GN23 • Nurses 2023

Table of Contents

GN23 • Nurses 2023

How to Receive Credit

NetCE 10 Hour Course #90241 • Pancreatic Cancer

90241 • Pancreatic Cancer

1. INTRODUCTION

2. EPIDEMIOLOGY

3. PATHOPHYSIOLOGY

4. PANCREATIC CANCER SCREENING

5. CLINICAL EVALUATION OF PANCREATIC CANCER

6. THE DIAGNOSTIC AND STAGING WORKUP

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #35270 • Multimodal Pharmacotherapy for Pain Management

35270 • Multimodal Pharmacotherapy for Pain Management

1. INTRODUCTION

2. THE PHYSIOLOGY OF PAIN

3. TYPES OF PAIN

4. ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT

5. USING MULTIMODAL PAIN THERAPY: EXAMPLES FROM THE PROFESSIONAL LITERATURE

6. CASE STUDIES

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #38950 • Pathophysiology: Muscles, Joints, and Connective Tissues

38950 • Pathophysiology: Muscles, Joints, and Connective Tissues

1. INTRODUCTION

2. MUSCLES, JOINTS, AND CONNECTIVE TISSUES: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

3. THE PROCESS OF SKELETAL MUSCLE CONTRACTION

4. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

5. RELATED INFLUENCES AND EFFECTS

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

7. SPECIFIC DISORDERS OF CONNECTIVE TISSUE AND MUSCLES

8. SPECIFIC DISORDERS OF THE JOINTS

9. CASE STUDIES

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

GN23 • Nurses 2023

Mark Rose, BS, MA, LP

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired)

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

GN23 • Nurses 2023

Expiration Date: 09/30/2025

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.

90241 • Pancreatic Cancer

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2024 NetCE, All rights reserved.

Pancreatic cancer, also referred to as pancreatic ductal adenocarcinoma (PDAC), is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic and neuropsychiatric symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective.

Table of Contents

90241 • Pancreatic Cancer

Course Overview

Audience

Accreditations & Approvals

Designations of Credit

Individual State Nursing Approvals

Special Approvals

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

Implicit Bias in Health Care

1. INTRODUCTION

2. EPIDEMIOLOGY

RACIAL SURVIVAL DISPARITIES

NON-GENETIC RISK FACTORS

3. PATHOPHYSIOLOGY

PRIMARY MUTATIONAL DRIVERS IN PDAC

MUTATIONAL SEQUENCE OF PDAC DEVELOPMENT

NATURAL HISTORY OF PDAC ONCOGENESIS

HEREDITARY PDAC

4. PANCREATIC CANCER SCREENING

GERMLINE AND SOMATIC TESTING AND MOLECULAR ANALYSIS

NOVEL APPROACHES TO PANCREATIC CANCER SCREENING

5. CLINICAL EVALUATION OF PANCREATIC CANCER

NEUROPSYCHIATRIC SYMPTOMS AND PANCREATIC CANCER

FAMILY HISTORY

COMMON PRESENTING SYMPTOMS AND SIGNS

PHYSICAL EXAMINATION

METASTATIC DISEASE

LABORATORY TESTING

DIFFERENTIAL DIAGNOSIS

6. THE DIAGNOSTIC AND STAGING WORKUP

IMAGING

BIOPSY

CARBOHYDRATE ANTIGEN 19-9 (CA19-9)

THE STAGING WORKUP

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

PATIENT FUNCTIONAL STATUS

RECOMMENDED TREATMENT OPTIONS BY CLINICAL STAGE

RESECTION OF PANCREATIC CANCER

CHEMOTHERAPIES IN PANCREATIC CANCER

RADIATION THERAPY FOR PANCREATIC CANCER

NEOADJUVANT THERAPY

LOCALLY ADVANCED PANCREATIC CANCER

METASTATIC DISEASE

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

VENOUS THROMBOEMBOLISM PROPHYLAXIS

PERI-PANCREATIC COMPLICATIONS

PAIN CONTROL INTERVENTIONS

CACHEXIA, WEIGHT LOSS, AND NUTRITIONAL COMPROMISE

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

90241 • Pancreatic Cancer

Education Category. Medical / Surgical

Release Date. 09/01/2024

Expiration Date. 08/31/2027

Course Overview

Pancreatic cancer, also referred to as pancreatic ductal adenocarcinoma (PDAC), is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic and neuropsychiatric symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective.

Audience

This course is designed for physicians, nurses, and other members of the interprofessional healthcare team involved in the care of patients with pancreatic cancer.

Accreditations & Approvals

In support of improving patient care, TRC Healthcare/NetCE is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is accredited by the International Accreditors for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU.

Designations of Credit

This activity was planned by and for the healthcare team, and learners will receive 10 Interprofessional Continuing Education (IPCE) credit(s) for learning and change. NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 9 pharmacology hour(s) for physician assistants. NetCE designates this continuing education activity for 9 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This activity has been approved for the American Board of Anesthesiology’s® (ABA) requirements for Part II: Lifelong Learning and Self-Assessment of the American Board of Anesthesiology’s (ABA) redesigned Maintenance of Certification in Anesthesiology Program® (MOCA®), known as MOCA 2.0®. Please consult the ABA website, www.theABA.org, for a list of all MOCA 2.0 requirements. Maintenance of Certification in Anesthesiology Program® and MOCA® are registered certification marks of the American Board of Anesthesiology®. MOCA 2.0® is a trademark of the American Board of Anesthesiology®. Successful completion of this CME activity, which includes participation in the evaluation component, enables the learner to earn credit toward the CME and/or Self-Assessment requirements of the American Board of Surgery's Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit. This activity has been designated for 10 Lifelong Learning (Part II) credits for the American Board of Pathology Continuing Certification Program. Through an agreement between the Accreditation Council for Continuing Medical Education and the Royal College of Physicians and Surgeons of Canada, medical practitioners participating in the Royal College MOC Program may record completion of accredited activities registered under the ACCME's "CME in Support of MOC" program in Section 3 of the Royal College's MOC Program. This home study course is approved by the Florida Board of Nursing Home Administrators for 10 credit hour(s). AACN Synergy CERP Category A. NetCE is authorized by IACET to offer 1 CEU(s) for this program.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353 (valid through July 30, 2029); Arkansas, Provider #50-2405; California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; District of Columbia, Provider #50-2405; Florida, Provider #50-2405; Georgia, Provider #50-2405; Kentucky, Provider #7-0054 through 12/31/2027; South Carolina, Provider #50-2405; West Virginia RN and APRN, Provider #50-2405.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to provide an updated clinical review of pancreatic cancer for healthcare professionals. It is intended to address knowledge gaps, enhance clinical skills, promote risk assessment and disease prevention, and guide appropriate management of patients with the disease.

Learning Objectives

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

1. Outline the epidemiology of and risk factors for pancreatic cancer.

2. Describe the pathophysiology of pancreatic cancers.

3. Identify high-risk patients for diagnostic screening for pancreatic cancer.

4. Describe key aspects of the clinical evaluation of patients with suspected pancreatic cancer.

5. Select the appropriate tools for diagnosis and staging of pancreatic cancer.

6. Apply models of assessing the functional performance status of patients with diagnosed pancreatic cancer.

7. Discuss the role of resection in pancreatic cancer treatment, including most appropriate approaches.

8. Compare and contrast chemotherapy regimens used in the treatment of pancreatic cancer.

9. Describe the use of radiation therapy as a component of pancreatic cancer treatment according to evidence-based guidelines.

10. Evaluate available interventions to manage symptoms and provide palliative care to patients with pancreatic cancer.

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

Mary Franks, MSN, APRN, FNP-C

Randall L. Allen, PharmD

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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Pancreatic ductal adenocarcinoma (PDAC) is relatively uncommon but carries a dismal prognosis. An estimated 64,000 new cases of PDAC are diagnosed each year, and the number is increasing at the rate of 0.5% to 1.0% per year [18,134]. Although pancreatic cancer accounts for 3% of newly diagnosed cancers (by comparison, prostate, lung, breast, and colorectal account for 48%), it is the third leading cause of cancer deaths and is projected to become the second-leading cause of cancer-related deaths by 2030 [18]. Onset of disease is insidious, and there is no highly effective screening modality to enable early detection of PDAC. Most patients present with locally advanced (30% to 35%) or metastatic (50% to 55%) disease at diagnosis [134]. The overall five-year survival rate has improved somewhat over the past two decades, from 5% in 2005, to 13% in 2024 [1,18]. However, almost half (47%) of patients with pancreatic cancer have late-stage disease at diagnosis, with a five-year survival rate of 3% [18].

There are four fundamental challenges to early diagnosis and reduction in mortality from PDAC: pancreatic anatomy, rapid disease progression, systemic effects, and limited treatment options. For patients with resectable disease at initial evaluation, surgery followed by adjuvant chemotherapy is the standard therapeutic approach, with the anticipation of median overall survival of 54.4 months [134]. However, only 15% of patients present with localized tumor amenable to surgical resection. Moreover, two-thirds of annual new cases are adults older than 65 year of age, a subset lacking the resilience aggressive surgery and chemotherapy require to achieve optimal treatment outcomes.

The pancreas is situated deep within the retroperitoneal space of the upper abdomen, behind the stomach and between the aorta and its major upper abdominal branches. Shielded from detection, pancreatic tumors often grow around and encase these vessels, making the cancer inoperable in nearly 85% of patients [2]. With this aggressive cancer, more than 50% of patients have locally invasive and/or distant metastases at diagnosis, and micrometastases are already present in most patients undergoing resection for apparently localized tumors [2,3,4].

Up to 80% of patients presenting with PDAC have cachexia, a wasting syndrome induced by the physiologic effects of the cancer. Cachexia dramatically weakens patients, limiting their ability to withstand aggressive treatment. Poor treatment tolerance by patients with cachexia is evidenced by decreased survival after resection or chemotherapy [2].

The complex tumor microenvironment and heterogeneity of gene mutations make PDAC one of the most drug-resistant cancers. Standard treatment options have limited effectiveness, and disease progression is usually rapid, with low complete responses to chemotherapy and radiotherapy [1,4]. Multi-agent chemotherapy regimens have a survival benefit of two to six months over what is achieved with single-agent chemotherapy [18]. For the 5% to 7% of patients with metastatic PDAC expressing specific pathogenic germline variants, such as BRCA1/2, maintenance therapy with olaparib (a poly adenosine diphosphate-ribose polymerase inhibitor) is an option that improves progression-free survival following initial platinum-based therapy (134).

