional pain medicine procedures [20].

3. RISK AND PROGNOSTIC FACTORS

RISK FACTORS FOR DEVELOPING BACK PAIN

Risk factors for developing LBP can be generally categorized as nonmodifiable, such as old age, female sex, poverty, and lower education level, and modifiable, including higher body mass index (BMI), smoking, lower perceived general health status, physical activity (e.g., bending, lifting, twisting), repetitive tasks, job dissatisfaction, and depression. The greatest contributors to LBP episodes are single-event or repetitive exposures to mechanical stress and age-related degenerative spinal changes. With chronic LBP, mechanical and biophysiologic factors play a minimal secondary role to the primary contribution from psychosocial factors [21].

Smoking

Smoking has been linked to a greater risk for chronic pain by multiple studies, and studies of LBP have found higher rates of intervertebral disk degeneration among smokers. A study of 5,333 patients with chronic back pain assessed pain levels before treatment (86.5% treated for spine degenerative disease) and at mean eight-month follow-up. Baseline pain levels were more severe in current smokers compared with never-smokers and former smokers, and this pattern continued through follow-up. At the last follow-up, a 30% or greater reduction in worst pain level was noted in 31.2% of never-smokers, 29.1% of former smokers, 16.6% of current smokers, and 32.0% of smokers who quit during the study. Never-smokers experienced the greatest reductions in disability compared with current smokers [22].

Obesity

Obesity contributes to factors that promote the development of some pain states, including LBP. Persons with LBP exhibit abnormal movement patterns that include gait and postural dysfunction, increased thoracolumbar stiffness, decreased proprioception, and alteration in abdominal and extensor muscle activation. Pain can result from joint or structural damage due to aberrant or increased biomechanical forces over time. These processes are accelerated by obesity, and regardless of age, obesity contributes to chronic LBP, mobility impairment, and ultimately physical disability. The relationship between obesity-related LBP and functional decline is mediated by skeletal muscle strength deterioration, systemic inflammation, and psychosocial characteristics, such as pain catastrophizing, kinesiophobia, and depression. Morbid obesity greatly alters biomechanical forces on lower back tissues to accelerate the development of chronic back pain syndromes [23].

Evidence Based Practice Recommendation

Although overweight/obesity and smoking are associated with the increased prevalence of low back pain, the Institute of Health Economics reports there is insufficient evidence to recommend modifying these risk factors for the prevention of low back pain.

https://www.guidelinecentral.com/summaries/guideline-for-the-evidence-informed-primary-care-management-of-low-back-pain/

Last Accessed: July 28, 2019

Strength of Recommendation: Systematic review

Overweight and obesity are risk factors for both lumbar radicular pain and sciatica, and a direct relationship exists between BMI and low back pathology and pain in men and women. A meta-analysis of 28 studies found overweight and obesity were associated with lumbar radicular pain, increased the risk of hospitalization for sciatica, and increased the risk of lumbar disk herniation surgery. These associations were similar for men and women [24]. Clarification of whether or not LBP precedes obesity was addressed by an 11-year longitudinal study of 25,450 individuals. Among those without LBP at baseline, a significant positive association was found between BMI ≥30 and risk of LBP in men and women, and risk of chronic LBP recurrence in women, but not men. In contrast, LBP at baseline had little effect on later changes in BMI [25].

Adipose tissue releases inflammatory mediators that contribute to the development of chronic, low-grade inflammation in obesity, which may accelerate the development of sciatica or cause sciatica symptoms to persist. Obesity may delay disk injury healing and lead to slower and less overall improvement in back-related disability, regardless of treatment modality. Obesity also increases the risk of recurrent disk herniation following lumbar surgical repair. Intervertebral disk nutrition may be disrupted by obesity, impairing the healing process. Long-term data have found BMI to be the strongest predictor of lumbar artery occlusion in patients with sciatica, suggesting impairment of nutrition as a pathway for the relationship between obesity and sciatica [26,27,28].

Age

Among those older than 60 years of age, more than 90% of the population demonstrate various degenerative spine changes on x-ray and magnetic resonance imaging (MRI), including disk herniation, spinal stenosis, and foraminal stenosis. In most persons, these changes are asymptomatic. Current thinking is that pain associated with lumbar disk herniation and radiating symptoms primarily results from inflammatory mediators rather than mechanical compression. It has only recently become clear that imaging-detected degenerative changes, disk abnormalities, and other spinal anomalies lack correlation with or prediction of pain [29].

Vitamin D Deficiency

Interest in the role of vitamin D deficiency in pain was spurred by findings of highly prevalent vitamin D deficiency among primary care patients with persistent, nonspecific musculoskeletal pain refractory to pharmacotherapy [30]. Pain patients with vitamin D deficiency also require twice the opioid dosing for substantially greater duration versus non-deficient patients [31].

Vitamin D is essential for normal muscle function and bone formation, maintenance, and remodeling, and it possesses anti-inflammatory properties through regulation of interleukin (IL), tumor necrosis factor (TNF), and macrophage activity. Vitamin D deficiency (hypovitaminosis D) is highly prevalent in patients with back pain, and symptoms often resolve three to seven months after vitamin D treatment. Hypovitaminosis D symptoms can appear before the onset of pathologic changes associated with persistent musculoskeletal pain conditions and persist following resolution of obvious pathology. These findings are relevant in the surgical treatment of LBP (e.g., lumbar fusion). Despite a technically successful surgery, many patients lack meaningful pain reduction, and in patients obtaining pain relief, many fail to show functional improvement. Hypovitaminosis D is thought to be a major contributing factor to the lack of analgesic or functional improvements in these patients [32,33].

Evaluation of 350 patients who had undergone lumbar spinal stenosis found vitamin D deficiency in 74.3%, with substantially higher prevalence in subgroups with medical comorbidity, urban residence, lower sunlight exposure, and severe leg and/or back pain. The association between pain and deficiency remained significant after adjusting for sunlight exposure [34].

RISK FACTORS FOR PROGRESSION OF ACUTE LBP TO CHRONIC LBP

Psychosocial factors, but not specific physical or imaging findings, have shown consistent utility in predicting the development of chronic LBP in patients with recent-onset LBP. This predictive ability has led to universal recommendation for psychosocial assessment of new patients with LBP. This is termed "yellow flag" assessment [35,36,37,38].

Perception of pain as a threat produces fear and anxiety and physiologic (e.g., increased heart rate, dilated pupils), cognitive (e.g., catastrophizing thoughts or decision making), and behavioral (e.g., fight-or-flight) responses. Pain-related fear can impose greater limitations in patient function than debility from pain itself, and the associated negative thoughts of treatment, the future, and oneself can disrupt rehabilitation and recovery [39,40,41]. This pessimism over one's ability to recover is a negative outcome predictor. In a study of patients with LBP evaluated in primary care and followed over several years, the greatest association with pain at five years was found with acute pain severity and conviction of one's pain persisting unchanged for an extended period. This negative pain belief predicted clinically significant LBP independent of numerous prognostic factors, including pain intensity. This predictive validity was found at short- and long-term follow-up [43]. Another trial followed patients with LBP from inpatient release through long-term follow-up and found affective health and coping during acute pain significantly predicted pain reduction and improved function [44].

Psychosocial factors for developing chronicity include [35,36,37,38]:

- Negative belief that pain is harmful or potentially severely disabling

- High levels of "fear avoidance" behaviors

- Poor or maladaptive coping strategies

- Expectation that passive, rather than active, treatment is beneficial

- Excessive focus on pain

- High emotional distress levels

- Depressed mood, low morale, and social withdrawal

- Resistance to change

- Low self-efficacy

- Family reinforcement of illness behavior

- Concurrent social or financial problems

- Troubled childhood (e.g., abuse, parental death, addiction)

Kinesiophobia describes the excessive, irrational, and disabling fear of movement and activity from its anticipated result of injury or re-injury. Pain-related fear is closely associated with catastrophic interpretations of pain and can promote behaviors such as avoidance, escape, and hyper-vigilance. While pain-related behaviors can lead to disuse syndromes from activity avoidance, greater consequences result from its role in complicating and perpetuating the underlying psychophysiologic contribution to chronic LBP [45,46].

Several work and workplace factors strongly predict work disability and development of chronic LBP. In workers with difficulty returning to normal job duties 4 to 12 weeks from acute LBP onset, the longer additional time is taken away from work for LBP, the lower the chances of ever returning to work. Fewer than 50% of patients disabled longer than six months return to work, and for those absent two years, the return to work rate is close to zero. Low workplace support is strongly predictive of chronicity in patients with acute back pain [21,38].

Specific work-related factors that may predict chronicity include:

- Job dissatisfaction

- Conflict with supervisors or coworkers

- High physical demands

- Inability to modify work

- High levels of job stress

- Disputed or unresolved workers' compensation claim

IATROGENIC RISK FACTORS

In the course of clinical evaluation and care, patient expectations and provider decision and communication style may inadvertently lead to an exacerbation of LBP or promote chronicity of the condition. The early use of MRI or other imaging modalities should be avoided in most cases of LBP, in part because it is unlikely to influence early management decisions. Moreover, nonspecific imaging abnormalities are often seen and reported, which, for the patient, may promote anatomic fixation, undermine patient perception of and confidence in their health, trigger pain-related fear-avoidance and catastrophizing behaviors, and increase the risk of iatrogenic precipitation of chronic LBP [47].

The lay public has repeatedly held fast to the belief that any given case of LBP must have a demonstrable structural cause, leading to doctor shopping and excessive demands for diagnostic testing. Pain care providers are also partially responsible, by reinforcing erroneous, disabling, and costly pain beliefs and behavior. Interventional pain medicine has a recognized but limited role in a few specific LBP indications. Interventional pain medicine physicians have been the focal point of criticism for perpetuating the reductionistic and disproven biomedical paradigm of nonspecific LBP origin and treatment, but practitioners of non-invasive back pain therapies, such as chiropractic, physiotherapy, and osteopathy, have also contributed to widespread counter-therapeutic patient beliefs [48].

PROGNOSTIC FACTORS OF UNSATISFACTORY TREATMENT RESPONSE

Several biopsychosocial factors can interfere with treatment response. The following factors should be assessed if pain and functional status do not improve or worsen without obvious cause [49]:

- Medical comorbidities

- Psychiatric and psychologic comorbidity

- Another pain condition

- Substance abuse

- Previous surgeries

- Tobacco use

- Head trauma history

- BMI

- Sleep disorders

- Employment status

- Concurrent pharmacotherapies

- Social support

- Physical conditioning

- Current pain intensity

Psychosocial factors of poor outcomes in lumbar surgery include mood disorders, unresolved litigation or claims, history of child abuse, and maladaptive pain coping or beliefs [50]. The predictive power of these variables on surgical outcomes surpasses radiographic findings, neurologic signs, and other medical indices. Psychologic screening of implantable neuromodulation device candidates increased successful outcomes from 33% to 70% and is now standard protocol. In outcome studies of spinal cord stimulation in patients with failed back surgery syndrome, inadequate psychologic screening was associated with 50% short-term and 35% long-term benefit, while adequate psychologic screening led to 85% short-term and 60% long-term success rates [50].

In patients with failed back surgery syndrome, risk factors of poor outcomes with spinal cord stimulation include [51,52]:

Pre-Operative

- Anxiety

- Depression

- Misidentification of pain origin

- Obesity

- Cigarette smoking

- Unresolved litigation or claims

Surgical

- Revision surgery

- Poor candidate for surgical technique

- Incorrect spinal level of intervention

Post-Operative

- Central sensitization

- Progressive spinal disease

- Epidural fibrosis

- Nerve injury

- Infection

- Hematoma

- Myofascial pain

4. CLINICAL COURSE

The most commonly cited short-term prognosis data state that most patients with acute LBP recover in a matter of weeks with limited or no therapy; specifically, 60% to 70% of patients recover by 6 weeks and 80% to 90% by 12 weeks [21,53]. These early prognosis projections are at variance with data derived from a study of patients presenting to primary care providers with nonspecific acute LBP [54]. This study found that 33% of patients experienced spontaneous resolution by 3 months, 57% still had problematic pain at 6 months, and 65% reported some degree of pain at 12 months after onset. Of patients with persistent pain at 3 months, only 1% to 7% experienced recovery 3 to 12 months from onset [54].

This study confirmed the impression of experienced clinicians that the clinical course of most patients with acute LBP in a primary care practice does not conform to the conventional notion that nonspecific acute LBP has a favorable natural history and resolves within several weeks [55]. The reason for this discrepancy may be that most patients who develop acute LBP with favorable prognosis do not seek medical care [383]. In those seeking care, pain and disability can be ongoing and recurrent pain episodes may be common. Up to 70% of patients who initially improve following medical care experience recurring pain episodes [55].

5. PATHOPHYSIOLOGY

The traditional biomedical paradigm considers back pain a symptom of a primary condition, resolved by treating the peripheral pain generator. While effective for specific LBP conditions with identifiable pain causality, this biomedical paradigm is not useful when applied to chronic back pain because it fails to consider the impact of peripheral and central nervous system (CNS) alterations that amplify and perpetuate pain and the substantial contribution from psychosocial factors [42,56]. A corollary of the biomedical paradigm is mind-body dualism, whereby pain causation is viewed as distinctly the result of either biologic or psychologic factors. Patients with severe chronic LBP who lack corresponding positive imaging findings may be informed their pain lacks organic basis and is therefore "all in their head" [57].

Chronic LBP reflects the uncoupling of pain from its original peripheral origin; it is a distinct disease process rather than a symptom [56]. Likewise, the extent of peripheral tissue damage is no longer viewed as the sole determinant of pain presence, severity, and duration. Chronic LBP is now understood as a multifactorial entity determined by inputs from numerous and complex electrochemical, biocellular, cognitive, and emotional factors. The broad range of individual pain responses to stimuli reflects the highly individualistic phenomenon of pain [58,59].

Pain is broadly categorized as nociceptive, inflammatory, neuropathic, or centralized. Nociceptive and inflammatory pain overlap and result from peripheral tissue injury, damage, or disease. Both are protective and adaptive for survival when acute but are considered pathologic when pain continues after peripheral tissue healing. Neuropathic pain results from injury, damage, or disease to peripheral nervous structures or sensory pathways in the spinal cord or brain, and regardless of duration, it is pathologic. Centralized pain reflects aberrant function in various CNS pathways and is now thought to account for fibromyalgia, irritable bowel syndrome, and other chronic conditions [60,61]. Centralized pain is not associated with any common back pain condition or peripheral tissue injury and therefore is not discussed further in this course. These pain subcategories are not distinct and do not account for individual variations. Many cases of chronic LBP represent a mixture of pain subcategories [60].

Neuroscience findings have refuted previous assumptions of back pain pathophysiology. Healthcare providers should understand these changes in how pain is conceptualized, because the management of LBP can hinge on proper matching of pain pathophysiology and treatment mechanism. Effective chronic LBP management requires replacement of several entrenched paradigms with the following [62]:

- Pain is not an accurate measure of tissue state.

- Pain is modulated by multiple factors across somatic, psychologic, and social domains.

- The relationship between pain and tissue state further weakens as pain persists.

- Pain represents a conscious correlate of the implicit perception that tissue is in danger, not the actual tissue state and not the actual threat to tissue.

This section describes the underlying pathways and mechanisms of pain processing and experience in the normal state and in chronic back pain. In addition, neuroscience discoveries in chronic LBP, and pathoanatomic processes in specific LBP conditions will be discussed.

PAIN PHYSIOLOGY

Pain begins when peripheral tissue injury, infection, or peripheral nerve injury triggers a complex local response that converts the injurious stimuli into an impulse. While local processes differ, the resultant nociceptive, inflammatory, or neuropathic pain impulse is transmitted to the brain through interconnected pathways involving similar mechanistic processes spanning the peripheral nervous system, spinal cord, and various brain regions. The structure and function of these mechanisms and pathways undergo alteration in chronic LBP and represent therapeutic targets.

Nociception is the mechanism that encodes and processes noxious (potentially injurious to tissue) stimuli. Nociceptors are sensory neurons that respond to noxious stimuli. Several events are required for nociceptor relay of noxious stimuli to the brain for pain perception: peripheral nociception, spinal cord transmission, brain projection of pain pathways, and relay down descending pain pathways.

Peripheral Nociception

Nociceptors are specialized high-threshold afferent (sensory) neurons. Activation by noxious stimuli (e.g., extreme heat/cold, cutting, inflammation) transduces energy into an action potential, transmitted to the spinal cord along an axon contained in a C (non-myelinated) or A-delta (myelinated) nerve fiber [61,63,64]. Several receptors also signal noxious stimuli, including transient receptor potential and acid-sensing ion channels and potassium channels [65,66].

Inflammatory Pain

Tissue injury or infection prompts the release of chemical mediators that trigger inflammatory response, including cyclooxygenase-2 (COX-2), mast cells, and other enzymes. Chemical mediators activate and sensitize nociceptors via ligand-gated ion channels or metabotropic receptors. Other modulators of nociception function are recruited as signaling molecules in pain pathways [66,67,68].

Nociceptor activation induces a cascade that sensitizes nociceptors and alters voltage-gated sodium and transient receptor potential channel kinetics and threshold. Substance P, calcitonin gene-related peptide (CGRP), and other neuropeptides are released from peripheral terminals to recruit serum factors and inflammatory cells at the injury site to produce neurogenic edema. Tissue sensitivity around the injury is termed peripheral sensitization and represents primary hyperalgesia. Inflammation alters protein synthesis in the dorsal root ganglion cell body, leading to ion channel expression of transient receptor potential vanilloid 1 (TRPV1) and transport of peripheral opioid receptors. This upregulation of opioid receptors in peripheral inflammation sites helps account for opioid efficacy in inflammatory pain [66,69]. In contrast, peripheral nerve injury can decrease mu-opioid receptor expression in dorsal root ganglion neurons, diminishing the analgesic efficacy of opioids [70].

In all peripheral pain types, sodium channels facilitate neuron excitability and signaling of action potentials to the spinal cord. Changes in sodium channel kinetics following peripheral tissue damage contribute to hyperexcitability, and different pain states are characterized by upregulation or downregulation in sodium channel expression [71].

Spinal Cord Transmission

The peripheral nociceptive signal is transmitted to the dorsal root ganglion, where the peripheral neuron synapses with a central neuron. The neuron terminals release excitatory neurotransmitters according to stimuli intensity. These include glutamate, aspartate, substance P, CGRP, and brain-derived neurotrophic factor (BDNF). Depolarized primary afferent terminals release glutamate, which activates postsynaptic AMPA receptors to rapidly signal the location and intensity of noxious stimuli. A high-intensity stimulus normally elicits brief localized pain, and the relationship between afferent input and dorsal horn neuron output is proportionate and predictable [72,73].

Before relay to the brain by ascending spinal pathways, the signal can be modulated by peripheral or descending spinal pathway neurons. Inhibitory mechanisms in the dorsal horn are activated to reduce excitatory response to persistent peripheral input, involving endorphins, enkephalins, serotonin, and norepinephrine [63].

Brain Projections of Pain Pathways

The pain signal is relayed through spinal pathways into the midbrain, forebrain, and cortex. Distinct qualities of the pain experience are mediated by activation of the specific brain regions receiving the ascending projections, including pain location and type by the thalamus and somatosensory cortex; integration of nociceptive information with arousal, homeostatic, and autonomic responses by the medulla and brainstem; emotional, affective, and motivational components of pain in the ventromedial hypothalamus, central nucleus of the amygdala, anterior cingulate cortex, insular, and prefrontal cortex; fight-or-flight response and stress-induced analgesia in the periaqueductal grey and rostral ventromedial medulla; and projections to the reticular formation that mediates regulation of descending pathways to the spinal cord [74,75]. Signal processing in the brainstem, thalamus, and cerebral cortex results in pain perception [63].

Descending Modulatory Pain Pathways

Descending pathways from the cortex, thalamus, or brainstem extend down the spine to the dorsal horns. With tissue insult, the nociceptive signal is relayed into and through the brain. The signal, now experienced as pain, is routed down descending pathways to the dorsal horn receiving peripheral inputs to dampen pain perception by modulating signal transmission through presynaptic and postsynaptic action and actions on intrinsic interneurons. This is termed the top-down pain modulatory system. The relative balance between descending inhibition and facilitation varies by type and intensity of stimulus and by time from injury. Serotonergic and noradrenergic pathways contribute to modulatory effect [74,76,77].

CHRONIC LOW BACK PAIN

The standard definition of chronic pain as pain lasting longer than three months provides a temporal index, but it is not very helpful as a biologic or mechanistic index [78]. Chronic LBP not only involves the dissociation of ongoing pain from the extent of tissue harm; it also impacts numerous brain circuits by inducing massive reorganization of cortical anatomy and physiology. The extent of this reorganization is largely driven by the saliency of unrelenting pain that recruits emotion-mediating brain regions, including limbic structures, which reorganize the cortex to reflect suffering and coping strategies. This in turn alters spinal cord processes through descending modulatory pathways [79].

Development of Chronic LBP

Progression from acute to chronic LBP coincides with the development of widespread alteration in pain pathways and brain regions that modulate specific aspects of pain processing. Psychosocial factors contribute to the development and perpetuation of chronic LBP. When chronic LBP is alleviated, some brain regions and mediated functions become normalized. Other brain regions may remain impaired, in which case, clinical improvement and restoration of the patient's functional status remains difficult.

Peripheral Sensitization

Peripheral sensitization develops at the site of peripheral nerve injury, tissue injury, or inflammation. With peripheral sensitization, nociceptors' nerve endings develop lowered threshold and heightened response to tissue stimuli that trigger activation.

Central Sensitization

Central sensitization refers to the amplification of neural signaling within the CNS that elicits pain hypersensitivity. When this process is established, little peripheral input may be required to maintain a painful state [80,81].

The process of central sensitization begins when post-synaptic terminals of ascending neurons in the dorsal horn become altered by nociceptive barrage. The surge of excitatory signaling transmitters and modulators (e.g., glutamate, substance P, CGRP, BDNF) bind to receptors on spinal cord neurons and activate intracellular signaling pathways, which phosphorylate membrane channels of the glutamate receptors N-methyl-D-aspartate receptor (NMDA) and AMPA. This lowers the threshold and opening characteristics of the channels and results is increased CNS neuron excitation, substantial increase in pain transmission, and the development of central sensitization. The greatest contribution to initiation of central sensitization comes from post-synaptic NMDA receptor activation in the spinal cord and, subsequently, in the thalamus, limbic system, and cerebral cortex [82,83,84,85].

Post-synaptic NMDA receptor activation alters signaling pathways, which amplifies nociceptive responses and can induce functional antagonism to opioid analgesic effects [86,87,88]. Acting in concert with other activated ligand-gated sodium and potassium channels, NMDA receptor activation allows entry of calcium ions, which alters intracellular signal processing in chronic pain. NMDA receptor ion channels possess binding sites for NMDA antagonists used in pain medicine, such as ketamine, dextromethorphan, amantadine, and memantine [86,89].

The onset of central sensitization promotes the transition from acute to chronic LBP. The core process that underlies the development of central sensitization is neuroplasticity, the cellular process of neuronal cytoarchitecture alteration through physical remodeling. The process of neuronal cytoarchitecture alteration begins with peripheral upregulation of COX-2 and IL-1b-sensitizing neurons, which sensitize second-order spinal neurons by activating NMDA receptor acid channels and signaling microglia [90]. Brain regions become activated, including areas that mediate sensory nociceptive and pain processing, emotional processing of pain, pain modulation, pre-motor activity, and pain cognition. The cascading changes in brain circuitry enhance pain pathway sensitivity; alter sensory, emotional, and modulatory pathways; and generate new behaviors, such as increased pain sensitivity/responses, depression, and altered cognition [85,91,92].

Central sensitization is difficult to control and is best treated by combining modalities with different mechanisms to target the peripheral nociception origin and top-down (brain-orchestrated) and bottom-up (peripheral input) mechanisms. Top-down interventions include opioids and combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor drugs. Bottom-up approaches include topically applied analgesics. Interventions that target metabolic (e.g., ketogenic diets) and neurotrophic factors (e.g., decrease BDNF) are novel and promising methods to diminish CNS hyperexcitability in central sensitization. Conservative therapy with pain neuroscience education, cognitive-behavioral therapy (CBT), and exercise therapy should be included to help modulate CNS excitation [62,93,94].

Neuropathic Involvement in Chronic LBP

Neuropathic contribution to non-radicular, nonspecific chronic LBP occurs in as many as 37% of patients and should be considered in the assessment and treatment of patients with nonspecific chronic LBP. Some mechanisms and targeting in neuropathic contribution to chronic LBP include ectopic impulses, central sensitization and plasticity, low threshold A-beta fiber-mediated pain, and loss of descending modulation [95].

Ectopic impulse activity causes sudden, brief pain with lancinating or sharpening features, resulting from increased density of dysfunctional sodium channels along the nerve length. Analgesia can be achieved by the sodium channel blockers lidocaine, mexiletine, carbamazepine, and lamotrigine. The role of NMDA receptor activation in synaptic plasticity and central sensitization can be targeted with the NMDA antagonist drugs ketamine and dextromethorphan and the opioid levorphanol.

Peripheral nerves can regenerate, but sprouting errors can occur when A-beta fibers become cross-linked to C fibers, inducing severe, sharp pain in areas where pain was previously absent. Mechanisms involve sodium channel excitability and spinal cord hyperexcitability; gamma-aminobutyric acid (GABA) inhibitory drugs and calcium-channel blockers are mainly used to address this type of pain.

Loss of descending modulation results from transmitter dysregulation. Serotonin and norepinephrine modulate pain in the descending control system. Drugs that inhibit reuptake of both transmitters are more effective for pain control than sole transmitter targeting and are more likely to improve mood symptoms. This explains why serotonin and norepinephrine reuptake inhibitors (SNRIs) are more effective than selective serotonin reuptake inhibitors (SSRIs).

Psychologic Factors

The contribution of psychologic factors to chronic LBP is essential to consider, as discussed. Depressive symptoms, pain catastrophizing, and fear avoidance in LBP are thought to enhance pain facilitatory pathways in the CNS, resulting in sensitization of dorsal horn spinal cord neurons and the development of exaggerated pain perception [81]. Pain catastrophizing refers to exaggerated negative thoughts and emotions surrounding pain, and this pain coping style significantly contributes to variability in pain perception. Catastrophizing adversely impacts pain by inducing an aroused, negative emotional state that worsens pain and fosters helplessness that decreases adaptive pain responding. This promotes the alteration of neural processes related to pain attention and response. People with trauma histories are more likely to catastrophize, suggesting that catastrophizing may mediate the effects of earlier psychologic stress on pain [57].

Emotional distress, including significant anxiety and depression symptoms, increases the neurotransmission of the inflammatory mediators substance P, IL-1, and IL-6, which triggers release of corticotropin-releasing factor and elevation of systemic corticosteroid levels. This further heightens pain sensitization and contributes to pain behaviors [96]. Individual differences in acute stress response may contribute to broad pain response variations by influencing neurophysiologic mechanisms that underlie pain perception [97]. Chronic pain does not disrupt acute stress response or the sensory dimensions of pain, but induces long-term alteration in neural systems that underlie affective-motivational functions [98,99,100].

In one study, patients with subacute LBP were followed over one year, and brain images of those with resolved or persistent LBP were compared. As LBP persisted, the location of brain activity in pain perception shifted from regions involved in nociception to regions that engaged emotion-related circuitry (i.e., the medial prefrontal cortex and amygdala). LBP persistence was also associated with declining activity in acute pain regions. These findings were replicated in a comparison of patients with LBP for two months or more than 10 years. The very high correlation between LBP for 1 year and more than 10 years indicates that as chronic LBP develops during the first 12 months from onset, the brain carves a chronic pain state, making this first year a critical period for LBP chronification. Despite reorganization of pain processing and response to brain emotion circuits, baseline depression and anxiety scores in patients who progressed to chronic LBP did not differ from patients who recovered from chronic LBP scores at 12 months. Instead, the qualitative subjective properties of the pain were sufficient to shift its representation from acute pain to emotion circuitry. This was the first study to identify a brain signature for the transition to chronic LBP [101].

Neuroscience Findings

Neuroimaging evidence shows that patients with chronic LBP develop alterations in brain structure, function, and chemistry. An effort has been made to identify the neural correlates of chronic LBP in order to better understand causation, consequence, and potential interventions in at-risk patients. Functional MRI has shown reversal in some of these changes [78].

It is well established that chronic pain is linked to impairment of memory, attention span, and mental flexibility, but less well studied is whether overall cognitive function predicts risk for chronic pain. A cohort of 189 patients assessed at pre-surgery (non-spinal) and at 6- and 12-months post-surgery found a significant (and predictable) correlation between persistent pain at 12 months and poor baseline performance in cognitive flexibility, visuospatial processing, and visual memory independent of anxiety or depression. Impaired cognitive performance also predicted pain intensity and neuropathic symptoms in patients with pain, unassociated with type of surgery or pre-surgical pain. These findings suggest that patients with deficits in executive functioning or memory have a greater risk of pain chronicity after a painful event [102]. In patients with chronic LBP, the strength of functional connectivity between the medial prefrontal cortex and nucleus accumbens predicted the transition to chronic back pain one year later with greater than 80% accuracy. These elements of emotional learning circuitry predicting transition to chronic pain may help identify strategies to prevent pain chronification [103].

Other research into neural factors that contribute to chronic LBP has found that subacute pain is associated with robust changes in hippocampal functional connectivity, the nature of which influences recovery. The reorganization of processing in the hippocampus, and between the hippocampus and the cortex, appears to contribute to the transition from subacute to chronic LBP and may explain learning difficulties and emotional abnormalities associated with chronic pain [104].

Functional and structural MRI studies in patients with chronic pain have identified brain and peripheral nerve abnormalities, with some pre-existing and others resulting from prolonged pain and related neuroinflammation over time. The data suggest that some chronic LBP arises from a combination of pre-existing vulnerabilities and sustained abnormal pain input [105].

Chronic LBP is associated with abnormalities in brain structure and function, including reduced cortical gray matter in the bilateral dorsolateral prefrontal cortex (DLPFC), thalamus, brainstem, primary somatosensory cortex (S1), and posterior parietal cortex. These abnormalities are not unique to chronic LBP and are found in many chronic pain conditions. Other studies have linked the DLPFC to pain modulation, placebo analgesia, perceived control of pain, and pain catastrophizing [106]. Some of these chronic pain-associated neuroanatomical and functional changes may be reversible with effective pain control. Patients with untreated chronic LBP have shown a thinner left DLPFC with abnormal activation during cognitive-related tasks. After six months of pain alleviation, the left DLPFC became thicker, and the extent of neuroanatomic recovery was dependent on the extent of clinical improvement. Successful pain reduction also normalized cognitive task-related brain activity in the left DLPFC [107].

Heritable Factors

Data show that pain sensitivity is heritable to some degree, with genetic contribution accounting for an estimated 50% of pain variance [80]. Statistically significant genetic-mediated responses have been found to most painful stimuli, varying by pain type, with provocation of different mechanistic pathways [108]. The catechol-O-methyltransferase (COMT) enzyme metabolizes catecholamines and modulates adrenergic, noradrenergic, and dopaminergic signaling. A functional polymorphism in the gene that encodes COMT reduces its activity and has been linked to pain sensitivity. In patients with discogenic subacute LBP and sciatica, this genotype did not influence pain or disability at new-onset, but significantly increased pain and disability after six months. Thus, COMT polymorphism may contribute to protracted LBP, sciatica, and disability following lumbar disk herniation [109].

A variation in the gene encoding serotonin receptor 3B (5-HTR3B) has been correlated with high scores on pain catastrophizing, pain-related magnification, and helplessness. The 3B receptor is associated with descending pain modulation pathways, and a relationship between pain catastrophizing and a serotonin receptor polymorphism is likely [110]. High expression of polymorphism in the promoter region of the serotonin transporter gene has been linked to increased pain intensity during unpleasant affective states and decreased pain intensity during positive (but not neutral) emotional states. This polymorphism may importantly contribute to the capacity for emotional modulation of pain [111].

PATHOANATOMIC BASIS OF COMMON LBP CONDITIONS

Definitions

LBP can originate from many underlying causes. The following are the most common LBP conditions.

Lumbar (intervertebral) disk disorders: Also simply referred to as disk disorders, this includes degenerative disk disease and disk herniation.

Degenerative lumbar disk disease: Degenerative changes in the three-joint complex, comprised of the facet joints and anterior lumbar disk. Annular fissures and tears develop from repetitive microtrauma. The disk becomes vulnerable to herniation, and resultant loss of water retention ability and disk height leads to disk resorption, internal disruption and additional disk tears, and loss of mechanical integrity at the three-joint complex. Further degeneration involves additional narrowing of disk space, fibrosis, and osteophyte formation [112,113,114].

Lumbar disk herniation: Displacement of disk material (e.g., nucleus pulposus) outside the annulus fibrosus due to progressive loss of disk hydration and height and inappropriate load transfer to annulus and endplates [114].

Lumbar radiculopathy: With L4–L5 involvement, pain that radiates down the leg below the knee in the distribution of the sciatic nerve [115]. Formerly thought to result from mechanical compression by disk material, now known to be caused by nerve root inflammation from leakage of inflammatory mediators from the nucleus pulposus into the epidural space. These include cytokines, leukotrienes, nitric oxide, immunoglobulins, ILs, PGE-2, and metalloproteinases [116,117,118]. Disk herniation can be asymptomatic and may not produce radicular symptoms [114].

Lumbar spinal stenosis: Narrowing of the central or lateral recesses of the spinal canal and/or the neural foramina [119].

Neurogenic claudication: Pain enveloping the buttocks, posterior thigh, calf, and groin, often, but not always, associated with lumbar spinal stenosis [119].

Lumbar spondylolisthesis: Subluxation or slippage of one vertebral body relative to another, which may cause pain and neurologic deficit [120].

Lumbar spondylosis: Degenerative osteoarthritic changes affecting the spinal unit [121].

Myofascial pain syndrome: A regional muscle pain syndrome caused by myofascial trigger points, which are hyperirritable zones in a palpable taut band of skeletal muscle. Symptoms include local and referred pain, muscle stiffness and weakness, and sensory changes [116,122].

Facet joint pain: Pain resulting from disruption in normal architecture, biomechanics, or function of facet joints, caused by degenerative changes, injury, or mechanical strain [123].

Failed back surgery syndrome: Failed back surgery syndrome is not a single entity, but a complex syndrome with multiple potential causalities, including structural pathogenesis, improper surgical technique, altered biomechanics, and/or central sensitization [52,115].

Anatomic Pathogenesis of LBP

In the typical healthy back, the basic unit of the spine (the "functional spinal unit") includes two adjacent vertebral bodies with two posterior facet joints, an intervertebral disk, and surrounding ligaments. The disk absorbs energy and distributes weight evenly from one spinal segment to the next while allowing movement of protective bony elements [21].

The lumbar spine (L1–L5) is inferior to the twelfth thoracic spinous process and superior to the first sacral spinous process. The sacral spine is inferior to the first sacral spinous process and superior to the sacrococcygeal joint. LBP may be more specifically termed lumbosacral spinal pain, because it encompasses lumbar and sacral spinal pain. Lumbosacral spinal pain can occur in either or both regions and represents "low back pain" [21].

Radicular pain results from spinal nerve provocation by inflammatory molecules, mechanical impingement, or both, and describes pain referred to the lower extremity along the corresponding dermatome. Also called sciatica, the term "radicular pain" may be preferred because pain originates from nerve roots or the dorsal root ganglion of a spinal nerve [21].

Repetitive mechanical stress or aging can lead to progressive degenerative changes in the functional spinal unit, usually at L4–L5 with LBP present. Early degenerative changes include loss of hydration of the nucleus pulposus along with mild loss of disk height. Internal disk disruption begins with radial and/or concentric fissures from the nucleus pulposus periphery to the annulus fibrosus [21]. Lumbosacral pain can develop when the fissures or material from the nucleus pulposus extend to the peripheral annulus fibrosis, activating the sinuvertebral nerve. Radicular pain can develop when material from the nucleus pulposus extends outside the annulus fibrosis (e.g., herniated nucleus pulposus) to produce an intense inflammatory reaction by surrounding the spinal nerve.

Advanced degenerative changes are associated with dehydration of the nucleus pulposus and marked loss of disk height, osteophyte formation, and ligament thickening [21]. Central canal lumbar stenosis results from the combined effects of facet hypertrophy (enlargement) and thickening of the ligamentum flavum and posterior longitudinal ligaments. These and other degenerative changes may produce neurogenic claudication. Progressive disk or facet joint degeneration may lead to chronic lumbosacral pain, while stenosis of the spinal canal lateral recess and the intervertebral foramen produced by facet hypertrophy causes nerve root compression and radicular pain.

Myofascial Pain Syndrome

Trigger points in myofascial pain syndrome develop from direct or indirect muscle trauma and overload. Primary causative factors are usually structural or mechanical (e.g., intense exercise, sustained abnormal postures, anatomic abnormalities, joint dysfunction, chronic repetitive overuse, poor work-related ergonomics). Nonstructural factors (e.g., anxiety, sleep deprivation, fatigue, chronic infection, iron, vitamin, mineral, and endocrine deficiency states) may also be at play, often working in combination with mechanical factors. An estimated 9 million people in the United States experience myofascial pain, and myofascial pain syndrome affects up to 95% of patients with chronic pain. One study at a large pain center found myofascial pain syndrome to be the primary cause of pain in 85% of patients [124,125].

Acute myofascial pain triggered by identifiable local muscle strain has a favorable prognosis. When myofascial pain syndrome expands from local to regional pain and becomes chronic, pain is often difficult to control. Myofascial pain syndrome can resemble or co-occur with other pain conditions and present as painful, restricted range of motion, stiffness, referred pain, or autonomic dysfunction. The pain pattern reflects the involved muscle(s) [122,124,126].

Failed Back Surgery Syndrome

Failed back surgery syndrome, also termed post-laminectomy pain, refers to post-spinal surgery chronic pain with or without lower extremity radiculopathy. More than 300,000 spine surgeries are performed annually in the United States for pain relief, and up to 100,000 patients develop failed back surgery syndrome [127,128]. Recurrent disk herniation, epidural abscess, scar tissue formation around nerve roots, facet joint syndrome, or muscle spasm may contribute to the clinical features of failed back surgery syndrome [29]. In patients with previous fusion surgery and worsening axial back pain, additional wear and tear on the facet joints and disks directly above and below the fused segment(s) can generate significant pain. Patients with persistent radicular pain often have chronic nerve injury requiring treatment for neuropathic pain. Clinical assessment should attempt to clarify the original LBP condition, the surgical approach, and whether the chronic LBP is recurrent or new-onset pain requiring further evaluation [116].

6. ASSESSMENT AND DIAGNOSIS

Roughly 85% of LBP lacks apparent etiology and is termed nonspecific. Clinical practice guidelines for LBP recommend assessment of new patients by triage, with LBP grouped as nonspecific, potentially serious, associated with radiculopathy or spinal stenosis. Several LBP syndromes and conditions have been studied with radiographic imaging (usually MRI) in an effort to establish causality. These include lumbago, myofascial syndrome, muscle spasm, mechanical LBP, lumbar strain, facet joint dysfunction, and bulging lumbar disk. No specific, defining radiographic abnormality has been identified. These conditions, often presenting as acute LBP, are considered vague and nonspecific, and imaging studies are of limited value in establishing the cause, directing therapy, or predicting the clinical course. As an example, many persons with lumbar spine degenerative change or disk protrusion evident on MRI are not experiencing LBP. Thus, some abnormalities detected by MRI are nonspecific and of uncertain relevance to the patient's complaint. A diagnostic imaging workup does not improve clinical outcomes in most patients with acute LBP [42].

While most LBP cases lack serious pathology, each case is deserving of a careful clinical assessment for symptoms and signs (termed "red flags") associated with serious pathology. Patients with red flags are redirected to urgent diagnostic workup and intervention. Patients without red flags should be assessed for the possibility of radiculopathy and lumbar spinal stenosis, which, with diagnostic confirmation, may require early specialist referral. LBP may be classified as nonspecific when there are no red-flag indicators, radiculopathy, or suspicion of lumbar spinal stenosis. Once red flag indicators are excluded, all patients should be evaluated for risk factors of poor prognosis and chronicity ("yellow flags"). Patients with yellow flags should receive psychosocial intervention to minimize chronification and disability. Patients with painful recurrence following LBP remission require assessment of new-onset LBP [37,47,115,116,129].

HISTORY AND PHYSICAL EXAM

Red Flag Assessment

Red flag assessment during history and physical exam identifies the subset of patients who may have serious pathologic conditions that require urgent diagnosis and therapeutic intervention. Such conditions include vertebral osteomyelitis, epidural space infection, tumor, osteoporosis, fracture, structural deformity, inflammatory disorder, or cauda equina syndrome. Because some red-flag conditions have low prevalence or less risk from delayed or missed diagnosis, some signs are more important to assess than others. A more focused red flag assessment is recommended, narrowed to identify malignancy, fracture, cauda equina syndrome, and vertebral infection (Table 2) [36,130,131,132].

Table 2: RED FLAG ASSESSMENT IN PATIENTS WITH LOW BACK PAIN

Possible Etiology

Red Flags

Malignancy

History of or current cancer diagnosis

Systemically unwell

Unexplained weight loss in the past six months

Constant, progressive, nonmechanical pain

Altered sensation from trunk down

Vertebral fracture

Age older than 70 years

Significant age-relative trauma

Long-term corticosteroid use

Altered sensation from trunk down

Pain worse with flexion, pulling up from supine to sitting position, and from sitting to standing

Cauda equina syndrome

Acute-onset urinary retention

Loss of anal sphincter tone or fecal incontinence

Saddle anesthesia

Widespread (more than one nerve root) or progressive motor weakness in legs

Gait disturbances

Vertebral infection

Systemically unwell

Constant, progressive, nonmechanical pain

Recent bacterial infection or spinal region wound

Intravenous drug abuse

Immunosuppression from steroids, transplant drugs, or HIV

Altered sensation from trunk down

Source: [36,130,131,132]

History

When evaluating back pain, it is important to ask patients about current pain characteristics, including pain severity; the time and event of onset; postures or activities that worsen or lessen pain; and occupational, social, and activity limitations from pain. The patient's prior history of systemic disease (e.g., osteoporosis, cancer, arthritis, infection), history of trauma, immunosuppression, constitutional symptoms, substance use, and previous back pain, including symptoms, diagnosis, testing or imaging results, treatment, and response, should be noted [35,36,47,133]. Possible origin outside of the spine should be considered, including pancreatitis, nephrolithiasis, aortic aneurysm, or systemic disease, such as endocarditis or viral syndromes. Sensory and motor changes may also provide insight into the underlying cause of back pain, and the pattern and nature of any lower extremity symptoms, gait abnormalities, and/or presence of significant neurologic deficits or bowel or bladder dysfunction should be explored.