Surgical resection of the pancreas with microscopically free margins (R0 resection) followed by chemotherapy remains the only realistic option for complete remission, but this is potentially achievable in only a fraction of patients [4,5]. Nonetheless, incremental gains have been increasingly frequent over the past decade, and more substantive gains are anticipated, pending clinical trial results. This course will describe the current standard of care for patients with pancreatic cancer and present information that may help increase earlier detection of this malignancy and improve the symptom burden and quality of life in these patients, regardless of disease stage.

Clinical practice guidelines for patients with pancreatic cancer have been published by the American Society of Clinical Oncology (ASCO), the NCCN (National Comprehensive Cancer Network), the American Society for Radiation Oncology (ASTRO), the European Society for Medical Oncology (ESMO), the National Institute for Health and Care Excellence (NICE), and others [6,7,8,9,10,11,12,13,14,15]. The recommendations are largely concordant on what constitutes multidisciplinary standards of care in the management of pancreatic cancer [2,16].

Most pancreatic cancers arise in the exocrine pancreas (95%). Tumors of the endocrine pancreas (<5%) are distinct from exocrine pancreas cancers and will not be discussed in this course [4].

PDACs account for more than 95% of exocrine pancreatic cancers. Other subtypes include acinar carcinoma, pancreaticoblastoma, and neuroendocrine neoplasia. PDAC and pancreatic cancer are commonly used as interchangeable terms in the literature and will be in this course [17].

2. EPIDEMIOLOGY

During 2024 in the United States, an estimated 64,440 people will be diagnosed with pancreatic cancer, which represents 3.3% of all new cancer cases and the 11th most common new cancer diagnosis. The median age at diagnosis is 70 years [18].

Approximately 1.7% of men and women will be diagnosed with pancreatic cancer at some point during their lifetime, based on 2017–2019 data. In 2021, an estimated 100,669 people were living with PDAC in the United States [19].

With an estimated 51,750 deaths in 2024, pancreatic cancer is the third leading cause of cancer death (after lung and colorectal cancer) in both men and women. As the incidence is increasing by 0.5% to 1.0% per year, it is expected to become the second leading cause of cancer death by 2030 [18,19,20].

Pancreatic cancer stage at diagnosis strongly influences the length of survival, as shown by data from 2014 to 2020 (Table 1) [19]. The five-year survival of PDAC, 12.8%, remains the lowest of all common cancers [19,21].

Table 1: PANCREATIC CANCER STAGE AT DIAGNOSIS AND ASSOCIATED SURVIVAL

Stage

Progression at Diagnosis

Five-Year Survival

Localized

14%

44.0%

Regional

29%

16.2%

Distant

51%

3.1%

Unknown

6%

10.6%

Source: [19]

Pancreatic cancer is more common among men than women, and the incidence rate increases with age. During the period 2017–2021, persons 65 to 84 years of age (median age: 70 years) accounted for 57% of newly diagnosed cases [19]. The annual pancreatic cancer incidence and mortality rates (per 100,000 persons) for all races were higher among men (15.4 and 12.9) than women (12.0 and 9.8). The rates were highest for Black men (17.7 and 15.3), followed by non-Hispanic White men (16.0 and 13.2). Rates were lower for Hispanics and lowest for Asian/Pacific Islanders and American Indian/Alaska Natives [19].

Using statistical models for analysis, the National Cancer Institute finds that age-adjusted rates for new pancreatic cancer cases have been rising on average 0.9% each year over 2012–2021, while age-adjusted death rates have been rising on average 0.2% each year between 2013 and 2022 [19]. Underlying these trends is a combination of an aging population, a longer lifespan, and the high prevalence of obesity and diabetes [11,18]. In 2015, lost earnings from person-years of life lost from pancreatic cancer were estimated at more than $6 billion [2].

RACIAL SURVIVAL DISPARITIES

In examining PDAC survival disparities over 2004–2015, the unadjusted median overall survival was slightly longer for White patients than Black patients (6.6 months vs. 6.0 months). Decreased survival for Black patients persisted after controlling for sociodemographic parameters. Conversely, controlling specifically for clinical parameters (e.g., disease stage, treatment) found a modest survival advantage for Black patients [22].

Black patients with PDAC present at younger ages with more advanced disease than White patients, possibly suggesting differences in tumor biology. Black patients receive less treatment stage-for-stage and fewer surgeries for resectable PDAC than White patients; these findings may be only partly associated with socioeconomic differences. In one study, when disease stage and treatment were controlled for, Black patients had no decrease in survival compared to other races [22].

Role of Implicit Bias

Health professionals' implicit biases shape behaviors, communications, and interactions, which then produce differences in diagnoses and ultimately treatments and interventions. Implicit biases are subtle and unconscious and may unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider.

Racial and socioeconomic differences in surgical intervention rates, treatment at high-volume hospitals/centers, and morbidity and mortality rates have been noted, with the largest disparities between Black (and to a slightly lesser extent Hispanic) and White Americans [23]. Several factors are implicated, but implicit biases and insurance status are identified as potentially modifiable contributors.

NON-GENETIC RISK FACTORS

The most common recognized risk factor for pancreatic cancer is cigarette smoking followed by obesity. Others include pancreatitis, diabetes, and family history of pancreatic cancer (Table 2) [13,24]. Periodontal disease is increasingly linked to pancreatic and other gastric cancers. Chronic pancreatitis substantially elevates the risk of developing pancreatic cancer and represents an opportunity for surveillance and monitoring. Most importantly, new-onset hyperglycemia or diabetes is now recognized as an early symptom of PDAC in an otherwise asymptomatic patient. Many recognized risk factors are modifiable for prevention of pancreatic cancer.

Table 2: COMMON RISK FACTORS FOR THE DEVELOPMENT OF PANCREATIC CANCER

Factor

Relative Risk

Cigarette smoking

1.7-fold to 2.6-fold

Obesity

1.1-fold to 1.5-fold

Diabetes

1.5-fold to 2-fold

Family history

1.7-fold to 2.3-fold

Chronic pancreatitis

13.3-fold

Source: [2]

Smoking

Cigarette smokers have at least a two-fold greater risk for pancreatic cancer than nonsmokers. The risk increases directly with daily number of cigarettes consumed and duration of smoking. In heavy smokers with polymorphism in the carcinogen-metabolizing enzyme gene glutathione S-transferase theta 1 (GSTT1), the risk is up to five-fold greater [25,26].

Excess risk decreases with smoking cessation. The risk of pancreatic cancer among current smokers (relative risk: 2.5) decreased 48% two years after smoking cessation, and within 10 to 15 years after cessation, it approximated that of nonsmokers [26].

In the United States, estimates indicate that 11% to 32% of deaths from PDAC are attributable to tobacco smoking. It is estimated that cessation of smoking could eliminate up to 25% of pancreatic cancer deaths [24,26].

Alcohol Consumption

Limited evidence suggests alcohol consumption may be associated with risk of developing PDAC, but findings of population-based studies are inconsistent. In pooled cohort data of 1.5 million light, heavy, or never-drinkers, heavy drinkers had a greater relative risk of developing PDAC than never-drinkers (relative risk: 1.29) or light drinkers (relative risk: 1.36). Light drinkers had no difference compared to never-drinkers (relative risk: 0.96) [27].

Smoking and Drinking

Most studies have assumed additivity between average effects of smoking and alcohol and oversimplified their impact on burden of pancreatic cancer. However, the combined effect of smoking and total alcohol intake on risk of PDAC is likely non-additive. It appears that only heavy consumption of liquor (but not wine or beer) increases the risk of PDAC in ever-smokers [27].

Obesity

Obesity (defined as a mass index [BMI] >30) during early adulthood is associated with a greater risk of certain cancers and earlier onset. Several studies have reported that the incidence of early-onset pancreatic cancer has been increasing in parallel with the expanding prevalence of obesity. Other obesity-related cancers increasing in incidence and early-onset include colorectal cancer, multiple myeloma, and cancers of the uterus, gallbladder, and kidney. An analysis of incidence data from 25 state cancer registries covering 14.7 million invasive cancers diagnosed between 1995 and 2014 found the incidence of PDAC was increasing among adults 25 to 49 years of age, with steeper rises in successively younger birth cohorts [135]. Diets high in processed meat, high-fructose beverages, and saturated fat were associated with obesity, diabetes, and PDAC. Obesity is associated with a 20% to 40% higher mortality rate from PDAC, and obesity at an older age is associated with lower overall survival [13; 28].

Although BMI is widely used as a marker for general adiposity, measures of visceral obesity show a stronger correlation with metabolic syndrome, insulin resistance, and certain gastrointestinal (GI) malignancies. The proximity to visceral organs and drainage via the portal system may explain the strong correlation of inflamed visceral adipose tissue (VAT) in obese subjects with metabolic dysfunction and pancreatic cancer [29].

Diet

There is some evidence that higher consumption of red/processed meat is associated with elevation in pancreatic cancer risk, but other studies have failed to identify dietary risk factors for PDAC [11]. Pancreatic cancer incidence may be lower in persons with higher intake of fresh fruits and vegetables rich in folate and lycopenes (e.g., tomatoes) [30].

A link between vitamin D and risk for pancreatic cancer is inconsistent, but some data suggest low plasma 25-hydroxyvitamin D levels may increase the risk for pancreatic cancer, especially in those with low retinol/vitamin A intake [31]. Coffee and tea consumption are not associated with pancreatic cancer risk, despite early reports to the contrary [24].

Systemic/Nonmodifiable Risks

Numerous studies and meta-analyses have found systemic/nonmodifiable factors that increased the relative risk, hazard ratio, or odds ratio of developing pancreatic cancer. These include individuals with greater height (relative risk: 1.81); individuals with blood groups A, AB, and B (hazard ratio: 1.32, 1.51, and 1.72, respectively); and patients with hepatitis B infection (odds ratio: 1.50) or systemic lupus erythematosus (hazard ratio: 1.43). Biologic explanations for some of these associations are not yet understood, and some data may have potential confounders. Infectious etiologies warrant more investigation [11,32].