As discussed, yellow flags are risk factors for poor treatment response and progression to chronic LBP and should be assessed in all patients. High-risk patients require psychosocial therapy because most interventions are ineffective in facilitating return to work following extended disability leave for LBP [35,36,37,38,47,116,133,134].

Physical Examination

All patients presenting with LBP should be observed for posture, seating position, spinal contour, and skin discoloration. The spine should also be palpated for tenderness. A thorough neurologic exam can help to identify spinal level and nerve root involvement. The exam should include [36,47,135,136]:

- Gait:

- Heel walking (L4–L5)

- Toe walking (S1)

- In standing position:

- Movement testing, flexion and extension

- Trendelenburg test (L5)

- Repeat toe raise (S1)

- In sitting position:

- Patellar reflex (L3–L4)

- Quadriceps power (L3–L4)

- Ankle dorsiflexion strength (L4–L5)

- Great toe extension (L5)

- Flexion strength (S1)

- Plantar response

- Upper motor test

- Kneeling position:

- Ankle reflex (S1)

- Supine lying position:

- Passive straight leg raise

- Prone lying position:

- Femoral nerve stretch (L3–L4)

- Gluteus maximus power (S1)

- Saddle sensation testing (S2–S4)

- Passive back extension (using arms to elevate upper body)

- Dermatomes

In addition, there is a group of physical signs that may indicate an underlying non-organic or psychologic basis for LBP. This group of signs, termed Waddell signs, includes [37]:

- Non-anatomic superficial tenderness

- Positive simulation tests (i.e., pain from axial loading and en bloc rotation)

- Non-positive tests with distraction (e.g., no pain with full knee extension while seated, but supine straight leg raise is markedly positive)

- Non-anatomic motor or sensory loss

- Verbal over-reaction or exaggerated body language

If three or more of these signs are positive, this suggests psychogenic contribution to LBP; at least two positive signs suggests poor surgical but not rehabilitation outcome, subjective pain reporting unreliable for evaluation of therapy response, and risk of disability. It is important not to label positive findings as malingering [37].

DIAGNOSTIC IMAGING AND TESTING

As noted, MRI is highly sensitive but often nonspecific in identifying back pain causation [137]. As such, MRI and x-ray are widely discouraged from use in the assessment of nonspecific acute LBP [36,47,131,136]. In the past, spinal MRI of asymptomatic persons was considered valuable for early detection and intervention of back problems invariably leading to pain. However, this has been dispelled by findings of highly prevalent MRI-detected spinal abnormalities in persons without LBP history (Table 3) [138,139,140,141,142,143]. In one study, asymptomatic persons with MRI-detected disk herniation were followed, and imaging abnormality lacked prediction of pain development [144]. In another study, patients with symptomatic lumbar disk herniation were treated conservatively and followed. Nearly all showed further disk degeneration, but baseline MRI findings were unrelated to pain continuation [145].

Table 3: PREVALENCE OF MRI-DETECTED SPINAL ABNORMALITIES IN PERSONS WITHOUT A HISTORY OF LOW BACK PAIN

MRI Finding

Frequency of Finding

Disk bulge

24% to 53%

Disk protrusion

20% to 63%

Disk extrusion

1% to 18%%

Any disk pathologya

57% to 64%

Nerve root deviation or compression

4%

aAny bulge, protrusion, extrusion, or sequestration

Source: [138,139,140,141,142,143]

Evidence Based Practice Recommendation

The American College of Radiology asserts that imaging patients with acute low back pain of less than six weeks' duration and no red-flag symptoms provides no clinical benefit. Numerous studies have shown that routine imaging is not beneficial, and the majority of disk herniations reabsorb or regress by eight weeks after symptom onset.

https://acsearch.acr.org/docs/69483/Narrative

Last Accessed: July 28, 2019

Strength of Recommendation: 2 (Usually not appropriate)

In the first visit, the use of imaging studies should be limited to suspected red-flag conditions. To minimize diagnostic and interpretation errors, imaging should only be ordered by clinicians with the skills to organize and interpret radiographic and MRI images [146].

MRI and computed tomography should be reserved for persistent pain and evidence of radiculopathy or lumbar spinal stenosis when surgery or epidural steroid injections are considered. Nerve root, facet joint, medial branch, or SI joint blocks lack sufficient evidence as LBP diagnostic procedures. However, medial branch nerve block has been recommended for diagnosing facet joint pain prior to radiofrequency denervation [146].

LABORATORY TESTS

Laboratory tests can help confirm suspicion of spinal infection or tumor. With spine infection, laboratory testing is low in specificity, and diagnostic confirmation requires MRI and, frequently, biopsy [131].

ENHANCING ASSESSMENT AND DIAGNOSIS

Efforts to improve outcomes in patients with LBP have included a focus on assessment and diagnosis, and specifically on identifying more accurate prognostic factors and subgrouping of patients categorized as having nonspecific LBP.

Subgrouping Patients with Nonspecific LBP

Many believe the current "one-size-fits-all" approach for nonspecific LBP contributes to poor patient outcomes because nonspecific LBP is not a homogeneous condition. This has prompted efforts to identify meaningful, clinically relevant typologies for patient subgrouping. Several approaches have been validated and published, with the goal of improving treatment outcomes through better disease-treatment matching.

Most guidelines for chronic LBP recommend a diagnostic triage to group patients by nonspecific, specific, and radicular LBP. This differentiation is not straightforward; patients with disk herniation are either grouped as specific with radicular pain or nonspecific with degenerative disk disease without radicular pain. Also, the definition of radicular pain is inconsistent.

To address these and other limitations with the triage approach, an alternative classification system for chronic LBP was developed to differentiate patients with pain of nociceptive, peripheral neuropathic, or central sensitization origin using a mechanism-based classification of LBP signs and symptoms [147]. The system was developed and validated using data from 464 patients with a range of back and leg symptoms; the majority had pain duration longer than three months (chronic). Factors with the greatest predictive ability for each of the three back pain mechanisms include [147,148,149]:

Nociceptive Pain

- Clear and proportionate mechanical/anatomical nature to aggravating and easing factors

- Usually intermittent and sharp with movement or mechanical provocation

- At rest, tends to be a constant dull ache or throbbing pain

- The absence of dysesthesia, disturbed sleep, antalgic postures, and pain of a burning, shooting, or electric shock-like quality

Peripheral Neuropathic Pain

- Pain referred in a dermatomal or cutaneous distribution

- History of nerve injury, pathology, or mechanical compromise

- Pain or symptom provocation with mechanical or movement tests that move, load, or compress neural tissue

Central Sensitization

- Disproportionate, nonmechanical, unpredictable pattern of pain provocation by multiple nonspecific aggravating or easing factors

- Pain disproportionate to the extent of injury or pathology

- Strongly associated with maladaptive psychosocial factors, such as negative emotions, poor self-efficacy, and maladaptive pain beliefs and behaviors

- Diffuse non-anatomic areas of pain tenderness on palpation

Building on this classification system, Vining et al. developed an evidence-based clinical tool for application in the assessment and diagnosis of patients with LBP (Table 4) [147,148,149,150,398]. This tool was created to help fulfill the unmet need for an easily applied diagnostic classification system based on the underlying pain mechanism, especially with nonspecific LBP [150].

Table 4: LOW BACK PAIN DIAGNOSTIC CATEGORIES AND KEY INFORMATION

Category

Definition

Key Findings

Diagnostic Standard Used

Screening

Findings indicating recent injury, special testing, referral, or need for emergent evaluation

Evidence of possible fracture, progressive neurologic deficit, infection, tumor, or other etiology

N/A

Functional instability

Disruption of neuromuscular control of a spinal joint neutral zone during normal physiologic demand

Positive prone passive lumbar extension

Hypermobile lumbar segment(s)

Absence of hypomobile lumbar segment

Radiographic measurements of intervertebral motion

Nociceptive (pain from noxious stimulation of peripheral tissues)

Discogenic

Pain from the posterior annulus and near the endplate

Centralization with repeated end-range loading

Any two: Centralization with repeated motion, vulnerable/apprehensive when stooped, lumbar extension loss

Lumbar discography

Sacroiliac joint

Pain from the sacroiliac joint and/or supporting ligaments

Sacroiliac joint area pain with three or more positive findings on: Gaenslen left and right, thigh thrust, sacral thrust, iliac comp, distraction tests

Fluoroscopically guided, controlled anesthetic block

Zygapophyseal joint

Pain from zygapophyseal joint structures, including the joint capsule and subchondral bone

Three or more: Age older than 50 years, relief by walking, relief by sitting, paraspinal onset, positive extension-rotation test

Fluoroscopically guided, controlled anesthetic block

Myofascial

Pain from muscles, tendons, and/or fascial tissue in the low back

Pain with use of involved muscle and trigger points

None

Neuropathic (pain from peripheral or central nervous system tissues)

Compressive radiculopathy

Pain from compression and inflammation of a nerve root

Absent ankle/knee reflex

Pain worse in lower extremity than in back

Dermatome distribution (cough, sneeze, straining)

Paresis (extremity motor strength loss)

Finger to floor distance >25 cm

Clinical findings in individuals with nerve root compression confirmed by MRI

LANSS score >12

Expert opinion

Non-compressive radiculopathy

Pain from compression, stretch and/or inflammation of peripheral nerve structures

LANSS score >12

Expert opinion

Compressive radiculopathy criteria are not met

N/A

Neurogenic claudication

Pain from ischemia/compression of individual nerve roots, the cauda equina, or the spinal cord

Age older than 60 years

Activity induced lower extremity pain with relief upon forward bending or rest

Symptoms worsened by standing or extension

Urinary incontinence

Expert opinion

Negative ABI

Doppler ultrasound

Central

Pain from a lesion or dysfunction within the central nervous system

Disproportionate pain

Unpredictable symptom aggravation and relief

Maladaptive psychosocial factors

Non-anatomic distribution

Expert opinion

Other

Other diagnoses

Diagnoses not categorized above

Dependent on suspected condition

N/A

ABI = ankle-brachial index, LANSS = Leeds assessment of neuropathic symptoms and signs pain scale, MRI = magnetic resonance imaging.

Source: Reprinted from Vining R, Potocki E, Seidman M, Morgenthal AP. An evidence-based diagnostic classification system for LBP. J Can Chiropr Assoc. 2013;57(3):189-204, with permission from the Journal of the Canadian Chiropractic Association.

Non-radicular chronic LBP was long assumed to be the prototype of the chronic nociceptive pain state. However, neuropathic pain can also result from injured afferent nerves, and back pain, including axial back pain, is now known to involve neuropathic pain components, making it a mixed pain syndrome with overall pain perception from both nociceptive and neuropathic mechanisms [151]. This mechanistic heterogeneity indicates a more complex framework than previously assumed and may explain the often-disappointing results with pharmacotherapy. Better approximation of the mechanistic contribution may be gained from a symptom constellation approach to assessment. Such an approach was evaluated in 7,772 patients with LBP (37% of which showed neuropathic pain as the dominant pain component) and 1,083 patients with axial LBP (of whom 12.1% showed sensory symptoms consistent with neuropathic pain). Five LBP subgroups were identified with distinct mechanistic and sensory profiles [152].

The largest subgroup (26%) displayed a lack of distinct sensory abnormalities and few sensory symptoms. Another subgroup (21%) reported a predominance of lumbar region "pain attacks," whereby lumbar spine movement induces severe lumbar pain lasting several seconds. Pain is evoked by ectopic discharges originating from sensitized nerves, such as those innervating facet joints and outer intervertebral disk layers. Pressure to the vicinity of afflicted nerves stimulates release of pro-inflammatory cytokines and neurotrophins, producing synergistic mechanical and chemical irritation to annulus fibrosus cells.

In a third group (21%), pain was primarily experienced as a dull and aching quality localized in the back. This nociceptive back pain is evoked by noxious stimulation of deep somatic structures in the lumbar spine, induced by the ingrowth of small nociceptive nerve fibers into degenerated intervertebral disks. Lumbar muscles are explicitly tender to pressure stimuli due to the musculoskeletal basis of the pain.

The last two groups experienced LBP characterized by burning and prickling sensations, reflecting an isochronic occurrence of neuropathic and nociceptive pain components. With intervertebral disk damage, the disk is invaded by blood vessels and small nociceptive nerve fibers. Macrophages secrete pro-inflammatory cytokines, TNF-α, and other neurotrophins that act as growth factors. Nociceptive fibers sprout from the outer part into the inner areas of the disk, including the nucleus pulposus. Axonal sprouts within diseased disks become damaged from compressing forces and irritated by contact with inflammatory agents, and these damaged afferent fibers in the disk develop neuropathic pain mechanisms reflected by neuropathic symptoms.

Data on these "nonspecific" subtypes suggest that sensory profiles based on descriptor severity may be more accurate than pain intensity alone, especially with different underlying mechanisms operating in tandem. These phenotypic differences in sensory profiles and comorbidities may explain inconsistent treatment response and assist in tailored individualized therapy for patients.

Prognostic Factors

Yellow flag assessment is widely used and necessary, but some have argued insufficient, to identify patients at high risk of progression to chronic pain and disability. This has prompted research to identify additional risk factors of chronic pain and disability.

To improve outcomes in the primary care of patients with LBP, a newer approach places patients into three subgroups based on core modifiable predictors of chronicity. This allows delivery of targeted treatment to intervene and alter the clinical course. A central feature for risk identification and subgroup placement is the Keele STarT Back tool, a validated instrument that includes nine items related to physical and psychologic predictors of chronicity. The scores place patients into low-, medium-, or high-risk categories. A six-item version was also developed for primary care use and identifies patients as either low risk or not low risk of chronicity. During the initial primary care contact, patients with low risk of chronicity should receive reassurance, education, and advice and be told to return if pain persists. Those scoring as not low risk are referred to a physiotherapist and are scored using the longer instrument. Medium-risk patients receive physiotherapy to address pain and disability, and high-risk patients receive additional cognitive-behavioral approaches that address psychosocial obstacles to recovery [153].

7. TREATMENT OPTIONS

Standard clinical practice guidelines for LBP are organized around the assumption of favorable prognosis, spontaneous resolution of most acute LBP cases, and conservative care dictated by the benign clinical course [54]. This assumption of benign prognosis is disputed by more recent data, which also stress the importance of earlier, more aggressive intervention to minimize the development of chronic LBP.

It is increasingly clear that nonspecific LBP is not a homogeneous condition, and "one-size-fits-all" treatment for nonspecific LBP may contribute to unsatisfactory outcomes for many patients. As discussed, several approaches to nonspecific LBP subgrouping have been validated and published, with the goal of improving treatment outcomes through better patient-therapy matching.

TREATMENT OF ACUTE AND SUB-ACUTE LBP

Clinical practice guidelines usually structure recommendations for LBP management by time from onset, with acute pain duration less than 4 to 6 weeks, sub-acute pain 6 to 12 weeks, and chronic pain longer than 12 weeks. During initial and all follow-up visits, pain level should be measured using a 0–10 point numerical rating scale to help monitor pain progression, remission, and treatment response [47]. The Oswestry Low Back Pain Disability Questionnaire may be considered to assess perceived level of disability related to functional limitation [37]. Patients should be asked if pain interferes with daily activities or impacts/changes social functioning, sleep, sexual activity, or weight [47].

Most patients with back pain report receiving limited information on self-management. Patients should receive sufficient information and resources, such as links to online audio and literature resources, paper-based information, and healthcare organizations specializing in pain or spinal disease that may be contacted for assistance by phone. With the burden imposed by LBP, direct support, reinforcement, and frequent primary care contact are often most important [146].

In the absence of red flags or radiculopathy, acute LBP is a condition and not a diagnosis. It is treated nonspecifically with pharmacotherapy, physical therapy, and advice on self-management. If LBP is severe or persistent, the underlying cause should be diagnosed to facilitate its management [47].

Acute LBP

Nonspecific Acute LBP

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, clinicians should advise patients with acute and subacute low back pain to stay active and continue activities of daily living within the limits permitted by their symptoms.

https://www.icsi.org/wp-content/uploads/2019/01/March-2018-LBP-Interactive.pdf

Last Accessed: July 29, 2019

Strength of Recommendation/Level of Evidence: Strong Recommendation/Moderate Quality Evidence

When a patient presents with LBP of less than four to six weeks, the mainstays of management are patient education, reassurance, and advice on self-management. Patients should be assured that prognosis is generally good, often resolving with little intervention. Self-care recommendations include [1,36,37,47,129,131]:

- Stay active, avoid bed rest, and return to normal activities as tolerated.

- Avoid twisting and bending.

- Use heat or ice packs, whichever provides the most comfort.

Analgesic medications may be used, and the selection is determined by pain severity. Except for minor pain, medications should be prescribed on a time contingent (every four to six hours) and not a pain contingent (as needed) basis. Most patients should start with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen; a muscle relaxant may be added, based on pain severity. With severe pain, a short course of opioid therapy may be warranted [1,36,37,47,129,131].

Spinal manipulation may be helpful for some patients. If it is not the first episode of LBP, physical therapy (e.g., McKenzie method, spine stabilization) should be considered.

In patients at risk for chronic LBP (i.e., who have yellow flags), discuss and address barriers to treatment success. These patients should avoid time off of work, if possible, and minimize activity restrictions. Short-term accommodations in the workplace may be discussed with employers [1,36,37,47,129,131].

If pain is not significantly improved after two to four weeks, the patient may switch to a different NSAID. If not done after the first visit, consider physical therapy or spinal manipulation. Adding a muscle relaxant or short-term (two weeks or less) benzodiazepine therapy may be considered. If pain persists in patients at risk for chronic disability, refer to a back pain specialist after two weeks or a multidisciplinary pain program after six weeks.

Acute/Sub-Acute Lumbar Disk Herniation with Radiculopathy

Pain from radiculopathy requires a unique care pathway, because patients can be in severe pain that often poorly responds to basic analgesics and neuropathic pain medications [37,146,154]. Earlier treatment may result in greater improvement, while delayed medical, physical, interventional, or surgical treatment may increase the risks of delayed recovery, chronic pain, and disability [118]. In those with severe pain and impairment, earlier referral (within two weeks of presentation) is probably most helpful [146].

At the first office visit, patients with less severe radicular pain may benefit from standard management. Patients should be advised that lumbar radiculopathy takes time to resolve, but 50% of cases improve by six weeks and 90% recover without surgery [37,146,154]. Bed rest for five or fewer days may be needed, but longer rests delay recovery. Remaining tolerably active and gradually returning to normal activities as one's condition improves speeds recovery.

The best positions/activities for patients with acute lumbar radiculopathy are those where they remain comfortable. Spinal manipulation may be helpful as well. Muscle relaxants can be useful, but patients with severe pain may require short-term opioid therapy [37,146,154].

If no improvement is noted after one to two weeks, the neurologic exam screening should be repeated to assess for new or worsening weakness. If the pain is not severe, physical therapy (McKenzie exercises) and/or specialist referral should be considered. Patients should be advised to view physical therapy as a learning opportunity, with the eventual goal of self-management at home. If no relief is noted after four to six physical therapy sessions, the treatment plan should be changed or physical therapy should be discontinued [37,146,154].

If pain continues for three or more weeks without improvement, an MRI should be ordered; if not diagnostic, an electromyogram (EMG) should be ordered. If pathology is proven by MRI/EMG, the patient should be referred for evaluation by a surgeon. If pathology is not proven by MRI/EMG, the patient should be referred to a back pain specialist. If strict criteria are met, epidural steroid injection may be considered [155]. These criteria will be discussed in detail later in this course.

Sub-Acute LBP

Nonspecific Sub-Acute LBP

In terms of physical and exercise therapy for nonspecific sub-acute LBP, the emphasis is on progression to normal functioning through aerobic conditioning, postural correction, and flexibility exercises. Physical therapy is recommended to optimize core strengthening and muscular stability by improving strength and endurance; neuromuscular control; proper load balance between trunk, pelvis, and legs; and soft tissue flexibility [36,37,47,115,156,157].

A multidisciplinary pain program or functional restoration with CBT is recommended to reduce work absenteeism from LBP. Patients with high disability and/or psychologic distress who lack response to one or more less intensive therapy should be referred to a specialist [36,37,47,115,156,157].

Over-the-counter analgesics are the first-line therapy for pain control. Alternative options include manual therapy and/or spinal manipulation, acupuncture, and participation in a multidisciplinary pain program. If over-the-counter analgesics are ineffective, a COX-2 inhibitor and/or weak opioid may be used. A tricyclic antidepressant (TCA) (e.g., amitriptyline, imipramine, nortriptyline, desipramine) or a short-term benzodiazepine trial may be added for continued pain despite other therapies. Strong opioids may be warranted for short-term use in severe pain, with specialist referral for patients requiring prolonged strong opioids [36,37,47,115,156,157]. CBT is effective in reducing duration of disability.

Any persistent, severe nonspecific LBP despite optimal care should initiate specialist referral to assess for suitability for invasive interventions. Appropriate care is required for any significant psychologic symptoms before surgery. Within the first three months of pain, surgery only benefits patients with severe spinal disease or debilitating symptoms and physiologic evidence with imaging confirmation of specific nerve root compromise.

TREATMENT OF CHRONIC LBP

In most patients presenting with chronic LBP, pain generation has expanded beyond the original peripheral spinal origin to involve a network of peripheral and CNS pathways and structures. In many cases, pain continues unabated despite resolution of the original peripheral tissue insult. For a minority of carefully selected patients, injection-based therapies can bring short-term pain relief, but multidisciplinary care is required for long-term improvement in pain and function.

All patients with chronic LBP should be provided with evidence-based information and advice to remain active and to use self-care options [36,47,156]. Patients with chronic back pain should receive multi-modality therapy, with medications used in conjunction with back care information and self-management. Many patients benefit from acetaminophen or NSAIDs, the first-line suggestions. With all analgesics, potential benefits should be weighed against risks and patient comorbidity. Interventional therapies are recommended only for symptomatic pain relief, with full discussion of the potential benefits, risks, and evidence with each suggested approach.

Nonspecific Chronic LBP

All patients with non-radicular LBP who lack response to standard therapies should be considered for intensive multidisciplinary pain programs with a CBT emphasis [47,115,158]. However, less intensive multidisciplinary pain programs (<100 hours) lack benefit beyond usual care or unimodality rehabilitation.

Functional restoration is more effective than standard physical therapies, exercise programs, spinal manipulation, and exercise therapy plus behavioral therapy for reducing time lost from work. It is important for functional restoration to include a CBT component. Exercise therapy that includes individual tailoring, supervision, stretching, and strengthening may be prescribed [47,115]. Massage may also be helpful.

Pharmacotherapies with proven efficacy include [47,115]:

- NSAIDs

- Norepinephrine reuptake inhibitors

- Oral mu agonist opioids

- Tramadol

- Short-term benzodiazepine trial

- Duloxetine

- Topical lidocaine patch

- Muscle relaxants (e.g., tizanidine)

- TCAs

In addition, the following alternative/complementary therapies have been suggested as beneficial [47,115,158]:

- Harpagoside (a molecule derived from the Harpagophytum procumbens root)

- Salix alba (white willow bark)

- Neuroreflexotherapy

- Acupuncture

- Yoga

- Transcutaneous electrical nerve stimulation (TENS) (as part of a multimodal approach)

Specific Spine Conditions

Lumbar Spinal Stenosis

Depending on the intensity of the pain associated with lumbar spinal stenosis, NSAIDs, short-acting or extended-release/long-acting opioids, muscle relaxants, antiepileptics, SNRIs, and/or TCAs may be prescribed [47,116,119,158,159,160]. Patients should be advised to avoid spinal extension and nerve root tension from exercise. When the pain is subacute, patients may undergo lumbar stabilization focusing on flexion-based exercises, pelvic posture correction, and core strengthening to prevent excessive lumbar extension and promote hamstring relaxation. Lumbar corsets to provide support and maintain a slightly flexed posture should only be used intermittently [47,116,119,158,159,160]. Alternative approaches, such as acupuncture, manual therapy, and TENS, should be considered. For persistent disabling leg pain, a decompression surgery consult may be necessary.

If neurogenic claudication is also present, lumbar epidural steroid injections may be used for short-term pain relief [155]. When walking limitations are present, gabapentin may be effective.

Myofascial Back Pain

The goal of treating myofascial back pain is symptom relief, trigger point inactivation, and resolution of perpetuating factors [122,161,162]. Potentially effective noninvasive modalities include manual therapy, stretching, heat/ice, ultrasound, electric stimulation, microcurrent therapy, and laser therapy. Stretching, strengthening exercises, massage, and iontophoresis may also be helpful.

The pharmacotherapy with the strongest evidence for myofascial pain is benzodiazepines combined with ibuprofen or amitriptyline (not as monotherapy) [122,161,162]. Second-line options include topical methyl salicylate, menthol, and diclofenac patch. Although antiepileptics, antidepressants, muscle relaxants, NSAIDs, and tramadol are widely used, they are largely lacking evaluation.

Trigger point injection with local anesthetic may also be used [116,158]. Efficacy depends on accurate identification of trigger points and needle placement and is enhanced by physiotherapy. There is less injection pain with lidocaine 0.25% than 1%, with comparable efficacy. Botulinum toxin may also be effective in treatment-resistant trigger points. The addition of a steroid to the local anesthetic is common but lacks supportive evidence and should be avoided due to risks of muscle necrosis, skin depigmentation, and other adverse events. Long-term pain relief requires resolution of underlying pathology, such as abnormal posture/muscle imbalance, depression, anxiety, sleep disturbance, metabolic abnormalities, psychosocial stressors, and fear avoidance behavior [122,161,162].

Failed Back Surgery Syndrome

Evidence Based Practice Recommendation

According to the American Society of Interventional Pain Physicians, spinal cord stimulation is indicated in chronic low back pain with lower extremity pain secondary to failed back surgery syndrome, after exhausting multiple conservative and interventional modalities.

https://www.painphysicianjournal.com/2013/april/2013;16;S49-S283.pdf

Last Accessed: July 29, 2019

Level of Evidence: Fair (Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, size, or consistency of included studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes)

As noted, failed back surgery syndrome is not a single entity, but a complex syndrome of multiple potential etiologies, including poor surgical technique, mechanical factors, central sensitization, or a combination. Successful identification of the pain mechanism and pain control outcome is best achieved by assessing the time frame of symptom development [115]. Spinal cord stimulation is recommended [115].

Other Conditions

Implantable intrathecal opioid infusion and spinal cord stimulation are recommended for severe, intractable LBP [4]. For patients with facet joint pain, radiofrequency denervation is recommended when previous diagnostic or therapeutic injection of facet joint or medial branch nerve have provided temporary relief [47,146,158]. Facet joint injection is not recommended [47,133,163,399].

Neuropathic Chronic LBP

The Canadian Pain Society recommends a fourth group of medications for patients with neuropathic LBP lacking benefit or tolerability to TCAs or gabapentinoids (first-line), SNRIs or topical lidocaine (second-line), or tramadol/traditional opioids (third-line) [164]. This group includes cannabinoids, methadone, mexiletine, clonidine, the SSRIs citalopram or paroxetine, and the anticonvulsants lamotrigine, topiramate, or valproic acid.

Intravenous lidocaine is recommended in patients unresponsive to oral analgesic therapy [4]. A trial of 5–7.5 mg/kg may provide pain relief from several hours to four weeks. Alternatively, intravenous ketamine is recommended for short-term pain relief. If used, it should be infused in a hospital setting under specialist care.

Considerations for Analgesia in Elderly Patients

Acetaminophen is recommended for initial and ongoing treatment of persistent musculoskeletal back pain in older patients [165]. There is a strong recommendation against the use of NSAIDs, amitriptyline, and imipramine due to the possible adverse effects. Systemic corticosteroids should only be used in pain from systemic inflammatory disease or metastatic bone pain.

Opioids are recommended for most elderly patients with moderate-to-severe pain, pain-related functional impairment, or diminished quality of life due to pain [165]. If opioids are warranted, around-the-clock dosing should be used to achieve steady-state in frequent or constant pain. If extended-release/long-acting opioids are used, it is vital to anticipate, assess, and prevent breakthrough pain or add short-acting or immediate-release opioid formulations. Do not exceed safe acetaminophen or NSAIDs limits with fixed-dose opioid combination agents [165].

Nonpharmacologic therapies and adjuvant analgesic drugs should be considered for all elderly patients with neuropathic back pain or refractory chronic LBP to enhance analgesia. In cases of localized neuropathic or non-neuropathic chronic LBP, consider topical NSAIDs or lidocaine. For regional back pain syndromes, capsaicin, menthol, or other topical agents may be beneficial. Clinicians are advised to cautiously consider glucosamine, chondroitin, cannabinoids, botulinum toxin, alpha-2 adrenergic agonists, calcitonin, vitamin D, bisphosphonates, and/or ketamine for specific pain syndromes.

NON-DRUG THERAPIES

Mattress Type

For chronic LBP, a randomized controlled trial found that a medium-firm mattress was superior for pain while lying in bed and was associated with greater improvement in pain-related disability after 90 days compared to a firmer mattress [166].

Patient Education

Educating patients with LBP about their condition and treatment options is essential in order to reduce misconceptions of therapy and, ultimately, to reduce disability. Education facilitates communication and allows the clinician to understand patient needs, goals, and beliefs or attitudes that can impose barriers to recovery. Addressing patient needs and goals can include discussion of pain concerns, rehabilitation options, pharmacotherapy, and smoking cessation. Education is also important for helping patients attain optimal pain outcomes. Without slow titration and education on prescribed drugs, patients are likely to abandon even the most established, high-evidence drugs when adverse effects begin [95,167].

Therapeutic Pain Neuroscience Education

With central sensitization present in chronic LBP, the brain produces pain, fatigue, and other "warning signs" of tissue harm without actual tissue damage or nociception. Explaining the mechanism of central sensitization with evidence from neuroscience to patients with chronic LBP is a therapeutic strategy known as therapeutic pain neuroscience education or TPNE [93,94].

TPNE helps patients with chronic pain understand their pain and make sense of the lack of objective biomarkers or imaging findings. A main goal is changing pain beliefs through the reconceptualization pain. This involves patient knowledge that pain persists without tissue damage, is disproportionate to tissue damage and/or that tissue damage (and nociception) does not by itself result in pain. The distinction between "hurting versus harming" is addressed [93,94].

Exercises and physical activity are introduced under time-contingent (e.g., perform for five minutes regardless of pain) instead of symptom-contingent (e.g., stop when painful) conditions. Research shows that symptom-contingent approaches can facilitate brain production of nonspecific warning signs, while time-contingent approaches can deactivate brain-orchestrated top-down pain facilitatory pathways. Reduced CNS hyperexcitability and increased prefrontal cortical volume have also been found in response to time-contingent therapy [168,169].

To reconceptualize pain and convince patients that CNS hypersensitivity, rather than tissue damage, is the likely cause of pain symptoms, TPNE is delivered in two to three sessions over two to three weeks. Potential patient misunderstanding of being told the pain is "all in their head" can be prevented by front-end coverage of pain neurophysiology and chronic pain, before discussing potential sustaining factors such as emotions, stress, illness perceptions, pain cognitions, and pain behavior [170].

Cognition-Targeted Neuromuscular Training

TPNE is optimally used in tandem with a time-contingent, cognition-targeted approach to daily activity and exercise therapy to address pain beliefs and cognitions before, during, and after exercise therapy. Neuroscience-informed exercise for chronic LBP involves a cognition-targeted neuromuscular training approach incorporating several modifications to conventional physical therapy that have been shown to improve patient outcomes. As noted, all exercises should be performed in a time-contingent instead of symptom-contingent manner. Progression to the next exercise level can be preceded by motor imagery for retraining brain circuitry responsible for successful execution of the targeted movement. The physical therapist should address patient pain cognitions to help patients attain positive perceptions about their pain, treatment, and exercise outcome. Discussion of patient perceptions about each exercise should include anticipated consequences (e.g., pain increase, further low back damage) and should challenge patient cognitions concerning the exercises. Pre-exercise communication reinforces the principles of TPNE and their application [93,94,171].

Patient Self-Management

Improving patient self-management is considered an important goal to decrease patient burden and service utilization. Patient self-management involves strategies to manage and monitor spinal health, assume a primary role in LBP management, and learn skills for daily use in managing back pain. Self-management of LBP is nearly universal in clinical practice guidelines for back pain, but patients often do not appreciate the improvements in their condition resulting from this approach [172].

In a meta-analysis of 13 randomized controlled trials of self-management in LBP, average improvement was calculated using a 0–100 scale. Evidence shows that patients with chronic LBP require a 20% to 30% pain and disability reduction to view an intervention as worthwhile, and the average improvement with self-management was 6% [173]. Therefore, patients are unlikely to consider the benefits from self-management efforts as meaningful. The small benefit in pain and disability challenges treatment guideline endorsement of self-management for LBP [172].

Exercise and Activity-Based Therapy

Exercise therapy produces moderate pain reduction in patients with chronic LBP independent of increases in musculoskeletal strength and significantly reduces work disability, regardless of exercise type [174,175]. Pain reduction can occur with physical therapy, but functional improvement is the primary goal. In patients with chronic LBP, studies have demonstrated positive outcomes with aggressive exercise. Exercise has been favorably compared with surgical intervention and has eliminated the need for spinal surgery in some patients. Patient care should include appropriately aggressive exercise as a core element in chronic LBP management [176].

The goal of returning patients to previous activity level is best achieved by increasing strength, flexibility, endurance, and balance. Resistance (strength) training is the only approach that improves all four factors at the same time and reduces kinesiophobia, depression, vertebral fractures, and recidivism [176].

Outcomes of core stabilization exercises are equivocal, but lumbar extensor strengthening has shown benefit by reducing pain and healthcare utilization and increasing quality of life. Motivational issues can detract from gains in function, and patients should receive time and distance guidelines and specific, measurable goals to help prevent engaging in progressively less intense home exercise [176]. Exercise frequency has been found more important than the type, duration, or intensity of the exercise [177]. A review of randomized controlled trials found that, compared with usual care, exercise therapy improved post-treatment pain intensity and disability and long-term function in chronic LBP [178].

It is important to consider that exercise worsens pain and symptoms in some patients. Poor exercise response is thought to reflect dysfunctional endogenous analgesia, with exercise failing to help restore homeostatic balance. This deficit of endogenous analgesia in some patients with chronic pain should be considered in order to help these patients avoid the detrimental effects of exercise-induced pain and distress [179].

Manual- and Physiotherapy-Based Therapies

Spinal Manipulation Therapy

Evidence Based Practice Recommendation

The American Physical Therapy Association asserts that thrust manipulative and nonthrust mobilization procedures can be used to improve spine and hip mobility and reduce pain and disability in patients with subacute and chronic low back and back-related lower extremity pain.

https://www.jospt.org/doi/full/10.2519/jospt.2012.42.4.A1

Last Accessed: July 29, 2019

Strength of Recommendation: A (Strong evidence)

Spinal manipulation therapy is performed by mobilization, whereby spinal joints are passively moved by a therapist, and by manipulation, whereby a manual impulse or thrust is applied to a joint at the end of a passive range of motion, often accompanied by a cracking sound [180]. For acute LBP, spinal manipulation therapy was found no more effective than inert interventions, sham spinal manipulation therapy, or use as adjunct therapy. Spinal manipulation therapy also seems no better than other recommended therapies [181].

For chronic LBP, spinal manipulation therapy has been found to produce a small but significant short-term effect on pain relief and functional status in comparison with other interventions. Spinal manipulation therapy has a significant short-term effect on pain relief and functional status when added to another intervention. No serious complications have been observed [182]. Spinal manipulation therapy is cost-effective as treatment of chronic back pain, either alone or in combination with general primary care, exercise, and physiotherapy [183,184].

Therapeutic Massage

A Cochrane review concluded therapeutic massage had no serious side effects and resulted in more beneficial pain relief than joint mobilization, relaxation, physical therapy, self-care education, or acupuncture for LBP [185]. Acupressure or pressure point massage provided more relief than Swedish massage. In another study, Chinese massage combined with herbal ointments was found more effective than massage plus placebo ointment among athletes with nonspecific LBP [186].

Psychologic Therapies

Encouraging patients with chronic LBP to participate in psychologic pain treatments can be difficult, because patients often insist on somatic interventions and regard psychologic interventions as inferior. Information on neurophysiologic changes associated with psychologic interventions can be presented to patients as a strategy to motivate acceptance and dispel preconception [187]. Information related to pain-related neurophysiologic alteration and treatment effects of psychologic therapies on brain and peripheral measures of pain is especially useful to enhance treatment motivation and facilitate treatment [187,188]. This is similar to pain neuroscience education.

CBT and behavioral therapies are the most widely used psychologic treatments for chronic pain. Operant-behavioral treatments, such as exposure treatment and acceptance- and commitment-based approaches, are also used. While relatively few studies have examined the neurophysiologic correlates of these therapies in patients with chronic LBP, CBT has been found effective in sub-acute or chronic LBP across a range of dimensions [184,187].

Cognitive-Behavioral Therapy

Interventions that use CBT include creative visualization, imagery, progressive muscle relaxation techniques, and problem-solving techniques. The goal of CBT is to promote patient understanding, acceptance, and self-management of chronic LBP through the development of adaptive coping behaviors and strategies, which eventually empowers the patient. CBT is effective for subacute and chronic LBP, and there is moderate-to-strong evidence for CBT use early in recovery in patients with specific biopsychosocial issues. Strong evidence indicates that CBT should be used in most patients with nonspecific LBP lasting longer than 12 weeks. Comparable outcomes have been found between fear-avoidance training and spinal fusion in chronic LBP. CBT is cost effective, adds 20% efficacy to usual rehabilitation, and reduces the duration of recurrence [42,189,190].

Studies have identified core brain regions that mediate effective cognitive interventions. These include increased rostral anterior cingulate cortex activation and decreased dorsal anterior cingulate cortex activation with cognitive distraction; involvement of the ventral lateral prefrontal cortex, mid-cingulate cortex, thalamus, amygdala, and post-central gyrus with cognitive reappraisal; and correlation of right anterolateral prefrontal cortex and the dorsal anterior cingulate cortex activation with increased self-control over pain [191,192,193].

Cognitive and learning factors contribute to placebo analgesia, considered a type of psychologic modulation of pain that is mediated by descending spinal pathways involving the anterior cingulate cortex and periaqueductal gray that alters transmission of nociceptive input at the spinal cord level [194,195]. CBT specifically alters prefrontal cortex activity in response to pain in patients with fibromyalgia [196]. Operant-behavioral therapies have been advocated for patients with low activity levels, with prominent pain behaviors that are reinforced by significant others [197,198]. Patients with fibromyalgia who received operant-based pain extinction training displayed a shift from greater anterior insula to posterior insula activation post-treatment. Changes in pain-related interference were closely related to changes in blood oxygen level-dependent activation of the posterior insula, primary somatosensory cortex, thalamus, and striatum [199]. These findings suggest that different behavioral treatments may impact different brain circuits [187].

Stepped Care in the Primary Care Setting

Measurement-based stepped care is a management approach for patients with chronic LBP in primary care that blends the stepped care approach used for many chronic diseases with the system of pain assessment and care used by pain specialists. Stepped care is well established in managing complex chronic illness, increasing treatment intensity levels for patients with no response to lower-level treatment intensity. This approach moves beyond the biomedical paradigm by systematically evaluating complex biopsychosocial factors associated with chronic pain. Systematic measurement enhances identification of specific problem areas at baseline and throughout treatment, assisting clinicians in deciding to intensify treatment or make specialist referral [200]. Relevant biopsychosocial domains are measured at baseline and during treatment with specific instruments [200]. Input from the results of these instruments helps guide the primary care provider to make referrals specific to the problem domain (Table 5) [200,400].

Table 5: BIOPSYCHOSOCIAL ASSESSMENT AND REFERRAL OF PATIENTS WITH CHRONIC LOW BACK PAIN

Domain

Instrument

Measurement-Based Score

Step Care Referral

Pain intensity

Intensity numerical rating scale (1–10)

Score ≥7 without diagnosis/plan

Pain specialist

Pain interference

Interference numerical rating scale (1–10)

Score >4

Physiatry, occupational therapy, and/or physical therapy or vocational rehabilitation

Mood

PHQ-4, PHQ-9, or PC-PTSD

PHQ-4 score ≥6 or PC-PTSD score ≥3a

Behavioral health specialist

Sleep quality

STOP-BANG

STOP-BANG score ≥3, high morphine equivalent dose, or the use of opioids and sedatives

Sleep specialist

Risk of opioid misuse

ORT

ORT score ≥8, more than four minor urinary drug test aberrancies, or any serious aberrancies

Addiction specialist

ORT = Opioid Risk Tool, PC-PTSD = Primary Care-PTSD Screen, PHQ = Patient Health Questionnaire, STOP-BANG = sleep apnea questionnaire.

aBased on DSM-V diagnostic criteria for PTSD. If using DSM-5 criteria, >3 is considered optimally sensitive and >4 is considered optimally efficient.