Periodontal Disease

Periodontitis describes a chronic inflammatory response to a disease-associated, multispecies bacterial community in the subgingival region. Periodontal disease is associated with pancreatic cancer, even when controlling for gender, smoking, BMI, diabetes, and alcohol consumption [33]. The inflammatory processes of periodontitis occur locally, but systemic dissemination of inflammatory mediators, subgingival species, and bacterial components contribute to digestive cancers (including PDAC) by activating proinflammatory pathways, inducing gene expression related to cell proliferation, apoptosis, and immune responses linked to carcinogenesis, cell migration, invasion, and metastasis [34].

Chronic Pancreatitis

A high-risk subgroup for PDAC are patients with chronic pancreatitis, often secondary to chronic alcohol use disorder, smoking, hypertriglyceridemia, diabetes, or renal failure [2]. Patients with chronic pancreatitis show a 26-fold increase in risk of developing PDAC. This risk increases with duration. Among patients with chronic pancreatitis of 20 years' duration, approximately 5% will progress to PDAC.

Concomitant smoking enhances the risk of neoplastic progression [2,35]. Hereditary pancreatitis further increases the risk of pancreatic cancer by more than 50-fold. In these individuals, the cumulative risk of pancreatic cancer by age 70 years is 40% [24].

Long-Standing Diabetes

Pancreatic cancer has complex relationships with diabetes and obesity that are only recently becoming understood. A population cohort study underscored the complex relationship between metabolic abnormalities and PDAC. Glycemic status, insulin resistance, and hyperinsulinemia were independently associated with an increased risk of pancreatic cancer mortality, even in individuals without diabetes [36].

The association between pancreatic cancer and diabetes was noted as early as 1833, clearly documented by the 1930s, and characterized in a large cohort of patients with pancreatic cancer from Mayo Clinic in 1958 [37]. Several meta-analyses have greatly refined the risk-factor status of diabetes.

Long-standing (i.e., more than five years) diabetes (both type 1 and type 2) is associated with increased risk of developing PDAC [13]. The overall risk for PDAC increases 4- to 7-fold in those with diabetes of a duration less than three years [38]. The relative risk associated with diabetes levels off after five years, with a 1.5-fold greater risk [39]. Increased baseline hemoglobin A1C (HbA1C) levels correlate with subsequent development of PDAC [40].

Long-standing diabetes modestly increases the risk of PDAC, which decreases with diabetes duration [11,37]. The initial three-year period after diabetes diagnosis is high risk for PDAC, as confirmed by prospective pancreatographic screening [41].

With diabetes medications, insulin use has been associated with increased risk of PDAC, but this finding is attributed to reverse causality [11,42]. Metformin use in patients with diabetes and PDAC was associated with improved two-year survival (30.1% vs. 15.4%) and median overall survival (15.2 months vs. 11.1 months) in patients without metastases [43]. One metformin study reported negative findings [44].

Long-standing diabetes in patients who develop PDAC is associated with significantly lower overall survival (14.4 months vs. 21.7 months) and significantly higher mortality (harm ratio: 1.52) compared with patients without diabetes who develop PDAC [11,45].

Postpancreatitis Diabetes Mellitus

Diabetes of the exocrine pancreas (formerly type 3c diabetes) is the second most common type of new-onset diabetes in adults (behind type 2 diabetes) [42]. Acute or chronic pancreatitis is one of the most prevalent risk factors for PDAC and the most frequent cause of diabetes of the exocrine pancreas. Pancreatitis leads to postpancreatitis diabetes mellitus in up to 83% of patients [42]. In a registry study involving 139,843 individuals, the proportion of pancreatic cancer was 3.1% among those with postpancreatitis diabetes mellitus, compared with 2.3% in those with type 2 diabetes followed by pancreatitis, 2.0% in those with pancreatitis alone, and 0.6% in individuals with type 2 diabetes alone [42].

Prediagnostic Metabolic and Soft Tissue Changes

Numerous clinical series have identified new-onset diabetes, weight loss, and soft tissue changes in patients with PDAC at diagnosis, but their inter-relationship and connection to PDAC remained unaddressed. From 2000 through 2015, temporal changes in the five years preceding PDAC diagnosis of 219 patients diagnosed with PDAC were compared to 657 controls [46]. From 60 to 30 months before PDAC diagnosis, patients did not significantly differ from controls. However, starting at 30 months prediagnosis, PDAC showed three distinct metabolic phases, each marked by onset and significant progressive worsening of one or more metabolic abnormalities [46]:

- Phase 1, hyperglycemia (30 to 18 months before PDAC diagnosis): A significant proportion of patients develop hyperglycemia, without soft tissue changes.

- Phase 2, pre-cachexia (18 to 6 months before PDAC diagnosis): Decreases in serum lipids, weight loss, and the first soft tissue change (subcutaneous abdominal tissue loss) are seen. A profile appears of advanced prediabetes (i.e., fasting blood glucose 120–126 mg/dL or A1c of 6% to 6.5%). In type 2 diabetes, this is associated with weight gain and hyperlipidemia due to insulin resistance. In PDAC, decreases in weight and serum lipids despite rising glucose levels are paradoxical.

- Phase 3, cachexia (less than 6 months before PDAC diagnosis): Onset of muscle loss, visceral adipose tissue loss, and decreasing high-density lipoprotein. Continued decreases in all other serum lipids, subcutaneous abdominal tissue, and weight. Fasting blood glucose continues rising.

Based on evidence of increases in body temperature before PDAC diagnosis, browning and loss of subcutaneous abdominal tissue is estimated to begin 18 months before PDAC. Browning of white abdominal tissue is a mechanism of subcutaneous abdominal tissue loss in cancer; its purpose is to generate heat [46].

Symptoms of cachexia and muscle loss (e.g., anorexia, fatigue, reduced exercise tolerance) appear shortly (less than six months) before PDAC diagnosis. The onset of objective weight loss precedes PDAC diagnosis by one year or more. New-onset diabetes appears a median of six to nine months before PDAC diagnosis [46].

Pancreatic Cancer Cachexia and Diabetes

Cancer cachexia is a paraneoplastic syndrome characterized by pronounced weight loss and muscle wasting triggered by cancer-induced systemic inflammation [47]. Cachexia develops in about 80% of patients with PDAC during the disease course, often before the tumor is clinically apparent. Cachexia negatively impacts treatment response and survival, and one-third of patients with PDAC die from cachexia-associated complications, including impaired immunity and cardiopulmonary dysfunction. No curative treatments exist [47].

Pancreatic cancer-associated diabetes mellitus might be a major contributor to PDAC-induced cachexia. The co-occurrence is frequent, and the relationship between pancreatic cancer-associated diabetes and PDAC-induced cachexia was clarified in a 2020 study [47]. Compared with patients without pancreatic cancer-associated diabetes, those with pancreatic cancer-associated diabetes did not have a higher risk of cachexia, a greater degree of weight loss, or lower skeletal muscle mass. Among patients with cachexia, weight loss and skeletal muscle mass were comparable between patients with and without pancreatic cancer-associated diabetes. Fasting blood glucose levels and PDAC-derived diabetogenic factors did not correlate with weight loss or muscle mass or predict cachexia in patients with pancreatic cancer-associated diabetes. A notable finding was the consistently high prevalence of cachexia and muscle wasting regardless of tumor size and stage in PDAC [47]. These results argue against pancreatic cancer-associated diabetes and hyperglycemia in mediating PDAC-induced cachexia.

Cancer cachexia is characterized by systemic inflammation with resultant skeletal muscle breakdown and increased circulating amino acids to support tumor growth. Pancreatic cancer-associated diabetes is a metabolic strategy by PDAC to fuel tumor growth. PDAC cells have a high demand for glucose (termed "glucose addiction"); hyperglycemia promotes invasion and migration of PDAC cells. PDAC-induced cachexia and pancreatic cancer-associated diabetes are distinct metabolic reprogramming induced by PDAC cells to secure amino acids and glucose for tumor growth [47].

Unexplained weight loss/cachexia is a clue to occult PDAC, but a modality that can identify PDAC-induced cachexia is needed to take advantage of this screening opportunity [47]. Optimizing glycemic control may not alleviate weight loss or muscle wasting, and therapies targeting mediators of pancreatic cancer-associated diabetes may not protect against the development of cachexia [47]. Management of cachexia in patients with PDAC is discussed in detail later in this course.

3. PATHOPHYSIOLOGY

PDAC is caused by somatic (acquired) and germline (inherited) mutations in specific cancer-associated genes. In PDAC, the accumulation of multiple combinations of gene mutations significantly perturbs major signaling pathways, leading to a malignant phenotype [13,48,49,50].

Like most solid tumors, PDACs are driven by mutations that disrupt intra- and extracellular networks that normally restrain abnormal growth, proliferation, survival, and invasion [51]. Four major genetic drivers are fundamental in nearly all PDACs. These involve mutational activation of the oncogene KRAS, and mutational inactivation of the tumor suppressor genes CDKN2A, TP53, and SMAD4[3,50,52,53]. Inactivation of genome maintenance genes that repair DNA damage is a third broad type of mutation in PDAC.

PRIMARY MUTATIONAL DRIVERS IN PDAC

KRAS encodes a GTPase molecule that acts as a transducer for growth factor receptors on the cell surface. KRAS mutations dysregulate intrinsic GTPase activity, stimulating downstream pathways that drive uncontrolled cellular proliferation, angiogenesis, suppression of apoptosis, and evasion of immune response [54].

CDKN2A encodes the proteins p16 and p14ARF, which are both cell-cycle regulators. With loss of CDKN2A gene function, inactivation of p16 results in unchecked cell cycle progression and enhanced tumor cell proliferation [3,49]. TP53 encodes the protein p53, called the "guardian of the genome," which plays a central role in DNA repair, cell cycle arrest, and induction of apoptosis in response to DNA damage or cellular stress [55].

Inactivation of p53 (loss of function mutation) allows DNA damage to go unchecked with failed apoptosis and unregulated G1/S cell cycle transition. Mutant p53 can also gain pro-oncogenic activities (gain-of-function mutation), promoting cell proliferation, survival, angiogenesis, and metastases [54].