Source: [200]

Multidisciplinary and Functional Restoration Programs

Evidence Based Practice Recommendation

The Colorado Division of Workers' Compensation asserts that interdisciplinary rehabilitation programs are the gold standard of treatment for individuals with low back pain who have not responded to less intensive modes of treatment. There is good evidence that interdisciplinary programs that include screening for psychologic issues, identification of fear-avoidance beliefs and treatment barriers, and establishment of individual functional and work goals will improve function and decrease disability.

https://www.colorado.gov/pacific/sites/default/files/MTG_Ex1_LBP.pdf

Last Accessed: July 29, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Multidisciplinary pain programs are used for chronic LBP with the goal of restoring and improving physical and emotional functioning and quality of life. In contrast to other pain programs, multidisciplinary pain programs provide interdisciplinary care, with collaboration by providers from different program components to develop and implement patient care. Core components of multidisciplinary pain programs are medical and behavioral therapy, physical reconditioning, and education; adjunctive modalities can be added. Multidisciplinary pain programs are often viewed as the last resort for intractable pain, and many enrolled patients have exhausted most other non-invasive options. However, they may be considered earlier in the disease course. Multidisciplinary pain programs may improve chronic LBP outcomes by simultaneously addressing multiple contributing factors to chronic pain [201]. These programs cause few if any adverse effects, in contrast to surgery or long-term opioid therapy [202]. The biopsychosocial model of chronic pain (the theoretical basis of multidisciplinary pain programs) describes psychosocial factors as part of a complex system with dynamic and reciprocal inter-relationships between biologic, psychologic, and sociocultural factors that shape patient pain experience and therapeutic response [203].

A review of 41 randomized controlled trials examining chronic LBP found that multidisciplinary pain programs resulted in significantly less pain and disability than usual care or physical modalities; these benefits persisted at long-term follow-up. A positive benefit was also found on work status versus physical modalities [204]. Multidisciplinary pain programs were found cost-effective as therapy for sub-acute or chronic LBP [184].

Multidisciplinary pain programs have been expanding in other countries, but have been declining in the United States. The most pressing problems are declining access and lack of reimbursement from third-party payers. The decline in multidisciplinary pain programs and their lack of recognition as the standard of care for chronic pain has been attributed to three dichotomies whereby the multidisciplinary pain program model inherently contradicts prevailing healthcare financing and provision [202,205,206]:

- Interdisciplinary collaboration in multidisciplinary pain programs versus the discipline-segmented organization of major medical centers: Multidisciplinary pain programs require integrated care across several disciplines; in contrast, major medical centers are aligned in silos by field and are increasingly competitive with each other for resources, including patients, space, and research dollars.

- Collaborative care in multidisciplinary pain programs versus the fee-for-service model of healthcare payments: Multidisciplinary pain programs face obstacles in adequate reimbursement for essential but time-intensive assessments and collaborative meetings. The pervasive fee-for-service model preferentially rewards spinal procedures and surgery over assessments and behavioral therapy.

- Rehabilitative therapy with focus on individualized patient assessment and behavioral change in multidisciplinary pain programs versus the curative medical model of treatment: This aspect of multidisciplinary pain programs is not only resisted by healthcare payers and providers wanting higher compensation, but also by patients with chronic pain, who may prefer to obtain "cure" from interventional, surgical, or drug therapy approaches than the intensive cognitive and behavioral changes required by multidisciplinary pain programs.

An intensive, multidisciplinary functional restoration program was prospectively evaluated in 87 patients with up to two-year follow-up. Results found a 60% reduction in the number of sick days [207]. Patient outcomes with the same functional restoration program were compared to less intensive ambulatory-based individual physiotherapy in a randomized controlled trial of 132 patients with chronic LBP. The more intensive functional restoration program was superior in reduction of sick days and physical capacity, but improvements in pain intensity and quality of life were comparable [208,209].

Predictive factors of positive functional outcome were studied in 524 patients with chronic LBP admitted to a two-week intensive multidisciplinary pain program with CBT, physical therapy, and educational components. Patients had a mean 13-year LBP duration. At one-year follow-up, employed patients with mild-to-moderate disability showed greatest benefit. Baseline psychologic factors were unrelated to outcome, indicating that highly distressed patients equally benefited. However, patients with formal psychiatric disorder were excluded from enrollment [210].

Lumbar spinal stenosis is considered most effectively treated by surgery. Although surgery may provide the best outcomes among therapeutic options in restoring function and reducing pain, surgery is often less than effective and a sizeable proportion of patients do not regain good function. Active rehabilitation has been found the most effective post-surgical rehabilitation approach for improving short- and long-term (back-related) functional status and secondary outcomes such as short-term improvement in LBP and long-term improvement in LBP and leg pain [211].

Functional Restoration

Functional restoration is a variant of multidisciplinary pain programs, with an emphasis on preventing disability and returning to work and previous functioning. Functional restoration programs incorporate the following approaches [212]:

- Repeated quantification of physical deficits to guide, individualize, and monitor physical rehabilitation progress

- Psychosocial and socioeconomic assessment to guide, individualize, and monitor pain, disability, behavior, and outcomes

- Multimodal disability management programs using CBT approaches

- Psychopharmacologic interventions, as needed, for detoxification and psychosocial management

- Ongoing outcome assessment using standardized outcome criteria and objective data collection through structured interviews

- An interdisciplinary, medically directed team approach with frequent conferences and collaboration

Systematic reviews and randomized controlled trials have found strong evidence of pain reduction and improved function with functional restoration compared with less intensive programs or usual care in patients with LBP [213,214]. Randomized controlled trials have shown prevention of progression to chronic LBP in patients with acute pain, and in patients with chronic LBP, substantially lower rates of chronic pain disability, healthcare utilization, medication use, self-reported pain variables, and back pain treatment costs relative to usual care. These positive outcomes have been consistent in studies conducted in states and countries with markedly different economic and social conditions and workers' compensation systems and in studies enrolling patients with unresolved workers' compensation claims [212]. Less intensive programs have no advantage over non-multidisciplinary outpatient therapy or usual care [215].

The primary deterrent to broader use of this approach is the reluctance of third-party payers to authorize its use because of its perceived high cost. These perceptions are misguided in terms of the potential long-term cost savings of such a program. Similarly, cost-saving efforts by third-party payers to reimburse for only a portion of functional restoration programs diminish effectiveness [212].

COMPLEMENTARY AND ALTERNATIVE THERAPIES

Complementary and alternative medicine (CAM) is widely used in the United States. In 2012, more than 59 million Americans made out-of-pocket CAM expenditures totaling $30.2 billion [216]. Of this, 60% was for manipulative and body-based therapies (e.g., chiropractic or osteopathic manipulation, massage therapy), 24% for mind-body therapies, 10% for alternative medical systems, and 6.4% each for biologically based and energy healing therapies [217]. Integrative medicine combines appropriate healthcare strategies and disciplines for patient benefit, typically by blending traditional medicine and CAM [218]. Many CAM modalities address LBP mechanisms, stress response, or both, and use as monotherapy or combined with other modalities may diminish chronic stress response and interfere with the pain-stress cycle [218,219].

Acupuncture

Evidence Based Practice Recommendation

According to the Colorado Division of Workers' Compensation, there is good evidence that acupuncture, true or sham, is superior to usual care for the reduction of disability and pain in patients with chronic nonspecific low back pain.

https://www.colorado.gov/pacific/sites/default/files/MTG_Ex1_LBP.pdf

Last Accessed: July 29, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Acupuncture is a Chinese medicine technique whereby needles are slightly inserted in particular points on the body to stimulate energy fields and meridians. There is now greater understanding of the mechanisms that mediate successful acupuncture therapy, specifically stimulation of the fascia, a web of connective tissue that envelops muscle fiber and surrounds, separates, and connects organs and allows them to slide past one another when necessary [220]. Thoracolumbar fascia mediates force transfer, and disruption of its self-regulatory features may contribute to LBP. Stimulation by acupuncture needles inserted into muscle fascia induces the realignment of fibroblasts [221,222,223].

A review of acupuncture randomized controlled trials in chronic LBP found significant reductions in pain and disability with acupuncture or sham acupuncture versus conventional therapy or no therapy; a significant difference in acupuncture versus no treatment or routine care at 8- and 12-week follow-up; and a significant improvement in pain, function, and quality of life with acupuncture versus routine care at three months. The results suggest benefit from acupuncture beyond improvement from usual care in chronic LBP [224]. Acupuncture was also evaluated in a low-income, urban healthcare setting in 226 patients with chronic pain (60% with chronic back pain). Treatment once weekly up to 18 weeks led to statistically significant but clinically modest improvements in pain and physical well-being [225]. Acupuncture has been found to be a cost-effective therapy for sub-acute or chronic LBP [184].

Reviews and clinical practice guidelines have broadly concluded acupuncture in acute LBP lacks evidence. However, a randomized controlled trial of 58 patients with severely disabling acute LBP compared diclofenac injection to motion-style acupuncture treatment, an approach whereby part of the body moves passively or actively while retaining acupuncture needles. Following a single session of both treatments, motion-style acupuncture treatment led to a 3.12 greater mean pain reduction (on a 0–10 scale) and a 33% greater reduction in disability than diclofenac. These differences remained significant two and four weeks post-treatment. Motion-style acupuncture treatment showed immediate pain relief and functional recovery in disabling acute LBP [55]. A Mayo Clinic review stated that acupuncture efficacy is difficult to evaluate under controlled conditions because of the individualized and tailored approach of acupuncture to specific patient needs [226]. Bias has also been identified in Cochrane reviews of acupuncture [227]. Positive response to acupuncture and other CAM therapies has long been attributed to placebo response from high patient expectations, but this has been generally disproven [228]. Due to ongoing interest in acupuncture as a therapy for LBP, a proposal was announced in July 2019 in which Medicare will cover acupuncture as an alternative to opioids for LBP research. If the proposal is accepted, participants must be enrolled in an approved study and agree to have outcomes data collected [408].

Yoga

Yoga is an ancient discipline, originating in the Indian subcontinent, designed to restore balance and health to the physical, mental, emotional, and spiritual dimensions of the practitioner. Yoga has gained popularity in the United States, and proponents claim benefits from yoga that include reduced inflammation and decreased heart rate and blood pressure [229]. Yoga has also become increasingly used in patients with chronic musculoskeletal pain, including back pain, and has been investigated in several trials [230]. A review of randomized controlled trials in chronic LBP found that yoga showed a medium-to-large effect size in reducing disability and pain. The same benefits remained at follow-up, with somewhat smaller effect sizes. Despite differences in yoga style and duration in the reviewed trials, treatment outcomes were consistent [231]. Little is known of the mechanisms in yoga benefit [232]. Generalizability to diverse populations was assessed in 95 low-income urban minorities with moderate-to-severe chronic LBP. Following 12 weeks of once- or twice-weekly yoga classes, both groups showed significant reductions in pain (30% and 36%, respectively) and disability (36% for both) [233].

Yoga is not free of potential injury. A survey of 1,336 yoga instructors found the most frequent and severe injuries involved the neck, lower back, shoulder, wrists, and knees. Risk factors for yoga injury include poor technique or alignment, previous injury, excessive effort, and improper instruction. Specific yoga forms were associated with specific injuries, including neck injuries from headstand and shoulder stand, and low back injuries from forward bends, twists, and backbends. Recommendations to reduce yoga injuries include population-specific instructor training, appropriate placement of new students, improved understanding of appropriate effort levels, improved teacher detection of overzealous students and improper alignment, and the use of assistants to watch for overzealous and poorly aligned students in large classes [234].

Mindfulness-Based Stress Reduction

Mindfulness is an approach derived from Buddhist spiritual tradition that has been secularized and integrated into behavioral treatment approaches. Mindfulness is described as a specific state of consciousness that is non-elaborative with non-judgmental moment-to-moment awareness. It helps achieve acceptance and trust in one's own experience. The most widely used of these interventions is mindfulness-based stress reduction, developed as a component of behavioral medicine for patients with chronic pain and stress-related complaints. Components of mindful-based stress reduction include sitting meditation, walking meditation, hatha yoga, and body scan, a mindfulness practice in which attention is sequentially focused on different parts of the body. Mindful-based stress reduction also instructs on applying mindfulness to everyday life [235].

A review of three mindful-based stress reduction trials involving 117 patients with chronic LBP found statistically and clinically significant short-term improvements in pain and disability compared with usual care in patients with failed back surgery syndrome, and no improvements in pain or disability but greater short-term improvements of pain acceptance in two trials of elderly patients with specific or nonspecific chronic LBP. In aggregate, these outcomes were inconclusive in pain reduction but suggest greater pain acceptance with mindful-based stress reduction in patients with chronic LBP [235].

Tai Chi

Tai chi is a traditional mind-body exercise that enhances balance, strength, flexibility, and self-efficacy. It has been found to reduce pain, depression, and anxiety in diverse groups of patients with chronic pain conditions. The physical component provides exercise consistent with guideline recommendations, while the mental component addresses the cognitive and emotional well-being of the patient. Tai chi is a safe and economical option that helps reduce disability without introducing an intrinsic risk and addresses the cognitive, emotional, and social needs associated with chronic pain and disability [236,237].

Therapeutic Ultrasound

Ultrasound involves the application of high-frequency sound waves up to 3 MHz to the low back surface (above the pain source). A randomized controlled trial found ultrasound effective in chronic LBP compared with placebo ultrasound [238]. A case series of patients with acute pain from lumbar disk herniation and radiculopathy found that 41% of subjects were free of pain following ultrasound, compared with 12% following sham ultrasound and 6.8% with analgesics [239]. However, a 2014 Cochrane review did not find any convincing evidence of the efficacy of ultrasound for LBP, and there was no high-quality evidence of improvement of pain or quality of life [401].

Low-Level Laser Therapy

Low-level laser therapy involves application of laser at wavelengths of 632–904 nm to the skin in order to direct electromagnetic energy to soft tissues. While the mechanism and optimal treatment parameters are unclear, low-level laser therapy may alter fibroblast function to reduce inflammation and accelerate tissue repair. A review of seven small studies in patients with nonspecific LBP found low-level laser therapy more effective in reducing pain versus sham laser [115,180,240].

Neuroreflexotherapy

Neuroreflexotherapy involves temporary superficial implantation of small staples into the skin over trigger points in the back and referred tender points in the ear. Similar to acupuncture, neuroreflexotherapy uses devices for skin puncture but is believed to stimulate different zones. In patients with chronic LBP, several randomized trials found neuroreflexotherapy substantially superior to sham therapy or usual care for short-term pain relief [115].

Interferential Therapy

Interferential therapy applies medium-frequency alternating current modulated to produce low frequencies of 150 Hz or less and is suggested to provide analgesia by increasing blood flow to tissues. Randomized controlled trials have found no difference in LBP outcomes with interferential therapy versus spinal manipulation, traction, or TENS [115,241].

Transcutaneous Electrical Nerve Stimulation

TENS uses a small, battery-operated device to provide continuous electrical impulses to the site of the most severe pain via surface electrodes. TENS is thought to reduce pain by modifying pain perception and possibly by raising spinal fluid endorphins. Despite widespread use, there is little published evidence from randomized controlled trials of efficacy in chronic LBP [115,242]. One meta-analysis of TENS for chronic LBP included 267 patients with a mean treatment period of six weeks and a mean follow-up of seven weeks. This study showed significant pain reduction when using TENS [402]. However, more studies are required to determine the efficacy of TENS on chronic LBP.

Percutaneous Electrical Nerve Stimulation

With percutaneous electrical nerve stimulation, low-level electrical stimulation is applied though acupuncture-like needles inserted into points that target dermatomal levels for local pathology. In chronic LBP with or without radiculopathy, research has shown superior pain reduction versus TENS and minimal exercise intervention, with benefit duration of two months or less [115].

Cranial Electrical Stimulation

Cranial electrical stimulation uses microcurrent therapy, with a mechanism that differs from TENS. A review found cranial electrical stimulation effective in the treatment of chronic pain, including headaches, and intractable pain conditions. It is promising as a treatment for chronic LBP, but little evidence has been published [242,243].

Biofeedback

Biofeedback has been widely used for managing chronic pain, especially tension and migraine headaches. EMG electrodes are placed on the involved muscle, and the patient learns to reduce muscle contractions through a feedback procedure. Biofeedback has shown benefit in pain with a muscle component, including some forms of back pain, and has been used as a component in stress reduction. Biofeedback can train patients to reduce bracing of posture and improve self-regulation of body physiology that impacts pain. However, biofeedback requires multiple sessions and trained personnel [242]. Electroencephalography (EEG) biofeedback is a newer approach and is little studied in chronic LBP.

Hypnosis

An analgesic effect from hypnosis has been confirmed, believed to result from selective reduction of pain-related affect, reductions in sensory pain, and inhibition of pain signaling at the spinal level of processing. However, little research is available in patients with LBP [242].

Ozone Therapy

Ozone (O_3) is an allotropic form of oxygen primarily used in Europe as an alternative treatment option for patients with LBP from disk herniation. Ozone is administered percutaneously as an oxygen-ozone gas mixture at nontoxic concentrations of 1–40 mcg ozone per mL of oxygen. Proposed mechanisms of analgesia include anti-inflammatory and antioxidant action on the nucleus pulposus. The safety and efficacy of percutaneous ozone injection in LBP secondary to disk herniation was reviewed using four randomized controlled trials and eight observational studies. Based on pain reduction at six-month follow-up, the authors strongly recommended intradiscal and paravertebral ozone therapy [384].

Another systematic review of 439 references selected seven studies reviewing ozone therapy for LBP from disk herniation [403]. Of these seven studies, researchers found that there was an improvement in pain and functional scores in all, but only three studies evaluated side effects, leading researchers to conclude that complications, both minor and serious, are under-reported. Due to inconsistent methodologies and findings, researchers in this study recommend additional studies to determine safety and efficacy of ozone therapy [403].

Essential Oxygenated Oil

Essential oxygenated oil is a topical analgesic new to the U.S. market, but used in Europe for decades. Essential oxygenated oil is obtained by subjecting corn or nut oil to an accelerated peroxidation process, producing triglycerol-oxyester oil. Its mechanism is not fully known but likely involves the microcirculatory system and inhibition of lipid peroxidation, inhibition of the arachidonic acid pathway, or both [244,385]. Several randomized controlled trials have evaluated essential oxygenated oil as an alternative to NSAIDs or opioids in patients with moderate-to-severe acute, chronic, or degenerative pain from sciatica, post-traumatic pain, tendonitis, back pain, or sprain. Treatment for 7 to 28 days showed positive analgesic effects in acute and chronic pain, improved oxygen content in the skin, few side effects, and no allergic reactions [244].

Comfrey Root

The root of comfrey (Symphytum officinale) has been used for centuries as a medicinal treatment of muscle and joint pain. It is thought that the root constituents of allantoin and rosmarinic acid contribute to the anti-inflammatory effects in back pain treatment. A safety concern involves pyrrolizidine alkaloids present in the raw plant material, which possess genotoxic properties. In Europe, all medicinal comfrey root products are required to be pyrrolizidine alkaloid-depleted or pyrrolizidine alkaloid-free [245].

In one study, patients with acute upper or lower back pain received comfrey root extract or placebo cream, applied three times per day for five days. Pain intensity on active challenge decreased a median 95.2% with comfrey and 37.8% with placebo. A rapid-onset effect (within one hour of application) was reported. Mild adverse events occurred in 5% of participants [246].

In another study, patients with acute back pain received comfrey extract plus methyl nicotinate, methyl nicotinate only, or placebo cream applied three times per day for five days. Average pain scores and pain at rest were significantly lower with combination therapy than methyl nicotinate alone, with both significantly lower than with placebo. Investigator assessment of "good" or "excellent" global efficacy was 93.3% with combination therapy, 51.2% with methyl nicotinate, and 7.6% with placebo. Application site reactions occurred in 5% of subjects, mostly with methyl nicotinate [247].

Patient Expectation and CAM Outcomes

Positive patient outcomes in CAM therapies have long been attributed to nonspecific placebo response, reflecting an expectation of benefit. In 64 patients with chronic LBP evaluated before CAM therapy, baseline treatment outcome expectations clustered into pain relief, improved function, improved physical fitness, and enhanced well-being. Patients were modest in expectation level of positive therapy outcomes and reluctant to articulate optimistic expectations, and many drew the distinction between expectation and hope. Improvements from therapy in pain level, function, physical fitness, and well-being were strongly inter-related, with improvement in one domain benefiting other domains. These findings contradict the belief that positive CAM benefit is solely explained by high pre-treatment expectations [228].

Likewise, in acupuncture-naïve patients with chronic LBP, higher pre-treatment expectations for success did not predict pain or functional improvement. An association did develop with ongoing treatments, but positive pre-treatment attitude toward acupuncture was not associated with superior outcomes [248].

PHARMACOTHERAPIES

There are few current, comprehensive practice guidelines for back pain therapy with analgesics. Therefore, this section will emphasize research identifying promising analgesic approaches, challenging current assumptions of the safety or efficacy (or the lack of) in established analgesic therapies, or modifying use or delivery of established therapies to improve safety or efficacy.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs represent the foundation of back pain pharmacotherapy. Anti-inflammatory activity accounts for a proportion of analgesia from NSAIDs. Cell injury generates enzymes that release arachidonic acid from cell membranes, and arachidonic acid is converted into prostaglandins, thromboxanes, leukotrienes, and other eicosanoids. The prostaglandins PGE2 and PGF2a contribute to inflammation and sensitize nociceptors innervated by A-delta and C nerve fibers. Other prostaglandins are needed for homeostasis. NSAIDs inhibit the enzyme cyclooxygenase (COX) required for synthesis of arachidonic acid into prostaglandins and other eicosanoids. COX-1 is noncontributory to inflammation but is involved in homeostatic functions and mediates gastrointestinal protection by the gastric mucosa. COX-2 is induced during inflammation and amplifies inflammatory response, but it also contributes to kidney and cardiovascular homeostasis and helps maintain vascular integrity. Thus, COX inhibitors reduce inflammation and pain but can interfere with homeostatic functions, such as proper renal blood flow and gastric mucosa protection. NSAID analgesia also results from central activity, possibly through substance P and NMDA inhibition [63,249,250].