SMAD4 encodes the protein Smad4, a downstream effector of transforming growth factor-beta (TGF-b) signaling pathway. SMAD4 inactivation and loss of Smad4 promotes cancer progression by removing the early growth inhibitory effect of the TGF-b pathway and is associated with higher rates of distant metastasis and poorer prognosis [54].

MUTATIONAL SEQUENCE OF PDAC DEVELOPMENT

Through pathways and somatic mutations that differ modestly in each lesion, PDAC develops from precancerous precursor lesions: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasms (MCNs). The most common are PanINs (approximately 90%), and the least common are MCNs (<15%). However, all precursor lesions have key similarities [4,48,50]:

- Early oncogene mutations initiate tumorigenesis.

- Later loss of tumor suppressor genes drives tumor progression, high-grade dysplasia, and invasive cancer.

- Increasing grades of dysplasia are associated with accumulation of somatic mutations in key driver genes.

Pancreatic Intraepithelial Neoplasia (PanIN)

PDAC develops in PanINs through a specific process [56]. First, mutational KRAS activation initiates pancreatic carcinogenesis. With tumor suppressor inactivation, cancer progresses. CDKN2A or SMAD4 are implicated in locally destructive disease; TP53 is involved in metastatic seeding; and concurrent SMAD4 and TP53 are often present in locally or metastatic dominant disease. IPMNs and MCNs often share the driver gene mutations and sequence of PanINs, but also show specific patterns.

Intraductal Papillary Mucinous Neoplasms (IPMN)

Lesions involving the main pancreatic duct have a higher malignant potential than those in the branches, with the risk of malignancy at around 62% [11]. More than 90% of IPMNs are marked by activating mutations in the oncogene GNAS and/or inactivating mutations in the tumor suppressor gene RNF43[48,53,54]. GNAS mutation causes constitutive activation of adenylyl cyclase, with downstream effects driving proliferation. RNF43 encodes E3 ubiquitin-protein ligase, which functions as a tumor suppressor in the Wnt-signaling pathway. After the initiating oncogene mutation, the progression of IPMN resembles PanIN.

Mucinous Cystic Neoplasms (MCN)

The risk of malignant transformation in MCNs is <15%, most often associated with an RNF43 gene mutation event (50%). As in PanINs, genetic changes accumulate with higher grade of dysplasia and invasiveness [48,53,54].

NATURAL HISTORY OF PDAC ONCOGENESIS

The PanIN Progression Model has been critical in shaping the perspective of how PDAC develops and progresses. PDAC arises through a specific sequence of genetic alterations over a gradual progression from early PanIN to late-stage metastatic disease [57,58,59].

The timeframe of PanIN progression has also been established. Based on computational modeling using autopsy cases, the estimated average time interval from initiation in normal cells to invasive ability (11.7 years), metastatic dissemination (6.8 years) and death (2.7 years) corresponds to an average of about 21 years from the initiating mutation until a patient's death [17].

Most cases with PDAC are diagnosed toward the end of this lifetime span, suggesting that poor prognosis is largely a function of late diagnosis in the natural history of PDAC, and that a golden opportunity of two or three years exists to diagnose "early" pancreatic cancer (i.e., Stage 0 or I) [60].

Chromothripsis, a recently identified phenomenon, is a catastrophic event causing tens to thousands of chromosomal rearrangements. Faced with hundreds of DNA breaks, the cell's DNA repair machinery attempts to rescue the genome, but the result bears little resemblance to its original structure [61,62]. This genomic disruption can drive the development of cancer through DNA copy number changes, including deletion of tumor suppressor genes and increased copy number (amplification) of oncogenes [61].

A 2016 study of more than 100 whole genomes from pancreatic cancer tumors found evidence of at least one chromothripsis event in 65% of tumors, and most copy-number changes seemed to occur after such catastrophic genetic events. With evidence of chromothripsis in some PDACs and nongradual tumorigenesis that defies the established mutational sequence, a punctuated equilibrium model was proposed, dividing tumor development into two major events [63]:

- A cancer-initiating event: PDAC preneoplasms acquire extensive mutation burden but remain non-invasive over a prolonged preneoplastic phase.

- A cataclysmic cancer-transforming event: Chromothripsis induces DNA copy number changes, creating genomic instability and generating invasive clones with rapid dissemination and colonization of distant sites. Why chromothripsis occurs in PDAC is not yet understood.

Non-Genetic Mechanisms

Rather than being uniformly aggressive, PDAC exhibits clinical (e.g., variable patient survival) and disease (e.g., variable chemotherapy sensitivity) heterogeneity [64,65]. The first whole-genome description of PDAC in 2008 prompted great effort to advance a patient-tailored precision medicine approach that could better address this heterogeneity. Genetic alterations and molecular subtypes in PDAC were characterized and published. PDAC was shown mutationally dominated by the four driver genes and homogeneous. In general, the findings importantly informed the biology and familial predisposition of PDAC.

However, by 2019 it was apparent that PDAC disease heterogeneity cannot be explained by genetic mutations alone, and non-genetic mechanisms, including epigenetics and the tumorigenic microenvironment, were the path forward [21,56,59,62,64,65,66,67].

Epigenetic Factors

Broadly speaking, epigenetic changes influence gene expression, without altering the DNA sequence, through modifications of DNA or chromatin structures [4]. In PDAC, these include DNA methylation and non-coding RNAs (ncRNAs).

Gene expression in PDAC can be silenced through non-mutational inactivation by aberrant promoter methylation, including the driver gene p16/CDKN2A[49]. Aberrant ncRNA expression plays a considerable role in initiation, proliferation, and chemo-resistance of PDAC. Oncogenic microRNA-21 promotes both cell proliferation and apoptosis and targets negative regulators of KRAS, which further enhances signaling by this oncogene [50,54].

Pancreatic Tumor Microenvironment

PDAC is comprised of cancer cells within dense fibrotic stroma consisting of extracellular matrix and non-neoplastic (e.g., fibroblastic, vascular, immune) cells [3]. Also described as PDAC fibrosis, the stroma makes up most of the tumor mass. This network of neoplastic tissue and stroma (the pancreatic tumor microenvironment) acts as physical barrier to drug penetration and has elements that impede host immune surveillance and antagonize host anticancer immune responsiveness, facilitating PDAC growth, survival, and treatment failure [21,51,68]. Current anti-cancer therapy includes novel approaches designed to enhance sensitivity of PDAC to the host immune system and reverse the immunosuppressive effects of the tumor microenvironment [134].

Pancreatic cancer progresses in tandem with extensive stromal deposition of extracellular matrix, recruitment and activation of cancer-associated fibroblasts, and high interstitial fluid pressures, which compresses blood vessels, causing localized hypoperfusion, reduced vascularity, and tissue hypoxia [21,69]. Extracellular matrix remodeling biomechanically induces intracellular signaling and tumor-stellate cell crosstalk. PDAC cells signal to stellate cells and recruit macrophages and immune suppressor cells. In turn, stellate cells secrete factors that promote PDAC cell proliferation, migration, and suppression of apoptosis [51]. Biochemical activation of signaling pathways regulates PDAC cell survival and promotes tumor growth and metastasis. Down-stream effects include immunosuppression, disease progression, epithelial-mesenchymal transition (a key step of the metastatic cascade) and invasive potential, and chemotherapy resistance [3,21,69].

Exosomes (a macromolecule involved in RNA degradation) released by PDAC cells accumulate in other tissues to create a premetastatic niche by activating stellate cells and inducing remodeling of the host extracellular matrix, which facilitates cancer cell invasion and growth [59,69].

HEREDITARY PDAC

In addition to the somatic mutations driving pancreatic tumorigenesis in all PDACs, specific pathogenic germline alterations impose a predisposition to PDAC in some patients [48]. In many of these germline mutations, the oncogenic mechanism involves inactivation of DNA damage repair genes [49].

There are two broad categories of inherited risk for PDAC [26,70,71]:

- Genetic predisposition or hereditary pancreatic cancer: Germline mutations in PDAC susceptibility genes are present.

- Familial pancreatic cancer: Familial clustering of PDAC (i.e., at least one pair of affected first-degree relatives) without known germline mutations

Most patients with PDAC have no identifiable genetic factor nor familial history; such cases can be classified as sporadic. The frequency of identifiable pathogenic germline mutations in persons with PDAC is about 10% [136]. The most common pathogenic alterations are in BRCA1, BRCA2, and ATM, which with the other more rarely identified genetic alterations have an aggregate frequency of 3.8% to 9.7% [136]. Approximately 3% to 7% of patients with PDAC harbor a BRCA1 or BRCA2 gene mutation. Identification of pathogenic gene mutations is important for therapeutic purposes and useful for screening and surveillance of at-risk family members.

Inherited Cancer Susceptibility Syndromes and Germline Mutations

Several genetic syndromes are associated with specific genetic alterations with an increased risk for pancreatic cancer (Table 3) [48,54]. Germline mutations in familial atypical multiple mole melanoma syndrome (CDKN2A) and Li-Fraumeni syndrome (TP53) are core gene drivers in sporadic PDAC. Peutz-Jeghers syndrome is caused by germline inactivation of STK11, a tumor suppressor gene. Somatic STK11 mutations are observed in approximately 4% of pancreatic cancers, suggesting STK11 inactivation plays a role in both sporadic and familial forms [49].

Table 3: PANCREATIC CANCER SUSCEPTIBILITY SYNDROMES AND MUTATIONS

Category

Specific Syndromes and Germline Mutations

Gastrointestinal tract cancers

Lynch syndrome, also termed hereditary nonpolyposis colorectal cancer (MLH1, MSH2, MSH6, PMS2)

Peutz-Jeghers syndrome (STK11/LKB1)

Familial adenomatous polyposis (APC)

Solid tumor cancers

Hereditary breast/ovarian syndrome (BRCA1/2, PALB2)

Familial atypical multiple mole melanoma syndrome (CDKN2A)

Li-Fraumeni syndrome (TP53)

Chronic pancreatitis-associated syndromes

Hereditary pancreatitis (PRSS1, SPINK1)

Cystic fibrosis (CFTR)

Neurodegenerative disease

Ataxia-telangiectasia (ATM)

Source: [48,54]

Familial Pancreatic Cancer

An estimated 10% to 15% of all pancreatic cancers are attributable to genetic causes. Pancreatic cancer aggregates in some families; 5% to 10% of individuals with pancreatic cancer have a family history of the disease [26,70,72]. Familial pancreatic cancer represents 90% of all hereditary PDAC cases. The relative risk of PDAC increases with the number of affected first-degree relatives.