NSAIDs are subgrouped by dominant COX isoenzyme activity. NSAIDs that inhibit COX-1 and 2 are termed non-selective NSAIDs. NSAIDs with greater COX-2 inhibition are termed coxibs, COX-2 selective NSAIDs, or COX-2 inhibitors. COX-2 inhibition is not an absolute NSAID characteristic, as COX-2 selective agents also possess varying degrees of COX-1 inhibition [250,251].

Gastrointestinal Toxicity

Nonspecific NSAIDs were the first to enter commercial use. However, evidence began accumulating that associated non-selective NSAIDs use with gastrointestinal bleeding and toxicity, and in 1997, nonspecific NSAIDs were linked to 107,000 hospitalizations and 16,500 fatalities from upper gastrointestinal morbidity [63,252]. All-cause mortality rates fell from 11.6% pre-1997 to 7.4% post-1997, while NSAID-induced mortality rates from upper gastrointestinal bleed or perforation increased from 14.7% before 1997 to 20.9% after 1997. Thus, mortality per event has fallen when unrelated to NSAIDs, while NSAID-associated mortality has increased [256].

Up to 40% of NSAIDs users develop upper gastrointestinal symptoms, most frequently gastroesophageal reflux and/or dyspeptic symptoms. Serious and potentially fatal upper gastrointestinal toxicities, including symptomatic and/or complicated peptic ulcer, bleeding, perforation, or obstruction, occur in 1% to 2% of NSAID users and are influenced by dose and exposure [253]. COX-2 inhibitors are associated with significantly lower risks of upper gastrointestinal perforation, obstruction, and bleeding compared with non-selective NSAIDs plus proton pump inhibitors [254]. The highest risk of serious gastrointestinal morbidity is found with piroxicam, azapropazone, and ketorolac; the lowest risk is with aceclofenac, ibuprofen, and celecoxib [253,255].

Piroxicam's half-life of greater than 30 hours may explain its propensity for gastrointestinal toxicity, and oral ketorolac dosing is limited to five days due to well-recognized gastrointestinal and renal toxicity profile. Ketorolac is a highly potent analgesic. While it is unsuitable to manage acute or chronic LBP, a role in hyperacute LBP is worth consideration, especially when opioid analgesia is not the best option [251].

The incidence of lower gastrointestinal toxicity with NSAID use has been increasing, likely due to enhanced detection by new diagnostic modalities (e.g., capsule endoscopy, device-assisted enteroscope). Evidence suggests comparable risks of lower gastrointestinal and upper gastrointestinal bleeding and perforation from NSAIDs. The most frequent lower gastrointestinal morbidities include increased gut permeability, gut inflammation, blood loss and anemia, malabsorption, and mucosal ulceration. Lower gastrointestinal complications from NSAIDs can be fatal [253].

Cardiovascular Toxicity

The COX-2 inhibitor celecoxib was introduced in 1999, quickly followed by rofecoxib and valdecoxib, to retain the benefits of non-selective NSAIDs without the associated upper gastrointestinal toxicity. However, rofecoxib and valdecoxib were withdrawn from the market in 2004 and 2005 due to adverse cardiovascular events [250,251]. Nonspecific NSAIDs have been assumed to carry the greatest risk of upper gastrointestinal morbidity with little risk of cardiovascular morbidity, with the reverse true for coxibs [257]. However, this was challenged by a meta-analysis that found comparable cardiovascular risks between coxibs, high-dose diclofenac, and possibly ibuprofen. The incidence of major cardiovascular events was increased 33% with diclofenac, primary from non-fatal myocardial infarction or coronary death. Ibuprofen increased the risk of major coronary event, while naproxen did not elevate the risk. Use of any NSAID roughly doubled the risk of heart failure [257,258].

Another meta-analysis found naproxen the least harmful NSAID in cardiovascular risk, with coxibs displaying the highest risk of myocardial infarction. Ibuprofen and diclofenac are associated with the highest risk of stroke, and diclofenac is associated with a high risk of cardiovascular fatality. Naproxen may be safer in risk for cardiovascular events but carries a very high risk of gastrointestinal complications. The authors concluded that no NSAID is safe for cardiovascular risk and prescribing any NSAID requires assessment of patient cardiovascular risk factors [259,260].

Efficacy

NSAIDs are effective in reducing acute LBP and pain associated with several chronic LBP conditions, though no benefit has been found in LBP with radiating symptoms [261]. The data on acute LBP are less convincing than with non-radicular chronic LBP, but, given the toxicity potential with acetaminophen, NSAIDs seem preferable in acute LBP [251]. NSAIDs have a ceiling effect, where further dose escalation increases side effects but not analgesia [263]. Analgesic efficacy between coxibs and non-selective NSAIDs is comparable, and consistent differences in pain reduction for specific NSAIDs have not been found [261]. For unknown reasons, up to 70% to 80% of patients preferentially respond to a specific NSAID. Response cannot be predicted, but some patients lacking response to one NSAID will achieve full benefit from another [262].

NSAIDs remain among the most commonly prescribed drugs for neuropathic LBP despite repeated demonstration of ineffectiveness, reflecting prescribers' unfamiliarity with the mechanistic basis of LBP [95]. Short-term use of NSAIDs for acute LBP is appropriate in most cases, but NSAIDs in chronic back pain should only be used in carefully selected patients for occasional use to manage pain flares, and never for long-term therapy [251].

Acetaminophen

Acetaminophen is a nonsalicylate antipyretic analgesic that may be used alone or combined with other agents (usually opioids). Unlike aspirin, it lacks antiplatelet effects and gastric mucosa compromise. Acetaminophen does not have peripheral anti-inflammatory effects and produces analgesia that is additive to NSAIDs. Despite decades of use, the exact mechanism of action for acetaminophen remains unclarified [63,263].

Acetaminophen is widely recommended as first-line analgesia for acute and chronic LBP because of enduring assumptions of efficacy and safety. However, research has challenged these assumptions. In one study, 1,649 patients with acute LBP were randomized to regular dosing (three times per day, ≤4,000 mg/day), as-needed dosing (take as needed for pain relief, ≤4,000 mg/day), or placebo. All groups were instructed continue as needed, up to 28 days. Average time to recovery was 17 days in the regular and as-needed groups, and 16 days in the placebo group. The average number of tablets consumed per day was about four in all groups. Side effects in each group were also similar [264].

With increasing evidence of liver toxicity, the U.S. Food and Drug Administration (FDA) recommends a maximum 3,250 mg/day dose ceiling for acetaminophen, and McNeil Consumer Healthcare voluntarily lowered the maximum dose of its 500-mg tablets of acetaminophen to 3,000 mg. Acetaminophen is usually well tolerated, but overdose can result in fatal hepatic necrosis, and patients with alcoholism or liver impairment risk hepatotoxicity at standard doses. Acetaminophen has a lower risk of gastrointestinal toxicity than NSAIDs and is rarely associated with renal toxicity [263,265].

TCAs

TCAs are subgrouped into amines and their demethylated amine derivatives. Common TCAs include amitriptyline, imipramine, trimipramine, clomipramine, doxepin, nortriptyline, desipramine, and protriptyline [266]. The mechanism of analgesic action includes norepinephrine and serotonin re-uptake inhibition in descending inhibitory pathways, and sodium channel blockade with amitriptyline and doxepin. Analgesic action is independent of antidepressant action, occurs at lower doses, and is much more rapid in onset. TCAs can enhance opioid analgesia and are more commonly used with neuropathic LBP [266]. TCAs are not FDA-approved for pain treatment due to possible side effects, which are more likely and consequential in frail patients [95]. Amitriptyline is approved solely for depression, but its off-label use is among the highest of all medications, primarily from use in pain therapy [267].

In chronic LBP, nortriptyline and desipramine are preferred over amitriptyline and imipramine as they show fewer side effects with comparable efficacy. TCA advantages include once-daily dosing and low cost [266]. However, TCAs exhibit a wide range of adverse effects, which differ among the various agents. Common adverse effects include anticholinergic effects, antihistaminergic effects, and orthostatic hypotension (α-1 adrenergic receptor blockade). Anticholinergic side effects include urinary retention, dry mouth, and constipation. Cardiac complications are described as a possible TCA side effect in patients with a history of coronary artery disease, more likely with doses greater than 100 mg/day. Potential side effects and overdose risks should be considered when prescribing antidepressants for chronic LBP; in TCAs, risks include weight gain, driving impairment, falls, and greater overdose lethality potential than other analgesic antidepressants [263,268].

Selective SNRIs

SNRIs are thought to alleviate pain through norepinephrine and serotonin re-uptake inhibition in descending inhibitory spinal pathways [269]. Duloxetine is efficacious in chronic LBP treatment, with significant pain reduction and improved function compared with placebo at 60 and 120 mg/day, with 120 mg more effective [270,272]. Responders in a randomized controlled trial showed further improvements in pain, physical function, and quality of life during open-label extension through one-year follow-up [271]. A database review found that patients with chronic LBP initiating duloxetine versus standard of care for pain management were less likely to use opioids, had fewer days on opioids, and initiated opioids later than the standard care cohort, suggesting an opioid-sparing effect of duloxetine in chronic LBP [269].

Venlafaxine has efficacy in several neuropathic pain conditions, but it is not as well researched in chronic LBP. At doses less than 150 mg/day, venlafaxine has greater serotonergic activity and behaves more like an SSRI; at doses greater than 150 mg, SNRI activity becomes dominant, suggesting a 150-mg dose "basement" as pain treatment. Venlafaxine requires tapering instead of abrupt cessation due to the potential for a withdrawal syndrome. Anticholinergic effects are virtually nonexistent from SNRIs, making them favorable in elderly or comorbid patients [273].

Anticonvulsants

Anticonvulsants produce analgesia through diverse mechanisms, including voltage-gated calcium or sodium channel modulation, glutamate antagonism, enhancement of GABA inhibitory systems, or a combination of these actions [263]. Gabapentin is the most widely prescribed anticonvulsant for chronic pain in the United States. Neuropathic pain efficacy with gabapentin was first demonstrated in 1998, along with analgesic synergism when combined with morphine. Gabapentin and its analog pregabalin lack hepatic enzyme induction and adverse drug-drug interactions. Common side effects include somnolence, dizziness, fatigue, and weight gain. Gabapentin is considered benign in overdose. The older anticonvulsants phenobarbital, phenytoin, valproic acid, and carbamazepine may be beneficial but are seldom used due to the risks for side effects, drug interactions, and toxicity [263,274]. Combining gabapentin or pregabalin with other analgesics has been recommended to target multiple pain pathways and increase analgesia over monotherapy [275].

Benzodiazepines

Benzodiazepines have intrinsic analgesic properties due to GABAA receptor binding that facilitates GABA activity in the CNS. These drugs are effective as muscle relaxants and may facilitate recovery from acute back pain. Patients with chronic LBP and comorbid anxiety, mood, or sleep disorders may benefit from short-term benzodiazepines, but long-term use is constrained by drowsiness, ataxia, and tolerance. Co-use with opioids may increase analgesia but potentiate respiratory depression, potentially leading to life-threatening consequences. Patient selection should consider history of substance abuse or addiction, as benzodiazepines possess abuse liability [263,276].

Skeletal Muscle Relaxants

Skeletal muscle relaxants are widely prescribed for relief of painful and disabling muscle spasms that can occur with LBP or myofascial pain syndrome [277]. Baclofen, dantrolene, and tizanidine are FDA-approved for spasticity and act through different mechanisms. Baclofen blocks pre- and post-synaptic GABAB receptors; tizanidine is a CNS α2 receptor agonist; and dantrolene inhibits calcium release from muscle sarcoplasmic reticulum. Diazepam, clonidine, gabapentin, and botulinum toxin are also used off-label for muscle spasticity [277].

Carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine are approved for musculoskeletal disorders. Their broad diversity can guide clinical use. Cyclobenzaprine, closely related to TCAs, should be avoided in patients at risk for arrhythmia or with lowered seizure threshold. Therapeutic actions of most are vague, but sedative effects may contribute [263,276,277].

Most skeletal muscle relaxants have similar efficacy and show superiority to placebo in acute and chronic LBP. With cyclobenzaprine or diazepam, significantly more patients attained moderate-to-marked improvement in muscle spasm compared with placebo. Patient preference was found greater for baclofen or dantrolene vs. diazepam. Side effects include drowsiness, dry mouth, and dizziness. Comparative studies of opioids and skeletal muscle relaxants have not been published [263,276,277].

Opioid Therapy

A variety of issues are encountered when prescribing opioids for back pain. This section will discuss the long-term use of opioids to manage chronic severe pain, use in specific LBP populations, and other information relevant to primary care practice.

The use of opioids to manage acute and cancer pain is established and relatively straightforward, but their appropriateness for chronic pain is sometimes disputed [202]. The most common side effects are dry mouth, constipation, and nausea. A substantial minority of subjects in randomized controlled trials of opioids for chronic noncancer pain drop out due to side effects (20% to 30% with opioids vs. 5% to 15% with placebo) [202].

Some patients on long-term opioid therapy receive increasing opioid doses over time. Potential causes include pain increase from progression of underlying disease, development of opioid tolerance, or development of opioid-induced hyperalgesia (i.e., increased pain sensitivity). In some cases, dose escalation may reflect addiction or drug diversion, though studies suggest fewer than one in five patients receiving opioids for chronic noncancer pain develop problems with abuse or addiction [202]. Still, opioids possess abuse liability, and use without medical supervision can be hazardous, despite the misperception of greater safety as a pharmaceutical versus a street drug. The abuse liability also requires patients to ensure safe storage of their opioid medication. Due to their abuse potential, opioids are strictly regulated at the federal and state level, imposing barriers for patients to receive appropriate opioid treatment. When prescribing opioids, extensive documentation should be maintained. A systematic review of abuse-deterrent and non-abuse-deterrent opioid formulations concluded that both produced significantly greater pain reduction than placebo and showed comparable efficacy and safety profiles [278].

Opioid Efficacy in Nonspecific Chronic LBP

A 2013 meta-analysis reviewed randomized controlled trials of analgesics for nonspecific chronic LBP, with emphasis on opioids. Opioid trials using opioid control groups were excluded. Tramadol, oxycodone, and oxymorphone studies had 12-week follow-up, while buprenorphine trials had 8- to 24-week follow-ups [279]. The magnitude of pain reduction was marginally greater with tramadol, comparable with oxycodone, dramatically greater with oxymorphone, and significantly greater with buprenorphine compared with placebo. Global improvement in patient functioning was substantially greater with tramadol, oxycodone, and oxymorphone, and comparable with buprenorphine. The side effect risk (vs. placebo) was significantly greater with tramadol and buprenorphine, marginally greater with oxymorphone, and comparable with oxycodone [279]. In this study, oxymorphone showed the greatest magnitude of improvement from baseline on measures of pain intensity and overall patient functioning, with side effects nominally higher than placebo [279]. Patients receiving placebo were as likely to also use acetaminophen or NSAIDs as those assigned opioids.

Another meta-analysis reviewed 15 placebo-controlled randomized trials of opioids in chronic LBP. The researchers found that tramadol was superior to placebo in improving pain and functioning in five studies, and comparable to celecoxib in one trial [280]. Transdermal buprenorphine was somewhat superior to placebo in pain control but not meaningfully different in improved function in two trials. The magnitude of pain reduction with strong opioids (i.e., morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) was large for ≥30% (moderate) reduction and for ≥50% pain reduction. One trial each showed comparable improvement in pain and function with morphine compared with TCAs in chronic radicular LBP and tramadol compared with TCAs in chronic LBP. In this meta-analysis, adverse events were not reported. Tramadol, buprenorphine, and strong opioids all showed efficacy in controlling chronic LBP for up to 15 weeks [280].

Long-Term Opioid Therapy

Although there is moderate evidence that opioids provide short-term relief for patients with chronic LBP, evidence of long-term effectiveness is poor, based on small-scale, uncontrolled studies [391]. One long-term (median: 8.5 years) study assessed opioid therapy in 84 patients with intractable, severe chronic pain [281]. Twenty-four patients with chronic LBP and radiculopathy were maintained on a median 510 mg/day morphine equivalent dose. The most commonly used opioids were oxycodone, morphine, transdermal fentanyl, and hydromorphone. The median duration of current opioid dose was 3.5 years. At baseline, all patients had severe or very severe pain. At last follow-up, 46% rated their pain as mild, 49% as moderate, and 5% as severe but reduced from baseline. After reaching stable analgesia, 81% rated pain reduction as ≥50%, and 42% rated their pain reduction as ≥70% [281]. In total, 26% reported significant side effects of constipation, fatigue/drowsiness, dry mouth, or weight gain. One event each of constipation, dry mouth, weight gain, urinary retention, memory impairment, vomiting, and reduced libido were described as intolerable.

In 78 patients with disability comparisons, the greatest changes occurred in 65 patients who were bedridden, chair bound, or incapable of any activity of daily living at baseline who became capable of doing some or all activities of daily living or returning to work at follow-up [281]. Quality of life ratings were slightly below normative age-matched population values and not indicative of significant impairment in health-related quality of life. Composite overall physical and mental health scores were slightly below normal.

No increase in infections was found relative to population norms. Sexual function was at least moderately impaired in 85%, but opioid attribution was obscured by age, concomitant medications, and serious medical comorbidity. Problematic opioid use developed in four patients (about 5%) with histories of alcohol use disorder or bipolar disorder early in treatment [281]. All regained opioid stability with good long-term pain control after comorbid psychiatric conditions were addressed.

In 95% of patients, pain levels were reduced from severe/very severe to mild or moderate [281]. Most did not report significant adverse effects; of those who did, few were intolerable. Unexpectedly, 70% reported mild or absent constipation, and hyperalgesia or immune impairment was not detected. Most patients were older than 65 years of age and/or had significant comorbidity, such as diabetes or vascular disease. Although uncontrolled, this long-term study provides information unobtainable by randomized controlled trials in a patient population with severe intractable chronic pain closely monitored over time. This small study shows that immune impairment, tolerance, or hyperalgesia may not develop from long-term opioid therapy in some patients. A caveat is that patients required opioid therapy before enrollment; those lacking opioid response or tolerability were unlikely to enroll [281].

Levorphanol

Termed the "forgotten opioid," levorphanol is not often prescribed but may be effective in hospice and palliative care or for neuropathic pain syndromes requiring opioids [282,283]. Although levorphanol has been available in the United States since 1953, it is largely unknown to most pain clinicians, in part because levorphanol is not marketed or promoted [284,285]. The unique, non-opioid properties of levorphanol suggest a potentially important role in pain therapy.

Advances in pain research during the 1990s began identifying the mechanistic basis of neuropathic and treatment-resistant chronic pain, and the centrality of NMDA receptor activation in both. Further research found that levorphanol and methadone possessed potent NMDA receptor activity [286]. Levorphanol and methadone are both potent mu opioid receptor agonists with unique non-opioid mechanisms. Both are NMDA receptor antagonists and serotonin and norepinephrine reuptake inhibitors [284]. Levorphanol differs from methadone by its more powerful NMDA antagonism (comparable in potency to ketamine), greater NMDA and mu opioid receptor affinity, lower serotonin and norepinephrine receptor affinity, and full kappa-opioid receptor agonism [287,288]. These properties suggest levorphanol efficacy in chronic neuropathic LBP and severe treatment-refractory nociceptive or mixed nociceptive-neuropathic back pain conditions.

Importantly, levorphanol has many safety advantages over methadone. Methadone's complex pharmacology imposes a hazard when prescribed without sufficient knowledge and experience to mitigate the risks that arise from the extended half-life (15 to 60 hours) exceeding analgesia (4 to 8 hours); numerous drug interactions, which may delay clearance with resultant accumulation to fatal levels; risk of prolonged QTc interval; and activity as a P-glycoprotein substrate. Between 2000 and 2007, methadone prescribing for pain increased dramatically , often by providers lacking sufficient training. By 2009, methadone accounted for 2% of written opioid prescriptions but more than 30% of prescribed opioid-related deaths [289,404]. In contrast, levorphanol lacks metabolic competition with most drugs, lacks known cardiac toxicity, and is not a P-glycoprotein substrate [283]. However, levorphanol does possess a half-life (11 to 16 hours) exceeding analgesia (6 to 15 hours), and safe prescribing requires dose titration spaced four days apart to avoid drug accumulation [290].