A specific gene defect responsible for familial pancreatic cancer has not been identified, but a rare autosomal-dominant gene may be responsible, putting 0.4% to 0.7% of the population at risk for developing PDAC [26,70,72]. Details about the relative and lifetime risks of PDAC, and the other prevalent cancers associated with specific germline mutations in cancer susceptibility syndromes and familial pancreatic cancer, are summarized in Table 4.

Table 4: PANCREATIC CANCER RISK IN PREDISPOSITION AND INHERITED CANCER SYNDROMES

Syndrome

Gene(s)

Risk of PDAC

Other Cancers

Relative

Lifetime

General population

–

1

0.5%

–

Hereditary breast/ovarian cancer

BRCA1

2 to 3

1.2% to 2%

Breast, ovarian, prostate

BRCA2

3.5 to 10

2% to 10%

PALB2

15

5% to 10%

Familial atypical multiple mole melanoma

CKDN2A

13 to 36

10% to 30%

Melanoma

Peutz-Jeghers

STK11

75 to 125

11% to 66%

GI, lung, breast, reproductive

Hereditary nonpolyposis colon cancer (Lynch II)

MLH1, MSH2, MSH6

8 to 10

3.7% to 10%

Colorectal, ovary, uterine, upper GI, urinary tract

Li-Fraumeni

TP53

7

unknown

Breast, brain, adrenal

Familial adenomatous polyposis

APC

4.5

Less than 5%

Colon, upper GI, thyroid, brain

Ataxia telangiectasia

ATM

8 to 9

1% to 5%

Breast, prostate

Hereditary pancreatitis

PRSS1, SPINK1

50 to 82

25% to 44%

–

Cystic fibrosis

CFTR

5

Less than 5%

–

Familial pancreatic cancera

1 first-degree relative

4.6

–

–

2 first-degree relatives

6.4

–

–

3 first-degree relatives

32

–

–

aRisk determined by number of affected first-degree relatives rather than specific gene.

Source: [49,54,70,73]

4. PANCREATIC CANCER SCREENING

With the low population incidence of PDAC (lifetime risk: 1.3%), absence of biomarker screening targets, and high cost of sensitive imaging methods, the U.S. Preventive Services Task Force recommended against screening for pancreatic cancer in asymptomatic adults in 2019, reaffirming its previous conclusion in 2004 [74]. As population screening to achieve earlier detection and intervention of PDAC is not currently feasible, other approaches for this objective have been identified.

In Australia, public awareness campaigns have highlighted the often-vague symptoms of PDAC and encouraged individuals to seek medical attention early. Underscoring this point, one study found that many people who were ultimately diagnosed with PDAC were falsely reassured by the subtle, intermittent nature of their symptoms over the preceding months [75,76].

As a relatively rare cancer, many primary care providers will only see a PDAC case every few years, making it imperative to elevate awareness of early PDAC signs and symptoms among these professionals. A retrospective case-control study in primary care found that patients sought medical attention 18 times on average in the period preceding their pancreatic cancer diagnosis. PDAC was associated with 11 alarm symptoms; back pain, lethargy, and new-onset diabetes were unique features of PDAC [75,77].

Specific screening efforts in PDAC have focused on identifying high-risk individuals [48]. In 2020, both the International Cancer of the Pancreas Screening (CAPS) Consortium and the American Gastroenterological Association (AGA) published updated recommendations for the management of individuals with increased risk of pancreatic cancer. Screening is recommended in first-degree relatives of patients with pancreatic cancer who have one or more other genetically related relative with the diagnosis. Screening should be considered in anyone with genetic syndromes associated with increased risk of PDCA. These include persons with Peutz-Jeghers syndrome, hereditary pancreatitis, or known CDKN2A gene mutation; and persons with one or more first-degree relatives with pancreatic cancer who are carriers of a germline BRCA1, BRCA2, PALB2, or ATM gene mutation (Table 5) [71;137)]. Surveillance of high-risk individuals is recommended to detect and resect early pancreatic cancer and its high-grade precursors (Table 5). No consensus was reached on whether surveillance should be performed for hereditary pancreatitis.

Table 5: INTERNATIONAL CANCER OF THE PANCREAS SCREENING (CAPS) CONSORTIUM CONSENSUS ON SCREENING FOR PANCREATIC CANCER IN PATIENTS WITH INCREASED RISK FOR FAMILIAL PANCREATIC CANCER

What is the goal of pancreatic surveillance?

The primary goal is to prevent the emergence of and death from pancreatic cancer by identifying and treating stage I pancreatic cancer (resected with negative margins) and pancreatic cancer precursor lesions with high-grade dysplasia (PanIN or IPMN).

Who should be screened?

All patients with Peutz-Jeghers syndrome (carriers of a germline LKB1/STK11 mutation)

All carriers of a germline CDKN2A (p16) mutation

Carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least one affected first-degree relative

Individuals with at least one first-degree relative with pancreatic cancer who in turn also has a first-degree relative with pancreatic cancer (familial pancreatic cancer kindred)

At what agea should pancreatic surveillance begin?

Familial pancreatic cancer kindred

Start at 50 or 55 years of age, or 10 years younger than the youngest affected blood relative

Mutation carriers

For CDKN2A and Peutz-Jeghers syndrome, start at 40 years of age

For BRCA2, ATM, PALB2, BRCA1, and MLH1/MSH2, start at 45 or 50 years of age, or 10 years younger than the youngest affected first-degree relative

What tests and indications?

Indication

Interval

Test(s)

Routine

At baseline and during follow-up

MRI/MRCP and endoscopic ultrasound

Fasting blood glucose and/or HbA1c

Concerning abnormalities for which immediate surgery is not indicated

After 3 to 6 months

Repeat follow-up testing

No abnormalities or only non-concerning abnormalities (e.g., pancreatic cysts without worrisome features)

After 12 months

Repeat follow-up testing

If concerning features on imaging

Upon indication

Serum CA 19-9

Solid lesions of ≥5 mm

Cystic lesions with worrisome features

Asymptomatic main pancreatic duct strictures (with or without mass)

Upon indication

Endoscopic ultrasound-guided FNA

Solid lesions, regardless of size

Asymptomatic main pancreatic duct strictures of unknown etiology (without mass)

Upon indication

CT

Positive FNA and/or a high suspicion of malignancy on imaging

Upon indication

Surgeryb

aAge to initiate surveillance depends on gene mutation status and family history. There is no consensus on the age to end surveillance.

bWhen surgery is indicated, it should be oncologic radical resection at a specialty center.

CA 19-9 = carbohydrate antigen 19-9; CT = computed tomography; FNA = fine-needle aspiration; HbA1c = hemoglobin A1c; IPMN = intraductal papillary mucinous neoplasm; MRI/MRCP = magnetic resonance imaging/magnetic retrograde cholangiopancreatography; PanIN = pancreatic intraepithelial neoplasia.

Source: [70,71]

However, it is important to remember that among patients with PDAC unselected for their family history of pancreatic cancer who had a germline susceptibility gene mutation, only 10% of these patients had a family history of pancreatic cancer, and most did not have a cancer family history to suggest an inherited cancer syndrome. Because family history remains one of the best predictors of future pancreatic cancer risk, routine gene testing of patients with newly diagnosed PDAC and their families may yield significant clinical benefits [78].

Genetic counseling of patients before and after any genetic testing is essential, to provide understanding and reassurance and to avoid harm. A challenge to less restrictive testing of patients with new PDAC is there are not enough genetic counselors to provide this service; this shortage of expertise applies to other cancers as well [78].

GERMLINE AND SOMATIC TESTING AND MOLECULAR ANALYSIS

With strong consensus that benefits outweigh harms, in 2018 the ASCO recommended germline genetic testing for patients with PDAC, even if family history is unremarkable, if an informative result could directly benefit the patient or their family members [73]. This stance was adopted in 2020 by the NCCN. Consensus has subsequently expanded.

All patients with pancreatic cancer should have germline testing and gene profiling offered as quickly as possible after diagnosis; the implications for first-line therapy and beyond are significant [79,80]. The 2020–2021 ASCO and NCCN recommendations are for all patients with PDAC to receive germline genomic testing using comprehensive gene panels for hereditary cancer syndromes, and targeted (somatic) profiling of tumor tissue using next-generation sequencing [10,11]. Patients with locally advanced or metastatic PDAC should have available tumor tissue tested for DNA mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status. It is also recommended that these patients undergo testing for actionable somatic mutations, including fusions (ALK, NRG1, NTRK, ROS1), mutations (BRAF, BRCA1/2, HER2, KRAS, PALB2), and mismatch repair deficiency (dMMR).

NOVEL APPROACHES TO PANCREATIC CANCER SCREENING

Advances in genomic analysis of human tissue from patients with pancreatic cancer and precancer are enabling the application of DNA-based molecular approaches to early detection of risk for PDAC. Circulating micro RNAs (miRNAs) are a group of small non-coding RNAs that regulate gene expression. These micromolecules are highly stable and can be quantified in small specimens of tissue or plasma. Using plasma samples collected from prospective cohort studies, investigators systematically screened for and validated specific circulating miRNAs as biomarkers associated with pancreatic cancer risk. Three miRNA targets, identified from prediagnostic plasma samples, were associated with the development of pancreatic cancer within five years of sample collection. In addition, five other specific miRNAs were associated with pancreatic cancer risk specifically among patients older than 65 years of age [138]. If confirmed by larger studies, miRNA biomarkers may be useful in identifying individuals at risk of developing pancreatic cancer, who then would be candidates for further screening and close surveillance.

5. CLINICAL EVALUATION OF PANCREATIC CANCER

Most pancreatic cancers (approximately 70%) originate in the head of the pancreas and present with biliary obstruction leading to dark urine (49%), jaundice (49%), loss of appetite (48%), weight loss (55%), and pancreatic insufficiency (25%) [134]. Symptoms of pancreatic cancer arising in the body and tail of the pancreas are more nonspecific, such as abdominal pain, back pain, weight loss and fatigue. Pancreatic cancers typically metastasize to regional lymph nodes first, then to the liver. PDAC can also directly invade surrounding visceral organs (e.g., duodenum, stomach, colon); metastasize to any surface in the abdominal cavity via peritoneal spread where development of ascites carries an ominous prognosis; or spread to the skin as painful nodular metastases. By the time of diagnosis, 85% to 90% of patients have locally advanced tumors that have involved retroperitoneal structures, spread to regional lymph nodes, or metastasized to the liver or lung [2,13,24,81].

Early-stage pancreatic cancer is notoriously difficult to diagnose. The most common symptoms in a series of patients diagnosed with PDAC were fatigue (86%), weight loss (85%), anorexia (83%), abdominal pain (79%), epigastric pain (71%), jaundice (56%), nausea (51%), diarrhea (44%), pruritus (32%), and steatorrhea (25%) [82].

Abdominal pain, jaundice, and weight loss are nonspecific, subtle in onset, and easily attributed to other processes. Unless the healthcare provider has a high index of suspicion for the possibility of underlying pancreatic carcinoma, this can make it difficult to know when to escalate a workup, as PDAC lacks a specified diagnostic algorithm [2,24].

Development of abdominal pain, jaundice, or weight loss in the context of newly diagnosed diabetes, family history of PDAC, or history of pancreatitis should trigger inclusion of PDAC in the differential diagnosis [2]. Furthermore, past three-year onset of diabetes or ongoing hyperglycemia with significant weight loss and decreasing serum lipids should be considered a potential PDAC, even if abdominal pain or jaundice are absent, with urgent referral a priority.

As noted, pancreatic cancer-associated diabetes and pancreatic cancer cachexia are distinct paraneoplastic syndromes with clinical parameters that may alert attentive clinicians to pursue an appropriately aggressive workup [47]. The lethality of pancreatic cancer merits such an approach despite the absence of formal diagnostic guidelines in this area.

NEUROPSYCHIATRIC SYMPTOMS AND PANCREATIC CANCER

A peculiar herald sign of occult pancreatic cancer is the insidious onset of an enigmatic depression, absent abdominal pain and often accompanied by anorexia and weight loss. In some patients, depression may be the most prominent presenting symptom, possibly secondary to delayed diagnosis. In addition, although patients may not communicate it to their families, they are often aware that a serious illness of some kind is occurring in them [24]. The risk of suicide among male patients with PDAC is almost 11 times higher than the general male population. Patients who underwent resection are more likely to commit suicide, specifically in the early postoperative period [83].

The association between mood disorders, fatigue, and PDAC has been assumed secondary to the psychosocial impact of diagnosis, loss of independence, and treatment toxicity [2]. However, it is now clear that PDAC has independent detrimental effects on the brain. These symptoms, often present before a diagnosis, are collectively the greatest drivers of declines in health-related quality of life and are independently predictive of survival. Evidence points to neuroinflammatory processes and the need to rethink PDAC as a systemic disease [2].

FAMILY HISTORY

The importance is emphasized of taking a thorough family history when seeing a new patient with pancreatic cancer. A family history of pancreatitis, melanoma, and pancreatic, colorectal, breast and ovarian cancers should be noted [11].

If a cancer syndrome is identified, at-risk relatives should be offered genetic counseling. With or without a known syndrome, individuals with a suspicious family history should be advised on risk-reducing strategies, including smoking cessation and weight loss. The possibility of screening for pancreatic and other cancers should be discussed.

Referral for genetic counseling should be considered for patients diagnosed with pancreatic cancer, especially those with a family history of cancer or who are young, those of Ashkenazi Jewish ancestry, or for whom a hereditary cancer syndrome is suspect. A free pancreatic cancer risk prediction tool, PancPRO, is available and may help determine risk [11].

COMMON PRESENTING SYMPTOMS AND SIGNS

Some, but not all, initial symptoms of PDAC result from a mass effect, such that pancreatic tumor location influences the stage of disease progression when symptoms appear [13].

Abdominal Pain

Abdominal pain is the most common symptom, usually insidious in onset and often present for one to two months at the time of presentation, the pain is often severe, and unrelenting in nature. The typical gnawing, visceral quality of pain is generally epigastric, radiating to the sides and/or straight through to the back; some patients may describe the pain as originating in the back. Nighttime pain is often the predominant complaint. Some patients note increased pain after eating and worsened pain when lying flat [24,81]. Rarely, acute pain develops when an episode of acute pancreatitis results in tumor occlusion of the main pancreatic duct [84].

While roughly one-third of patients may not have pain at the time of initial presentation, all patients will develop pain at some point [24]. Pancreatic cancer is one of the most painful malignancies, and effective pain control is extremely important [85]. This issue will be discussed in detail later in this course.

Jaundice

The most characteristic sign of tumor in the pancreatic head is obstructive jaundice, for which patients may seek medical attention before their tumor grows large enough to cause abdominal pain (and thus, a somewhat better prognosis). These patients usually notice a darkening of their urine and/or lightening of their stools before they or their families notice the change in skin pigmentation. Jaundice secondary to a tumor in the body or tail of the pancreas typically occurs at a later stage and may be secondary to liver metastases of PDAC [2,84].

Pruritus can accompany and often precedes obstructive jaundice. If present, it is often the patient's most distressing symptom [24].

Significant Weight Loss

A characteristic feature of pancreatic cancer, significant weight loss may be related to cancer-associated anorexia and/or subclinical malabsorption from pancreatic exocrine insufficiency caused by pancreatic duct obstruction. Nausea and early satiety from gastric outlet obstruction and delayed gastric emptying from the tumor can contribute to weight loss [24]. Significant weight loss is a symptom of cachexia.

Cachexia

Pancreatic cancer cachexia is a multifactorial paraneoplastic syndrome characterized by a loss of skeletal muscle mass, commonly associated with adipose tissue wasting and anorexia, fatigue, and reduced exercise tolerance. Cachexia develops in approximately 80% of patients with PDAC, in whom the syndrome is typically present at diagnosis and responds poorly to therapeutic interventions [47,86].

Pancreatic cancer leads to the development of cachexia through a combination of distinct factors that explain its high prevalence and clinical importance in this disease [86]:

- Systemic factors, including metabolic changes and pathogenic signals related to PDAC tumor biology

- Factors resulting from the disruption of the digestive and endocrine functions of the pancreas

- Factors related to the close anatomic and functional connection of the pancreas with the gut

Additional Symptoms

The initial assessment can uncover additional diagnostic clues. Undiagnosed diabetes leads to symptoms of glucose intolerance (e.g., polyuria, polydipsia). PDAC can interfere with production of digestive enzymes by the pancreas (pancreatic exocrine insufficiency) and with the ability to break down food and absorb nutrients (malabsorption) in some patients. This malabsorption causes bloating, gas, and a watery, greasy, and/or foul-smelling diarrhea, leading to weight loss and vitamin deficiencies [81].

While long-standing diabetes is a risk factor for later development of PDAC, new-onset hyperglycemia or diabetes has been identified in most patients at diagnosis of otherwise asymptomatic PDAC. Deregulation in glucose homeostasis is often accompanied by changes in subcutaneous adipose tissue. Both represent paraneoplastic syndromes caused by the underlying PDAC [2].

This research is among the most important knowledge advances in PDAC in the past decade. In addition to metabolic deregulation, the pre-diagnostic soft tissue changes and symptoms of cachexia have profound implications for screening, early diagnosis, treatment selection, and patient prognosis [2].

Tumors can also grow locally into the duodenum (proximal for the head of the pancreas, distal for the body and tail of the pancreas) and result in an upper gastroduodenal obstruction [13]. Tumor in the body or tail of the pancreas may cause splenic vein obstruction, resulting in splenomegaly, gastric and esophageal varices, and gastrointestinal hemorrhage [81].

PHYSICAL EXAMINATION

Clinical signs of PDAC during physical examination include jaundice, pruritus, steatorrhea, and vascular issues [2,24,82,84]. Healthcare professionals can usually recognize clinical jaundice when total bilirubin reaches 2.5–3 mg/dL. Patients and their families do not usually notice clinical jaundice until total bilirubin reaches 6–8 mg/dL. Patients with jaundice may have a palpable gallbladder (i.e., Courvoisier sign). As noted, patients with clinical jaundice may have skin excoriations from unrelenting pruritus. If the pancreas has lost the ability to secrete fat-digesting enzymes or if the main pancreatic duct is blocked, steatorrhea will develop.

Migratory thrombophlebitis (i.e., Trousseau syndrome) and venous thromboembolism, reflecting the hypercoagulable state that frequently accompanies pancreatic cancer, may be the initial clinical sign. Thromboembolic events (both venous and arterial) are especially prevalent in advanced disease, and thromboembolic complications occur more commonly with tumors in the pancreatic tail or body.

Multiple arterial emboli resulting from nonbacterial thrombotic endocarditis may be the presenting sign of PDAC. Marantic endocarditis (also known as nonbacterial thrombotic endocarditis) may develop in patients with pancreatic cancer and possibly mimic subacute bacterial endocarditis.

METASTATIC DISEASE

Metastatic disease most commonly affects the liver, peritoneum, lungs, and less frequently, bone [24,84]. Patients presenting with or developing advanced intra-abdominal disease may have ascites, a palpable abdominal mass, hepatomegaly from liver metastases, or splenomegaly from portal vein obstruction. Subcutaneous metastases (termed Sister Mary Joseph nodules) in the paraumbilical area signify advanced disease; pancreatic cancer is the origin of a cutaneous metastasis to the umbilicus in 7% to 9% of cases [24,84]. A metastatic mass in the rectal pouch may be palpable on rectal examination (Blumer shelf). As a metastatic node, left supraclavicular lymphadenopathy may be palpable, while other nodes in the cervical area may also be involved.

LABORATORY TESTING

Routine laboratory tests are often abnormal but nonspecific for PDAC. Common abnormalities include an elevated serum bilirubin and alkaline phosphatase levels, and presence of mild anemia [84].

Patients presenting with jaundice or epigastric pain should be evaluated with complete blood count, blood chemistry panel, and liver function tests to help assess the extent of cholestasis (bilirubin), liver metastasis (alkaline phosphatase), hepatitis (aminotransferases), and nutritional status (albumin, prealbumin). With epigastric pain, serum lipase should be measured to evaluate for acute pancreatitis [2].