Few studies of levorphanol have been published; its generic status eliminates market incentive for drug company-funded research [285]. An eight-week trial randomized 81 patients with severe, chronic, treatment-refractory neuropathic pain to high-dose (0.75 mg) or low-dose (0.15 mg) levorphanol capsules, titrated to a maximum 21 mg per day. Pain reduction was 36% with high-dose (mean: 8.9 mg/day) and 21% with low-dose (mean: 2.7 mg/day) therapy. Both dose groups showed comparable improvement in sleep and affective distress. Pain levels returned to baseline after levorphanol taper. No addictive behavior was observed [291]. In a separate case series, 31 patients with severe, chronic neuropathic pain received levorphanol following treatment failure with other opioids, including methadone. Pain relief was rated excellent by 52% and fair by 22%, for a response rate of 74%. Some levorphanol responders were methadone nonresponders [285].

An extended-release levorphanol formulation has been developed and is undergoing evaluation by Relmada Therapeutics [292]. While the levorphanol molecule is intrinsically long acting, the extended-release formulation is proprietary, and the patent protection makes the development, evaluation, and marketing (assuming FDA approval) commercially viable.

Methadone

As noted, methadone was increasingly prescribed for the treatment of chronic pain beginning in 2000. Deaths related to methadone peaked in 2007 and have been gradually declining since, mostly due to increased education and stricter prescribing guidelines [404]. This focus on safety was prompted by data showing large increases in methadone-associated overdose deaths paralleling its increasing use for chronic pain. Clinical practice guidelines were developed to promote safer methadone prescribing for chronic pain. Among the recommendations are [293]:

- Educate patients on methadone safety.

- Use electrocardiogram to identify patients at greater risk for methadone-related arrhythmia.

- Use alternative opioids in patients at high risk of QTc interval prolongation.

- Use careful dose initiation and titration.

- Be diligent in monitoring and patient follow-up.

Cannabinoids

Cannabinoids, which include the plant Cannabis and several pharmaceutical products that mimic the analgesic molecular constituents of Cannabis, have shown increasing promise in alleviating severe LBP and neuropathic LBP in particular. However, evidence of efficacy is preliminary. If used, it should be considered an adjunctive option for patients for whom first-line options have failed [7,405].

Combination Pharmacotherapy

When managing chronic LBP, the use of multiple analgesics with complementary pharmacologic mechanisms—termed rational polypharmacy—may offer advantages of additive pain control, fewer adverse events, and reduced opioid dosing (when opioids are included) [283]. Despite a robust theoretical basis, few well-designed, randomized controlled trials using a combined mechanism approach in chronic LBP have been published, and chronic LBP guidelines have not addressed it. Scarcity in the literature is likely the result of difficulty and complexity in performing clinical trials of multiple active treatments, the inherent inflexibility of clinical trial protocols in allowing individualized dosing and titration, and the absence of an economic incentive [294]. However, the findings of published studies suggest an added benefit with combined pharmacotherapies [294].

Celecoxib Plus Pregabalin

Patients with chronic neuropathic or nociceptive LBP from disk prolapse, lumbar spondylosis, and/or spinal stenosis treated with celecoxib and/or pregabalin for 12 weeks showed significantly greater pain reduction with combined therapy than with monotherapy. Pregabalin dose requirements were significantly lower when combined with celecoxib. Monotherapy and combination treatment showed similar incidence of adverse events [295].

Buprenorphine Plus Pregabalin

In one study, patients with chronic neuropathic or nociceptive LBP received buprenorphine transdermal system for four weeks and were then randomized to additional pregabalin 150 mg or placebo for four weeks. After one month, transdermal buprenorphine produced significant pain reduction. After two months, further reductions in pain scores were only significant in patients receiving transdermal buprenorphine plus pregabalin [296].

Morphine Plus Nortriptyline

A trial randomized 61 patients with chronic lumbar radiculopathic pain to morphine (15–90 mg), nortriptyline (25–100 mg), morphine plus nortriptyline, or active placebo (benztropine) therapy for nine weeks. More patients attained moderate or better pain reduction with combination treatment (67%) than placebo (37%), morphine alone (42%), or nortriptyline alone (40%). The additive benefits from morphine plus nortriptyline may reflect successful targeting of multiple pain pathways in this difficult-to-treat pain condition [297].

Topical Analgesics

Some analgesics are now formulated to bypass the systemic distribution produced by oral administration through transdermal delivery. Topical analgesics are used for the delivery of locally effective drug concentrations to the peripheral application site, with low systemic exposure and, presumably, lower risk of systemic adverse effects [298]. Potential benefits of topical analgesic delivery include reduced side effects, painless drug delivery, improved patient adherence and acceptance, ease of discontinuation, avoidance of first-pass metabolism, and direct access to the peripheral tissue target [299].

Although most topical analgesics produce clinically effective drug concentrations at the peripheral site without clinically relevant systemic concentrations, the therapeutic effects may not be strictly limited to the peripheral target. For example, topical morphine and fentanyl produce analgesia through central and peripheral mechanisms of action despite low systemic concentrations. Factors that influence penetration and absorption of topical analgesics include the biochemical properties of adjuvants in the topical formulation and inter-individual variability in skin absorption [300,301]. Compounding pharmacies often include dimethyl sulfoxide in topical formulations of drugs that lack the properties for optimal cutaneous absorption [298].

In general, topical opioids, NSAIDs, and salicylates have not shown the systemic side effects that limit the use of their oral counterparts [302]. However, topical analgesics are not without side effects, most commonly skin irritation or dryness. Penetration enhancers (e.g., dimethyl sulfoxide) are associated with significant skin dryness resulting from lipids dissolving on the skin surface [303].

NSAIDs

Effort has been made to improve NSAID tolerability for elderly and medically comorbid patients by shifting from oral to topical NSAIDs. As of 2009, topical NSAIDs were recommended in seven of nine clinical guidelines for pain [304].

NSAIDs are the most widely studied topical analgesics [302]. Topically applied NSAIDs are suitable for the treatment of many back pain conditions as they penetrate the muscle and joint tissues proximal to and below the site of application. A comparison study of topical NSAIDs, topical salicylate, and capsaicin in chronic musculoskeletal pain found highest rates of significant pain control with topical NSAIDs [305,306,307].

Of all topical NSAIDs, diclofenac has the most evidence supporting its use and is the sole NSAID with FDA approval for topical use. Approved formulations include diclofenac sodium 1% and 3% gel, diclofenac sodium 1.5% topical solution in 45.5% dimethyl sulfoxide, diclofenac epolamine topical patch 1.3%, and diclofenac sodium topical solution 2% [298,310]. Topical diclofenac has shown efficacy in pain reduction superior to placebo; comparable to topical NSAIDs indomethacin, ketoprofen, and piroxicam; and comparable to oral NSAIDs diclofenac, ibuprofen, and naproxen. The effectiveness, safety, and tolerability of topical diclofenac support its use for a variety of inflammatory chronic back pain conditions [305,308]. Randomized controlled trials of diclofenac applied three times daily showed that benefits began at 1 week, were fully apparent by 4 weeks, and were maintained to 12 weeks [309].

The most common adverse effects with diclofenac are mild site reactions, such as erythema or pruritus. No severe or systemic gastrointestinal effects have been observed with topical diclofenac or other topical NSAIDs, and skin irritation is significantly less common with patch versus gel [302]. Systemic exposure from diclofenac epolamine topical patch is 1% that of an oral 75-mg dose. The steady-state plasma concentrations are also significantly lower and unlikely to result in COX-1-mediated effects [311]. From 1993 to 2008, 46 million patients worldwide received diclofenac epolamine topical patch, and adverse events were reported in 108 patients. Most were skin reactions or lack of efficacy; six were serious gastrointestinal events, but none were believed causally related to the diclofenac epolamine topical patch [312]. The FDA requires that manufacturers incorporate standard NSAID warnings of serious liver disease risks into the labeling of topical diclofenac; however, to reach systemic levels from one 150-mg oral dose of diclofenac, 100 patches would need to be worn simultaneously [251,283,313].

NSAIDs are recommended for analgesia in many LBP conditions, and topical formulations should be considered for use in patients with acute or chronic back pain conditions for which oral NSAIDs are indicated [302,314]. It is important to note that, unlike oral NSAIDs, topical NSAIDs cannot target central and peripheral pain mechanisms, are ineffective for neuropathic pain and widespread musculoskeletal pain, and lack sufficient penetration for use in chronic LBP caused by arthritis [283].

Anesthetic Analgesics

Aberrant ion channel (particularly sodium channel) activity contributes to chronic pain conditions involving neuropathy. Topical anesthetic analgesics produce analgesia by disrupting pain signal transmission between afferent nerve fibers and the CNS, primarily from binding affinity to voltage-gated sodium and/or potassium ion channels. Lidocaine is nonselective for sodium and potassium ion channels, while tetracaine is more selective for sodium ion channel binding. Binding to these receptor sites reversibly inhibits neuronal action potential to prevent transmission and conduction of nerve impulses, producing analgesia through inhibition of ectopic discharge in sensitized and hyperactive subcutaneous nociceptors. Lidocaine also shows widespread nerve fiber activity suppression, while tocainide is more selective to C-afferent conductivity suppression [298,315,316].

Topical analgesic agents that interact with sodium and potassium channels include lidocaine 5% patch; a self-heating patch containing 70 mg each of tetracaine and lidocaine; a eutectic mixture of 2.5% each of lidocaine and prilocaine; and a cream with 7% concentrations of lidocaine and tetracaine [298]. Lidocaine-containing creams show a maximum skin penetration depth of 3–5 mm, and circulating lidocaine levels following topical application vary broadly across patients. Systemic absorption of topical anesthetics does occur but has not been associated with side effects or toxicity. The primary side effects are application-site reactions, such as skin discoloration, erythema, and irritation [298,317].

Lidocaine 5% patch or plaster has efficacy superior to placebo and comparable or superior to oral pregabalin in pain reduction with postherpetic neuralgia or diabetic neuropathy. It has also shown greater improvements in quality of life and fewer side effects than oral pregabalin [302]. In patients with post-traumatic peripheral neuropathy, lidocaine 8% pump spray significantly reduced pain and tactile allodynia for a median five hours after application [318].

In some patients with chronic back pain with neuropathic contribution, lidocaine 5% patch may be effective in reducing pathologic pain from abnormally increased sodium channel expression, although patient response is variable [315]. A placebo-controlled trial of 5% lidocaine patch in chronic LBP found no difference between active and placebo patch; however, 50% of subjects in both groups experienced substantial pain reduction, and the high placebo-response rate to the inert patch created difficulty in appraising true lidocaine efficacy [315].

Capsaicin

Capsaicin is a constituent of hot peppers and a topical analgesic with efficacy in several musculoskeletal and neuropathic pain conditions. The mechanism of analgesia is mediated by action on TRPV1 receptors, temperature sensors that regulate pain signaling on peripheral sensory neurons. TRPV1 receptors are initially activated and then desensitized by capsaicin, leading to reversible loss of C fiber function [309]. Capsaicin also inhibits the activity of bradykinin, a neuropeptide involved in the inflammatory process [298].

Capsaicin is available as 0.75% or 0.5% cream or 8% patch. The 8% patch is associated with significant local reactions, including pain, pruritus, and swelling. Instructions for its use state that application should only be performed under physician supervision, and pre-treatment of the application site with a local anesthetic is recommended [298]. A single 60-minute application of the 8% capsaicin patch has shown significantly greater pain relief compared to a low-concentration 0.04% capsaicin patch, a difference that was sustained as long as 12 weeks [319].

Opioids

Peripheral tissue inflammation upregulates opioid receptors and stimulates local endogenous opioid peptide production in immune cells. These cells provide the targets for opioid binding and activation by opioid drugs and the rationale for topical opioid analgesia. Topical application also bypasses systemic distribution and side effects [320].

Topical opioids are not commercially available and require compounding pharmacist preparation [321]. Most studies have evaluated morphine and have found side effects of application site itching and burning with morphine and placebo vehicle-gel [321,322]. Case series trials found rapid reduction of pain from tumor skin infiltration, malignant and non-malignant skin ulcers, severe oral mucositis, knee arthritis, and tenesmoid pain. Randomized controlled trials in painful skin ulcers found significantly lower pain scores with topical opioids compared with placebo [322].

In a small study, patients with chronic, intractable pain (due to disk degeneration in 61% of cases) received topical morphine, oxycodone, or hydromorphone for six months to apply as needed. Treatment was used at least once per day by 100% of participants and for breakthrough pain by 67%. Effective pain relief up to three hours per application was reported by 85%, and reductions in oral opioids, pain flare-ups, and stiffness were reported by at least 30% of participants [323]. In a separate study, patients with severe back pain received morphine cream, applied one to three times per day. Following application, 88% reported pain reduction of 40% to 50% lasting four or more hours; 19% reported relief lasting longer than one day. Responders were then randomized (double-blind) to active or placebo cream. Twenty-four hours post-treatment, pain-free movement was experienced by 44% with morphine vs. 0% with placebo [324].

TCAs

Although recommended as a treatment option for chronic LBP, TCAs are inappropriate for many patients, and others may find the side effects intolerable. Topical TCA formulations have been developed to offset these potential risks, and other topical formulations combine TCAs with another analgesic acting through complementary pain pathways. A 2% amitriptyline/1% ketamine formulation has shown efficacy in various neuropathic pain conditions in the absence of meaningful systemic concentrations. Topical 3.3% doxepin/0.025% capsaicin has also been found effective in other types of neuropathic pain [303,325,326].

Injection, Intravenous, and Infusion Therapies

Lidocaine

Lidocaine has been used systemically as an analgesic in diverse chronic back pain conditions, typically as single IV infusion at sub-anesthetic doses ranging from 1 mg/kg to 6 mg/kg over 30 to 120 minutes [327]. Lidocaine relieves pain by blocking spinal dorsal horn sodium ion gate channels and by inhibiting neuronal ectopic discharge and aberrant electrical discharge in peripheral neuromata and dorsal root ganglia. The analgesic effect of IV lidocaine is unrelated to its anesthetic mechanism, as lidocaine half-life is 120 minutes and analgesia substantially longer [327,328,329,330].

A review of IV lidocaine found that lidocaine 5 mg/kg showed clear benefit in reducing chronic pain immediately post-infusion, but pain relief did not persist longer than one week. The most common side effects were somnolence, light-headedness, headache, nausea, dry mouth, and perioral numbness [327].

Ketamine

Ketamine infusion has demonstrated efficacy in chronic pain, including chronic neuropathic LBP, but side effects have limited its use. The most common of these are hallucinations or depersonalization/derealization. Other less troublesome side effects include somnolence, feelings of insobriety, nausea or vomiting, and drowsiness. Benzodiazepine co-administration may eliminate or dramatically reduce the development of hallucinations, depersonalization/derealization, and insobriety [331]. In addition to pain alleviation, trials of ketamine infusion in severe chronic LBP have demonstrated opioid-sparing effects, reductions in opioid tolerance, and suppression of opioid-induced hyperalgesia [332].

Botulinum Toxin A

Botulinum toxin A was evaluated in 31 patients with chronic LBP randomized to injections of botulinum or saline at five lumbar paravertebral sites on the side with pain. After three weeks, pain reduction of 50% or greater was attained by 73.3% of patients treated with botulinum and 25% of those treated with saline. At eight weeks, ≥50% pain reduction was reported in 60% of patients who received botulinum toxin A, compared with 12.5% of those who received saline. Improved functioning at eight weeks was found in 66.7% with botulinum toxin A and 18.8% with saline. No patients reported side effects [333].

A single-blind, randomized clinical trial study of 50 patients with refractory chronic LBP similarly assigned patients to receive either botulinum toxin or saline injections in the paraspinal muscles where the pain localized [334]. After four weeks, 76% of the participants receiving botulinum reported improvements in pain, compared with 20% of patients receiving saline. After eight weeks, the botulinum treatment group was significantly more likely to report improvements in functionality (68% vs. 12%) [334]. The American Academy of Neurology has concluded botulinum toxin A is possibly effective for chronic, predominantly unilateral LBP, but its role in chronic LBP treatment should be clarified by larger randomized controlled trials in homogenous populations [335,406].

Bisphosphonates

A randomized, placebo-controlled study evaluated the analgesic effect of IV pamidronate in 44 patients with chronic LBP and evidence of degenerative spine disease. Pamidronate administered as two 90-mg infusions decreased pain intensity for six months, with significantly different improvements from placebo in daily average pain score, proportion of responders, changes in worst pain, and pain interference of daily function. No serious pamidronate-related adverse events or other significant safety findings were observed [336].

Zoledronic acid was evaluated in a study of 40 patients with chronic LBP of moderate-severe intensity, with MRI-detected modic changes (i.e., pathologic vertebral endplate and bone marrow changes). After one month, single-infusion zoledronic acid 5 mg led to significantly greater reduction in pain and disability compared with placebo, but no differences were observed at one year. NSAIDs were used by 20% of patients randomized to zoledronic acid and by 60% of those receiving placebo. Acute fever, flu-like symptoms, or arthralgia occurred in 95% with zoledronic acid and 35% with placebo [337].

Anti-Nerve Growth Factor

Nerve growth factor (NGF) is a neurotrophic factor associated with pain signaling, active in several mechanistic pathways to initiate and maintain hypersensitivity and persistent pain. Clinical trials have shown pain reduction using NGF antagonists in osteoarthritis and interstitial cystitis, and agents with anti-NGF activity may be efficacious in chronic back pain [338]. In a review of four randomized controlled trials of anti-NGF agents in back pain treatment, two studies of tanezumab in chronic non-radicular LBP showed significant pain and disability reduction at 12 weeks compared with naproxen or placebo controls. Reduction was greater in pain than disability. Trials of fulranumab or REGN475 did not show benefit. Possible anti-NGF side effects include headache, hyperesthesia, abnormal peripheral sensation, and dizziness. Serious side effects were not observed in any trial [338,339].

Tumor Necrosis Factor Antagonists

In a review of randomized controlled trials of anti-TNF in discogenic lumbar radiculopathy, a significant reduction in LBP and/or leg pain was found in 60% of epidural etanercept participants compared with placebo. A three-arm study found adalimumab superior to etanercept in LBP, and a dose-response study found significant pain reduction only with the lowest (0.5 mg) etanercept dose. Subcutaneous adalimumab led to significantly decreased back pain scores from six weeks through six months and less need for surgery than patients receiving placebo. No differences from placebo were found in oral REN-1654, subcutaneous etanercept, intravenous infliximab, or intradiscal etanercept. Adverse events with epidural etanercept were similar to placebo. In aggregate, the data are promising, but further research is needed to clarify optimal dose, route of administration, and anti-TNF agent [340].

Endocrine-Targeted Therapy in Chronic Refractory Pain

A subgroup of patients with chronic pain is refractory to standard drug and non-drug therapies. Uncontrolled pain profoundly impacts endocrine function, and normalization of key hormones may reduce pain. Hormone abnormalities were assessed in 61 patients with treatment-resistant chronic pain. Most (80.3%) had at least one abnormality, most commonly related to adrenocorticotropic hormone (27.3%), cortisol (32.8%), pregnenolone (20.8%), progesterone (20.8%), dehydroepiandrosterone (37.2%), and testosterone (37.2%); 11.5% showed significant hypothalamic-pituitary-adrenal suppression. Therapy was targeted at normalizing hormone elevations or deficiencies. Within 60 days, hormone abnormalities were normalized, and pain alleviated to the extent that all patients resumed normal function. This suggests that patients with chronic pain who lack pharmacotherapy response may have profound hormone abnormalities that, once corrected, can facilitate effective pain control from standard approaches. While not specific to chronic LBP, these results may be relevant due to shared physiologic effect of severe uncontrolled pain and common mechanisms of chronic pain [341].

Pharmacotherapy for Neuropathic LBP

Confirmation of neuropathic involvement in chronic LBP has challenged conventional assumptions and management [151]. Evaluation of 7,772 patients with chronic LBP found predominant pain contribution from neuropathic causes in 37%, with higher pain intensity experienced by this subgroup [342].

Patients with radiculopathy pain are five times more likely than patients with non-radicular LBP to receive pharmacotherapy, but most lack sufficient evidence to explain their widespread use [36,343,344]. Radiculopathy and other neuropathic LBP types are often undertreated or ineffectively treated. Treatment paradigms have come under increasing scrutiny as a result of the greater understanding of neuropathic mechanisms, including those of radiculopathy. Mediocre pain outcomes in radiculopathy may be largely due to failure in using mechanism-based treatment approaches [345]. Medications effective in other neuropathic conditions (e.g., nortriptyline, morphine, pregabalin, topiramate) are largely ineffective for lumbosacral radiculopathy, and departure from suggested first- and second-line medications may be required [346].

INTERVENTIONAL PAIN MEDICINE THERAPIES

Use of interventional pain medicine in back pain increased 11.8% per year between 2000 and 2009, but began declining at a rate of 0.6% per year between 2009 and 2016. Even with the decline in interventional pain medicine, there were 5,509,306 procedures performed in the Medicare population in 2016, a275% increase compared with the number performed in 2000 [19,393]. In contrast, the Medicare beneficiary population grew 42.6% between 2000 and 2016. In 2016, 58% of interventional pain medicine interventions were epidural adhesiolysis procedures, 52% were SI joint and facet joint injections, and 45% were other nerve blocks [19,393]. All were for spinal pain. Again, these figures apply to the Medicare population only, and exclude continuous epidurals, intra-articular injections, trigger point and ligament injections, peripheral nerve blocks, vertebral procedures, and implantables [19,393].