DIFFERENTIAL DIAGNOSIS

Differential diagnosis before imaging and biopsy includes acute/chronic pancreatitis, cholangitis, cholecystitis, choledochal cyst, peptic ulcer disease, cholangiocarcinoma, and gastric cancer [85]. Unlike pancreatic exocrine tumors, the symptoms of pancreatic neuroendocrine tumors are distinctly related to excessive secretion of hormones such as insulin, glucagon, gastrin, somatostatin, and vasoactive peptide, resulting in hypoglycemia, hyperglycemia, and GI disturbances such as peptic ulcer and diarrhea.

When diagnostic imaging in a patient presenting with obstructive jaundice reveals an abnormality of the region of the pancreas, the differential diagnosis is usually that of a soft-tissue mass involving the head of the pancreas, causing common bile-duct obstruction. Imaging studies help characterize such lesions as either extrapancreatic, cystic or solid pancreatic mass lesions [139]. Extrapancreatic masses, which can be difficult to distinguish from intrinsic pancreatic lesions, include those caused by regional lymphadenopathy and ampullary, duodenal, and bile duct neoplasms. Cystic pancreatic masses include retention cysts, papillary neoplasms, and mucinous cystic or serous cystic neoplasms. When imaging shows a solid pancreatic mass, the possibilities include exocrine pancreatic cancer (PDAC), pancreatic neuroendocrine tumor, autoimmune pancreatitis, metastatic cancer, and lymphoma [139].

6. THE DIAGNOSTIC AND STAGING WORKUP

It is not possible to reliably diagnose a patient with pancreatic cancer based on symptoms and signs alone. Abdominal imaging is used in the diagnostic and staging workup of a patient with suspected PDAC. Additional testing is based on the initial findings, the patient's clinical presentation and risk factors [2].

Accurate PDAC detection and staging at the time of presentation carries substantial implications for appropriate recommendation to patients of the most suitable treatment option, thus maximizing the survival benefit for patients in whom complete resection can be achieved and minimizing the morbidity from unnecessary laparotomy or major surgery in patients with high risk of residual disease following resection. The accuracy critically depends on the appropriate imaging protocol and radiologist experience [2,87]. As such, decisions about diagnosis, resectability, and management of pancreatic cancer should involve multidisciplinary consultation at high-volume centers [11].

IMAGING

Multidetector Computed Tomography

Evidence Based Practice Recommendation

The American Society of Clinical Oncology recommends a multiphase computed tomography (CT) scan of the abdomen and pelvis using a pancreatic protocol or magnetic resonance imaging (MRI) be performed for all patients with pancreatic cancer to assess the anatomic relationships of the primary tumor and to assess for the presence of intra-abdominal metastases.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 27, 2024

Strength of Recommendation/Level of Evidence: Strong/high

Multidetector computed tomography (MDCT) angiography with intravenous (IV) contrast is the preferred imaging for initial evaluation of suspected PDAC. The Pancreatic CT Protocol standardizes its use, making MDCT highly accurate for assessing tumor extent, vascular invasion, and distant metastases [11,16,88,89]. The degree of contact between the tumor and local blood vessels (i.e., uninvolved, abutted, or encased) is used to define the most optimal initial treatment [134]. The NCCN recommends that MDCT angiography should also cover the chest and pelvis for complete staging [11].

MDCT is 77% accurate in predicting resectability and 93% accurate in predicting unresectability [85]. MDCT may be superior to magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) in vascular enhancement of a PDAC, the most important parameter of resectability. However, MDCT is inferior to MRI/MRCP in depicting isodense tumors or tumors smaller than 1.5 cm in size [54].

Magnetic Resonance Imaging/Magnetic Resonance Cholangiopancreatography (MRI/MRCP)

Abdominal MRI/MRCP with IV contrast also employs a standard multiphase protocol in PDAC, with efficacy comparable to MDCT in preoperative evaluation and assessment of vascular invasion. The sensitivity of MRI/MRCP in detecting liver metastases is nearly 100% (vs. 80% with MDCT) [81,85].

Selection of initial MDCT or MRI/MRCP is typically based on local availability and expertise [81,85]. Following initial MDCT, MRI/MRCP is used when PDAC is highly suspected but negative on MDCT, for characterizing small or indeterminate pancreatic and hepatic tumors, and in patients with severe allergy to iodinated IV contrast material used in MDCT [54,81,85].

Endoscopic Retrograde Cholangiopancreatography (ERCP)

With endoscopic retrograde cholangiopancreatography (ERCP), contrast dye is injected into the biliary ducts and pancreatic duct with an endoscope, and the level of obstruction is delineated. In some case, placement of a biliary stent can help relieve symptoms of jaundice [85]. Patients with obstructive jaundice may have ERCP as the first diagnostic procedure [81].

Ultrasonography

Transabdominal ultrasonography is useful in initial screening of patients who present with possible obstructive jaundice and can rapidly and accurately assess for biliary obstruction. However, definitive diagnosis requires other imaging [24].

Endoscopic ultrasonography is superior to MDCT in detecting solid pancreatic lesions less than 2 cm in size, with accuracy of about 92% [54]. Endoscopic ultrasonography-guided fine-needle core biopsy (preferred over fine-needle aspiration) is recommended to obtain a histologic diagnosis and to provide material for molecular testing [134].

With the restricted field of view, endoscopic ultrasonography is complimentary to MDCT, but it should be used before other imaging options if no pancreatic mass is evident on MDCT. Endoscopic ultrasonography is also valuable in detecting tumor involvement of blood vessels or lymph nodes [11,89].

Positron-Emission Tomography (PET)

Positron-emission tomography (PET) imaging alone does not offer added advantages to MDCT. Combining PET with CT (PET/CT) is a more recent development that may enhance the detection of occult metastases in pancreatic cancer. The NCCN guidelines consider PET/CT an evolving technology; its role in the diagnosis of PDAC is not yet established [11].

BIOPSY

Endoscopic ultrasound-guided biopsy is preferable to a CT-guided biopsy in patients with non-metastatic disease because of better diagnostic yield, safety, and lower risk of peritoneal seeding when compared with the percutaneous approach. Biopsy proof of malignancy is not required before surgical resection, and a non-diagnostic biopsy should not delay surgical resection when the clinical suspicion for pancreatic cancer is high [11]. However, when histologic confirmation of a pancreatic cancer diagnosis is required, as in certain situations, endoscopic ultrasonography-guided fine-needle core biopsy is the best modality for obtaining a tissue diagnosis.

A pathologic diagnosis is indicated to confirm PDAC in locally advanced or metastatic disease, before neoadjuvant therapy, and in atypical presentations in which differential diagnosis is needed with other pancreatic masses (e.g., pancreatitis, lymphoma, tuberculosis). If a biopsy does not confirm malignancy, it should be repeated at least once [16].

The difficulty of diagnosing PDAC in patients with underlying chronic pancreatitis is noteworthy. In such cases, all typical imaging methods may show abnormalities that do not differentiate between PDAC and chronic pancreatitis, and carbohydrate antigen 19-9 (CA19-9) may be similarly elevated in pancreatitis. These patients may require combined multiple imaging modalities, close follow-up, serial imaging studies, and in some cases, empiric resection to diagnose an underlying pancreatic carcinoma [24].

CARBOHYDRATE ANTIGEN 19-9 (CA19-9)

CA19-9 is a sialylated Lewis A blood group antigen, commonly expressed and shed in benign and malignant pancreatic and biliary disease. Although not sufficiently sensitive or specific for routine screening, CA19-9 is the most clinically useful biomarker in PDAC, with sensitivity (79% to 81%) and specificity (82% to 90%) in symptomatic patients. A normal serum level is 37 U/mL [90].

Preoperative CA19-9 provides important prognostic information. Levels <100 U/mL imply likely resectable disease, while levels >100 U/mL suggest unresectablity or metastatic disease. Fewer than 4% of patients with levels >300 U/mL have resectable tumors [24,90].

In one study, patients with preoperative CA19-9 levels <37 U/mL showed longer median survival (22 to 40 months) than patients with levels >37 U/mL (7 to 30 months). Post-treatment changes (two to five weeks post-resection; six to eight weeks post-chemotherapy) from baseline may predict overall survival [90,91].

CA19-9 is a useful biomarker for monitoring treatment response. Post-operative CA19-9 levels of <37 U/mL, <200 U/mL, and >500 U/mL were associated with three-year survival rates of 49%, 38%, and 0%, respectively. Post-chemotherapy CA19-9 decreases of ≥20% predicted prolonged disease-free survival and overall survival [90,91].

Limitations

Around 5% to 10% of the population lacks the enzyme necessary to produce CA19-9; monitoring pancreatic cancer with this marker will not be possible in these individuals [24]. Biliary obstruction also stimulates the secretion of CA19-9. Hyperbilirubinemia is associated with elevated CA19-9 and false positivity in patients with obstructive jaundice. Following the treatment of obstruction, re-evaluation of CA19-9 should improve its diagnostic utility [92].

The NCCN recommends measurement of serum CA19-9 levels after neoadjuvant treatment, prior to and immediately following surgery before adjuvant therapy, and in surveillance. The importance is stressed of obtaining CA19-9 immediately before a therapeutic intervention to have an accurate baseline from which to follow response [11].

THE STAGING WORKUP

When a solid tissue mass lesion of the pancreas is detected on MDCT (with or without additional imaging), it is reasonable to conclude that a neoplasm is present and is most likely malignant PDAC. After a probable diagnosis of pancreatic cancer is made, the next step is the staging evaluation to establish disease extent and resectability. Unlike many other cancers, imaging is the primary means through which the stage of pancreatic cancer is determined [11].