There is a vast array of interventional approaches to the diagnosis and treatment of LBP. Few have been rigorously evaluated, and fewer still have shown consistent benefit. However, several non-interventional pain medicine organizations have included interventional approaches in their clinical practice guidelines for severe intractable pain.

Spinal Surgery

Roughly 80% of patients evaluated by neurosurgeons are referred for spinal pain, but surgery is indicated in fewer than 10% [347]. In many cases, primary care providers lack an understanding of back pain amenable to surgery. Patients in pain may wait for extended periods for initial consult, only to be sent back to primary care; improved knowledge can limit inappropriate patient referral. Spinal surgery in acute LBP is limited to patients with severe or progressive motor weakness or cauda equina syndrome. Surgical options and appropriate chronic LBP indications include spinal compression surgery, fusion surgery, and disk arthroplasty [347,348].

Spinal decompression surgery involves complete or partial removal of lumbar spine structures causing neural impingement, such as large disk herniations and spinal stenosis. This includes open discectomy, microdiscectomy, and laminectomy. Fusion surgery joins adjacent vertebrae in an unstable vertebral motion segment to alleviate pain in advanced spinal degeneration. Disk arthroplasty treats degenerative changes confined to one vertebral motion segment by disk removal with artificial disk replacement.

Evidence supports laminectomy for disabling leg pain due to spinal stenosis and open discectomy or microdiscectomy for radiculopathic pain associated with lumbar disk herniation. Post-surgery symptom relief seldom persists longer than two years. Better outcomes with radiculopathy and lumbar disk herniation are associated with patient age younger than 40 years of age and symptom duration less than three months [154,347]. Fusion surgery has a weak recommendation for non-radicular chronic LBP associated with degenerative disk disease, with greatest benefit in patients with moderately severe pain or disability, one or more years of conservative management without improvement, and absence of psychiatric or medical comorbidities [115,347].

Epidural Steroid Injection

Epidural steroid injection involves corticosteroid plus local anesthetic injection into the space between the dura and the spine. Arachidonic acid release from tissues is induced by phospholipase A2. Metabolism of arachidonic acid by the COX and lipoxygenase pathways generates prostaglandins, prostacyclins, thromboxanes, and leukotrienes. Prostaglandins and other arachidonic acid byproducts initiate or exacerbate pain by inducing inflammation and sensitizing peripheral nociceptors. Corticosteroids inhibit phospholipase A2, accounting for their anti-inflammatory properties. Steroids may also inhibit pain by suppressing ectopic discharge from injured nerve fibers and blocking conduction of normal unmyelinated C fiber [349].

Some potential mechanisms of epidural steroid injection benefit do not actually involve steroids. Local anesthetic injection can increase blood flow to ischemic nerve roots and, similar to steroids, suppress ectopic discharges from injured neurons to inhibit or block nociceptive transmission. In addition, epidural administration of any injectate, including saline, can promote analgesia through washout of inflammatory molecules. A significant correlation has been found between epidural volume and pain relief, regardless of steroid dose, at 6- and 12-week follow-up [349,350].

Epidural Steroid Injections for Lumbar Radiculopathy

Corticosteroid injection into the epidural space for LBP treatment was first reported in 1953, and despite numerous publications and exponential increases in use, its efficacy and safety remain controversial [349]. Interventional pain medicine specialists strongly believe in the efficacy of this intervention for lumbar radicular pain, reinforced by more than five decades of use and centrality in numerous pain programs [351]. The benefit of epidural steroid injection varies, with efficacy best demonstrated in short-term pain relief of persistent radiculopathy with lumbar disk herniation [47]. Evidence for epidural steroid injection in spinal stenosis is less robust than for herniated disk, but greater than with failed back surgery syndrome and axial back pain without radiating symptoms [349]. The conceptual appeal of epidural steroid injection is that subsequent pain relief allows the body time to heal while avoiding the long-term consequences of central sensitization. However, more than 70% of radiculopathies recover within six months, and a similar proportion of disk herniation undergoes resorption within one year [349].

Epidural steroid injection is also advocated as an effective means to reduce lumbar surgery. This is contradicted by epidemiologic data showing increased lumbar surgery in those receiving epidural steroid injections, especially with more than three epidural steroid injections over a two-year period [11]. Some advocate for epidural steroid injection as a non-addictive LBP treatment that eliminates or seriously reduces need for opioids, but this is not yet supported by evidence [11].

Clinical practice guidelines generally support the use of epidural steroid injections for patients with disk herniation and persistent lumbar radiculopathy who are experiencing pain severe enough to cause functional impairment with failure of noninvasive care after four weeks [47,133,155]. Contrast-enhanced fluoroscopy is suggested for accurate delivery [154]. There is no evidence that any specific injection approach (e.g., interlaminar, transforaminal, caudal) influences the risks or effectiveness [154]. This approach is suggested only for short-term (two to four weeks) pain relief in lumbar radiculopathy; epidural steroid injection has no impact on functional impairment, need for surgery, or pain relief beyond three months [4,154,155,352].

Epidural Steroid Injections for Spinal Stenosis

Roughly 25% of the estimated 2.2 million lumbar epidural steroid injections performed annually in Medicare patients are for lumbar spinal stenosis [353]. Epidural steroid injection is presumed to relieve pain by reducing nerve root inflammation and ischemia, and it is widely used for lumbar spinal stenosis despite the lack of rigorous evidence and the despite the fact that clinical practice guidelines have found insufficient evidence to evaluate the benefits and harms of this use [4,133,354,355].

In a multisite, randomized controlled trial, 400 patients (mean age: 68 years) with lumbar spinal stenosis and moderate-to-severe leg pain and disability (duration of three months or longer in 80% to 88%, respectively) were randomized to receive an epidural injection of corticosteroid plus lidocaine or lidocaine alone. At six weeks, patients in both groups had improved, with no between-group differences with respect to improvement in functional status or leg pain intensity scores; no differences were noted with different sites of injection (interlaminar vs. transforaminal) either. A greater number of participants in the epidural steroid injection group reported treatment satisfaction (67% vs. 54%) and depression symptom improvement. Those who received epidural steroid injection showed higher cortisol suppression levels at three and six weeks, possibly from systemic steroid absorption [354]. Despite modest benefit at three weeks, the anticipated longer-term benefits never materialized, raising serious questions regarding the benefits of this approach in lumbar spinal stenosis [354,355].

In another study, researchers reviewed data from 13,741 patients in the six-month period before and after epidural steroid injection for LBP. Roughly 64% of patients used opioids before epidural steroid injection and 67% used opioids after. About 38% were prescribed opioids after but not before epidural steroid injection, while 16% were prescribed opioids before but not after. Those receiving more than three epidural steroid injections were significantly more likely to begin opioids and undergo lumbar surgery than those who received three or fewer injections [11,356].

Ketamine-Augmented Epidural Steroid Injection

To evaluate ketamine-augmented epidural steroid injection, 200 patients with lumbar disk herniation and radiculopathic pain were randomized to epidural steroid injection (triamcinolone/bupivacaine) plus ketamine (30 mg) or placebo. Mean pain scores were significantly lower with ketamine-augmented therapy compared with placebo at every follow-up point from 1 month to 12 months. Likewise, at every follow-up, disability scores were significantly lower in the ketamine group. Ketamine side effects included post-injection delusions lasting a mean 45 minutes; none required intervention [357]. It is important to note that racemic ketamine should be avoided for epidural use because the preservatives have shown neurotoxicity [357].

Adverse Events

In 2014, the FDA issued a warning regarding rare but serious adverse events associated with epidural steroid injection use. Serious adverse events included death, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke, seizures, nerve injury, and brain edema. Many cases were temporally associated with the epidural steroid, occurring within minutes to 48 hours post-injection. Many patients did not recover. Healthcare professionals should include this information when discussing benefits and risks of epidural steroid injections with patients [358].

Neuromodulation Interventions

Implantable devices are available for patients with severe refractory chronic LBP. Positive response to a temporary trial is required before permanent implantation.

Spinal Cord Stimulation

Spinal cord stimulation is primarily used to reduce severe and persistent neuropathic pain from lumbosacral radiculopathy or failed back surgery syndrome. It acts by modulating spinal cord and CNS afferent input. A comparison of spinal cord stimulation with conventional medical management in failed back surgery syndrome with radicular pain found greater than 50% pain reduction at one- and two-year follow-up in 48% and 47% of patients with spinal cord stimulation vs. 9% and 7% of patients managed conventionally. During the trial, 31% of patients undergoing spinal cord stimulation required device-related surgical revision [47,359,360]. As such, spinal cord stimulation should be considered in patients with failed back surgery syndrome who are not candidates for corrective surgery and have failed conservative evidence-based treatment [4].

The most challenging aspect of spinal cord stimulation therapy is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months [4]. Psychologic assessment is required to identify motivational, social, psychologic, and social support factors that predispose to poor treatment outcome. Failure of spinal cord stimulation treatment is associated with active substance abuse, secondary gain, unrealistic expectations, personality disorders, litigation, and depression. These factors may account for previous treatment failures to a greater extent than sole inability to control the biologic cause of the pain [116].

Implantable Intrathecal Drug Delivery

Implantable intrathecal drug delivery systems are routinely used for cancer pain when oral or transdermal analgesics are ineffective or intolerable. In LBP, implantable intrathecal drug delivery is reserved for severe, chronic, refractory axial or neuropathic radicular pain, most frequently in failed back surgery syndrome, spinal stenosis, and intractable LBP with or without radicular pain. Similar to spinal cord stimulation, implantable intrathecal drug delivery is reserved for patients who have exhausted other options, with psychologic screening for negative prognostic factors [116]. Evidence in chronic LBP is limited, but several trials have found significant pain relief lasting longer than one year [361]. Pain control usually requires multiple analgesics, typically an opioid, local anesthetic, and alpha-2 agonist. Baclofen is often added for refractory spasms and additional analgesia. Patients are seen at least monthly for pump reservoir refill. Symptoms consistent with spinal cord or nerve root compression, known adverse events with implantable intrathecal drug delivery, require prompt, aggressive investigation [116].

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

Over the past two decades, healthcare expenditures for LBP have increased dramatically. While a large volume of pre-clinical and clinical research, review papers, and practice guidelines on chronic LBP have been published, patient outcomes remain unimproved. Chronic LBP remains a frustrating condition for clinicians and for patients, who often obtain little improvement in pain and functioning with standard therapies. Data indicate that more effective patient care is hampered by several factors, including:

- Flaws and limitations in pain therapy research

- Biased or deficient clinical practice guidelines

- Declining availability of multidisciplinary pain programs

- Increasing dominance of interventional pain medicine and replacement of the biopsychosocial approach by the biomedical treatment model

- Conflicting interests that supersede delivery of patient-centered care

- Fundamental structural flaws in health care, reimbursement, and compensation systems

The International Association for the Study of Pain has identified areas of crisis in pain care in the United States: poor evidence base in most treatment approaches; inadequate primary care provider pain education; the unknown value of opioid therapy for chronic pain; pain provider reimbursement; and declining access to multidisciplinary pain programs [5].

LIMITATIONS IN PAIN THERAPY RESEARCH

A frequent criticism of opioid therapy for chronic pain is the publication of few long-term (i.e., longer than one year) randomized controlled trials, cited as proof that long-term opioid safety and efficacy lacks evidence. However, this is not unique to opioids, as no analgesic used in chronic pain has evidence of long-term efficacy [392]. Pharmaceutical randomized controlled trials usually do not extend past 8 to 12 weeks, and long-term randomized controlled trials are difficult to perform for many reasons. The complexity and expense of evaluating combined drug therapies create obstacles for investigators and are unattractive to industry funding [294,362]. Ethical constraints interfere with initiating long-term placebo-controlled analgesic trials, such as the necessary encouragement of patients in moderate-to-severe pain to remain adherent to possibly inert placebo therapy for study duration [291].

Randomized controlled trials are considered the "gold standard" in evidence-based medicine, but possess important limitations. Trial outcomes may have limited clinical use because typical patients with chronic LBP often bear little resemblance to tightly screened participants. With complex comorbidity, older age, and requirement of multiple medications the norm, patients with chronic LBP seen in practice more closely resemble patients excluded from enrollment. Randomized controlled trials also typically use strict, inflexible dosing parameters. This can lead to dropout by patients lacking benefit or tolerance who would otherwise show good therapeutic response using a tailored approach. Opioid randomized controlled trials often have high dropout rates, which can drive down efficacy to result in underestimation of true patient benefit [362].

Long-term observational studies provide clinically important information unobtainable by randomized controlled trials [5]. Although non-blinded trials have the potential for confounding by subject and observer bias, multiple-year trial durations make dissipation of earlier placebo response from investigator enthusiasm or subject expectation highly probable [281]. Spontaneous remission in the natural history of pain is also unlikely in a cohort with intractable chronic pain [362]. Placebo-controlled randomized trials have long been the preferred study design, but comparative effectiveness research is becoming emphasized to address numerous concerns over the process of new technology entrance into clinical practice.

DECLINING AVAILABILITY OF MULTIDISCIPLINARY PAIN PROGRAMS

The inadequate care of chronic LBP is in part the result of the demise of multidisciplinary pain programs and the dominance of interventional pain medicine, a reflection of a movement away from biopsychosocial-based care and toward the biomedical model. With sole emphasis on the neurophysiologic aspects of pain and the pain experience, the biomedical model is reductionistic in its approach to chronic pain [363]. The old biomedical model viewed LBP causation as tissue pathology involving structural, anatomic, and biomechanical factors. Largely ineffective for chronic LBP, the biomedical approach led to unacceptable failure rates, adverse iatrogenic effects, and escalating costs [17,127]. Recognition of a need for an alternative model of care coincided with breakthrough insights in back pain mechanisms, evolution of the biopsychosocial pain model, and development of biopsychosocial-based multidisciplinary chronic pain management programs, also termed multidisciplinary pain programs [364].

Earlier multidisciplinary pain programs were generally located in academic medical centers and staffed by scientist-practitioners, attracted by the resources and opportunities to improve chronic pain patient care. With increasing popularity and demand, some programs began delivering diverse, uncoordinated, and ineffective care while remaining highly profitable. The efficacy and cost-effectiveness shown in the published research increasingly did not apply to many programs calling themselves "multidisciplinary," because the positive outcomes in the literature reflected multidisciplinary pain programs in academic medical centers, where quality of care (not profit) was the objective. Erosion in quality and patient outcomes in many multidisciplinary pain programs led to declining reimbursement, the closing of effective academic multidisciplinary pain programs, and conversion of others to interventional pain medicine centers. Fueling this trend were changes in reimbursement and health insurance practices and financial incentives in anesthesiology residency programs, which also began using interventional pain medicine procedures as a primary measure for pain medicine competence [50,365].

THE RISE OF INTERVENTIONAL PAIN MEDICINE

Against the backdrop of preferential reimbursement for procedure-based patient care in the current healthcare system, a small but influential subgroup has been remaking the care of patients with spinal pain. The American Society of Interventional Pain Physicians (ASIPP) is the largest and most influential interventional pain medicine professional organization. Aggressive interventional pain medicine advocacy by the ASIPP has fueled guideline conflict with the American Pain Society (APS), which some see as a battle by proxy between interventional and medical pain practitioners. Following publication of guidelines by the APS that concluded interventional pain medicine therapies were not recommended for nonspecific chronic LBP, the ASIPP has refuted the APS's conclusions and underlying evidence, essentially challenging the tenets of evidence-based medicine, comparative effectiveness research, and guideline development [115,366,367,368,369]. All back pain clinical practice guidelines lacking key contribution by interventional pain medicine physicians have been declared invalid by the ASIPP [370]. (Note: The APS voted to file for Chapter 7 bankruptcy dissolution in 2019, partially due to the national public attention of opioid overprescribing and lawsuits against pharmaceutical companies, leading to withdrawal of financial support to such societies [407].)

The growth of interventional pain medicine has fundamentally altered the nature of medical care for patients with chronic LBP by shifting the orientation from a patient-centered to a modality-centered model. The premise of interventional pain medicine is that targeted peripheral tissue intervention alleviates LBP and broadly improves patient mood, physical function, and quality of life. Maladaptive pain behaviors and psychosocial dysfunction associated with chronic pain are largely unaddressed. Patients may be referred to an allied pain therapist, but benefits from combining therapies may be undermined by lack of coordinated and integrated pain care. Peripheral target identification relies on imaging findings, despite the lack of correlation between imaging results and pain and the discouragement of imaging in most patients with LBP [50,371,372].

As discussed, research indicates that psychosocial factors largely influence patient outcomes across the spectrum of LBP interventions. The highly variable outcomes of interventional pain medicine and the inability of imaging and physical findings to predict nerve blockade outcomes for chronic LBP suggest benefit from using psychologic predictors of interventional pain medicine outcome [50].

Maladaptive pain beliefs may be encouraged by the interventional pain medicine approach. For patients with unrelenting LBP, interventional pain medicine may seem to be the only means for achieving cure, leading patients to believe that return to more normal function requires dramatic pain reduction and relieving them of responsibility for their own pain management. Desperation for pain relief, and unrealistic expectations of interventional pain medicine, can trigger dysfunctional pain behaviors and a cycle of unneeded diagnostic testing, repeated ineffective interventional pain medicine, doctor shopping, delay or avoidance of pain therapy emphasizing functional improvement, risk for iatrogenic complications, and eventual disability and hopelessness.

Any modality that views chronic LBP in strictly physiologic terms deviates from modern understanding of pain pathophysiology and the principles of effective pain management [50,373,374]. An effective pain management plan acknowledges that perceived belief of one's ability to control pain is associated with less severe pain and higher levels of functional activity. Self-efficacy is the conviction that one can perform a specific task or induce a desired outcome and is strongly associated with reduced pain, disability, and depression. Self-efficacy and confidence in one's ability to control pain can be attained with psychologic interventions in a multidisciplinary context [50].

It is important to remember that some patients with chronic LBP clearly obtain meaningful and prolonged pain relief from interventional pain medicine, and some techniques seem uniquely effective in specific severe, chronic conditions. This indicates the best interests of pain medicine are served by interventional pain medicine as a partner in the family of pain therapies [50].

FINANCIAL AND MONETARY INFLUENCES

The quality of pain treatment is adversely impacted when patient-centered care is superseded by conflicting financial interests or lack of reimbursement for needed care. Numerous technologies have been developed for minimally invasive intervention in LBP, only to be later found as inferior to existing therapies [11,375].

Full discussion of funding and reimbursement for LBP care is beyond the scope of this course. However, inadequate pain care is facilitated by a reimbursement system structured to favor procedures over assessment, problem-solving, and patient support related to psychosocial issues. This reimbursement system has contributed to interventional pain medicine proliferation over the past 20 years [5]. Along with rewarding procedure-based care, there is a corresponding disincentive, through lack of reimbursement, for taking the time to listen and understand the social and cognitive concerns of patients [376].

HEALTHCARE PROVIDER EDUCATION

The high prevalence of patients with LBP dictates that primary care clinicians provide the majority of care. According to the Institute of Medicine, provider education deficits remain the primary contributor to inadequate pain treatment in the United States [12]. The hours for teaching cannot be increased, and replacement of any existing curricular content with pain education is unlikely [5]. Similar gaps in knowledge regarding chronic pain have been noted in nurses, occupational therapists, and physical therapists [377,378,379]. Improvements in knowledge and practices regarding chronic pain management would directly impact patient outcomes and appropriate prescribing practices.

PATIENT SATISFACTION RATINGS

Patient satisfaction is an essential aspect of clinical care, and patient satisfaction surveys are increasingly used as a benchmark of quality of care; however, their use can have unintended consequences, such as the promotion of opioid prescribing. Clinical practice guidelines suggest taking necessary time to inquire about psychosocial concerns and to discuss the range of more appropriate alternative approaches when patients request opioids [380]. Such encounters can be challenging and time-consuming. Patients may lack interest in non-opioid alternatives and may be dissatisfied if their requests are not met. Fulfilling patient expectations usually results in a more satisfied patient, while nonfulfillment correlates with dissatisfaction [381].

Compensation may partially depend on the quality of services provided, which is increasingly measured by achieving patient satisfaction targets. Patients may become frustrated or angry when they do not receive the treatment they want and confuse getting what they want with good medical care [381,382]. While patient satisfaction is important, it should not be sought at the expense of quality of care.

COMMUNICATION WITH NON-ENGLISH-PROFICIENT PATIENTS

Pain is a subjective experience, and strong patient-clinician communication is a cornerstone of effective pain management. Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 64 million Americans speak a language other than English in the home, with approximately 25.6 million of them (8.5% of the population) speaking English less than "very well" [386]. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" [387]. In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [387]. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [388,389].

"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters [390]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members. A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters [389].

9. CONCLUSION

Back pain in general, and LBP in particular, is highly prevalent and is associated with substantial economic expenditures (mainly health care) and losses (e.g., absenteeism, lost productivity). It can incur serious and prolonged patient suffering, diminished quality of life, and disability. LBP is the chronic pain syndrome responsible for the greatest clinical, social, economic, and public health burden in the United States [6,393]. By completing this course, healthcare professionals should have a greater understanding of the pathophysiology and differential diagnosis of LBP conditions, the distinction between acute and chronic back pain and its management implications, and knowledge of appropriate treatment options that are guided by advances in pain neuroscience.

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