Using initial MDCT (with or without additional imaging), two different systems are involved [11,93]:

- American Joint Committee on Cancer (AJCC) TNM staging system, to assess tumor status/extent (T), lymph nodes (N), and metastasis (M)

- NCCN guideline to characterize resectable, borderline resectable, or locally advanced disease

TNM Staging

The AJCC system (Table 6) is used for staging PDAC in two contexts [16,94]:

- Clinical staging of all patients with imaging assessment of tumor size and extension, nodal involvement, and distant disease spread

- Pathologic staging of tissue specimens obtained during resection for presence of viable tumor cells

Table 6: AMERICAN JOINT COMMISSION ON CANCER EXOCRINE PANCREATIC CANCER TNM STAGING

Category

Criteria

Primary tumor (T)

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ, including high-grade PanIN (PanIN-3) and IPMN, ITPN, or MCN with high-grade dysplasia

T1

Tumor ≤2 cm in greatest dimension

T1a

Tumor ≤0.5 cm in greatest dimension

T1b

Tumor >0.5 and <1 cm in greatest dimension

T1c

Tumor 1–2 cm in greatest dimension

T2

Tumor >2 and ≤4 cm in greatest dimension

T3

Tumor >4 cm in greatest dimension

T4

Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size

Regional lymph nodes (N)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in one to three regional lymph nodes

N2

Metastasis in four or more regional lymph nodes

Distant metastasis (M)

M0

No distant metastasis

M1

Distant metastasis

IPMN = intraductal papillary mucinous neoplasm; ITPN = intraductal tubulopapillary neoplasm; MCN = mucinous cystic neoplasm; PanIN = pancreatic intraepithelial neoplasia

Source: [93]

Clinical staging identifies the primary tumor and its vessel involvement, enlarged or suspicious lymph nodes, and metastatic disease sites. TNM staging provides important prognostic information (Table 7) but does not assess whether the PDAC tumor is amenable to surgical resection [54,94].

Table 7: AMERICAN JOINT COMMISSION ON CANCER ANATOMIC STAGE/PROGNOSTIC GROUPS FOR EXOCRINE PANCREATIC CANCER

Stage

T

N

M

A

T1

N0

M0

IB

T2

N0

M0

IIA

T3

N0

M0

IIB

T1–T3

N1

M0

III

Any T

N2

M0

T4

Any N

M0

IV

Any T

Any N

M1

Source: [93]

Resectability Assessment

Complete resection is the only potentially curative treatment for PDAC, but fewer than 20% of patients presenting with PDAC have localized and easily resectable tumors, and noncurative resections provide no survival benefit. Thus, accurate assessment of resectability is crucial [24,87,89].

The NCCN guideline classes PDAC resectability into the following clinical stages [11]:

- Stage 1: Resectable

- Stage 2: Borderline resectable (i.e., tumors that are involved with nearby structures so as to be neither clearly resectable nor clearly unresectable with a high chance of removal of all macroscopic disease)

- Stage 3: Locally advanced (i.e., tumors that are involved with nearby structures to an extent that renders them unresectable despite the absence of metastatic disease)

- Stage 4: Metastatic (i.e., non-resectable)

Localized PDAC falls on a spectrum from high to low resectability, determined by the extent of vessel contact and whether the involvement is arterial or venous (Figure 1) [11,54,84,87,89,95]. Major peripancreatic vessels include the superior mesenteric vein and artery, portal vein, common hepatic artery, and celiac artery. Tumor contact can be characterized as encasement (≥180 degrees of the vessel circumference), abutment (<180 degrees of the circumference), or direct involvement (absence of fat plane between tumor and vessel).

Figure 1: SPECTRUM OF PANCREATIC CANCER RESECTABILITY

Source [84,89,95]

In the past, vascular infiltration by PDAC was considered unresectable, but surgical advances have increased the number of patients with initial borderline resectable or locally advanced disease who can undergo resection. In general, venous abutment or encasement is usually borderline resectable as long as the venous segment is reconstructable. Arterial reconstruction is substantially more difficult and riskier than venous reconstruction with comparable tumor contact.

Based on PDAC clinical status of resectable, borderline resectable, locally advanced, or metastatic disease, additional considerations and therapeutic approaches will be undertaken. The time-urgency between the first availability of full imaging findings, multidisciplinary evaluation, the diagnostic and staging workup, discussion with the patient of available treatment options, and treatment initiation cannot be overstated in this aggressive malignancy.

7. TREATMENT APPROACHES FOR PANCREATIC CANCER

As mentioned, the initial imaging workup of PDAC confirms the diagnosis, searches for evidence of metastases, and classifies nonmetastatic PDAC into resectable, borderline resectable, or locally advanced disease based on the involvement of surrounding arterial (superior mesenteric artery, common hepatic artery, and celiac axis) and venous (superior mesenteric vein or portal vein) structures, and other nearby organs and lymph nodes [96].

On average, 10% to 20% of patients initially present with "up-front" resectable PDAC. However, an increasing number of patients with initial borderline resectable or locally advanced disease are eligible for surgical resection as a result of neoadjuvant (i.e., before resection) therapies which may downstage the tumor, and advances in surgical technique, such as venous reconstruction in a vascular infiltration formerly considered unresectable [2].

In all therapeutic decisions, multidisciplinary collaboration to formulate treatment planning and disease management that incorporates patient preferences and available support, their comorbidity profile, symptom burden, and performance status should be the standard of care [6,7,10].

PATIENT FUNCTIONAL STATUS

Evidence Based Practice Recommendation

According to the ASCO, the baseline performance status, symptom burden, and comorbidity profile of a person diagnosed with potentially curable pancreatic cancer should be carefully evaluated.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 27, 2024

Strength of Recommendation/Level of Evidence: Strong/high

Performance status is an important indicator of general well-being and the ability to perform activities of daily living in patients with cancer and is frequently assessed in both clinical and research settings. Performance status is repeatedly shown to predict important clinical outcomes, including quality of life, chemotherapy toxicity, response to chemotherapy, terminal illness, progression-free survival, and overall survival in patients with cancer [97].

The Karnofsky Performance Status tool has been used for this purpose, but PDAC guidelines and randomized controlled trials now solely employ the Eastern Cooperative Oncology Group Performance Status (ECOG) scale (Table 8) [97]. For instance, some chemotherapies are indicated solely for patients with good ECOG performance status (0 or 1).

Table 8: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS SCALE

Score

Definition

0

Fully active

No performance restrictions

1

Strenuous physical activity restricted

Fully ambulatory and able to carry out light work

2

Capable of all self-care but unable to carry out any work activities

Up and about >50% of waking hours

3

Capable of only limited self-care

Confined to bed or chair >50% of waking hours

4

Completely disabled

Cannot carry out any self-care

Totally confined to bed or chair

5

Deceased

Source: [98]

Baseline functional status and comorbidity profile should be carefully evaluated, because both have major implications for a person's ability to tolerate therapy. Performance status is consistently identified as a prognostic factor for people with pancreatic cancer. It is also an important determinant in treatment selection; some patients with up-front resectable PDAC may be physically weakened by weight loss and cachexia to an extent that places them at high risk of serious complications or mortality from definitive surgery. Performance status also helps predict chemotherapy toxicity, which can determine the treatment approach for patients with performance status 0 to 1 (multi-agent regimens) or performance status ≥2 (e.g., single-agent gemcitabine) [8].

Similarly, the comorbidity profile can influence the choice of chemotherapy, such as avoiding fluoropyrimidine-based regimens in patients with a known history of uncontrolled coronary artery disease. Nonetheless, performance status and comorbidities alone should not be used simply to rule in or out patients for treatment. For instance, disease control of comorbidities, such as controlled type 2 diabetes, can indicate that patient benefit from treatment may outweigh risks associated with poorly controlled comorbid diabetes [8].

RECOMMENDED TREATMENT OPTIONS BY CLINICAL STAGE

Treatment approaches for PDAC include surgical resection, chemotherapy, radiation therapy, and combined regimens (chemoradiation therapy). Chemotherapy is the backbone of pancreatic cancer treatment and is employed in all stages of PDAC. This includes preoperative neoadjuvant therapy (resectable or borderline resectable), postoperative adjuvant therapy, and first-line or subsequent therapy in locally advanced, metastatic, and recurrent disease [11]. Most patients present with disease too far advanced to benefit from surgery or that surgical resection alone will not provide a survival advantage over what can be achieved with supportive care. Chemotherapy and radiation therapy also have a role in palliation, as will be discussed in a later section [99].

Curative surgical approaches for resectable pancreatic cancer are well-established. In contrast, the pace of new U.S. Food and Drug Administration (FDA) approvals and/or phase III evidence continue to make chemotherapy, molecular-targeted therapy, radiation, and chemoradiotherapy approaches a fluid, evolving area, requiring frequent updating and revisions in multidisciplinary clinical practice guidelines for pancreatic cancer treatment. Many potential treatment approaches lacking phase III or prospective evidence are being addressed, with publication of trial results awaited [2].

Resectable or Borderline Resectable PDAC

For patients with resectable or borderline resectable PDAC, neoadjuvant therapy consists of chemotherapy with or without radiation therapy before radical pancreatic resection [99]. Radical pancreatic resection may include Whipple procedure (pancreaticoduodenal resection) or total pancreatectomy when necessary for adequate margins. Distal pancreatectomy is indicated for tumors of the body and tail of the pancreas. Following surgical resection, patients may receive postoperative chemotherapy or postoperative chemoradiation therapy [99].

Locally Advanced PDAC

Chemotherapy with or without targeted therapy is recommended for patients with locally advanced PDAC [99]. For patients without metastatic disease, this should be followed by chemoradiation therapy. If removal is a possibility, radical pancreatic resection may be attempted. Palliative surgery options include surgical biliary and/or gastric bypass, percutaneous radiologic biliary stent placement, or endoscopic biliary stent placement.

Metastatic or Recurrent PDAC

Treatment of metastatic or recurrent PDAC is limited to chemotherapy with or without targeted therapy [99]. Palliative approaches should be used whenever available and feasible to improve patient comfort and quality of life.

RESECTION OF PANCREATIC CANCER

Selecting patients for surgery should be based on the probability of cure as determined by resection margins. Other factors include comorbidities, overall performance status, and age. Pancreaticoduodenectomy and distal and total pancreatectomy are curative resection options based on the location, size, and locally invasive aspects of the tumor. Each has its own set of perioperative complications and risks, which should be considered by the surgical team and discussed with the patient [24].

Mortality rates from resection have fallen significantly, but morbidity remains common and interferes the delivery of adjuvant therapy in up to 40% of patients. The NCCN recommends that patients seek out high-volume centers performing more than 15 to 20 resections annually, with multidisciplinary expertise to optimize their treatment plan and increase opportunities for clinical trial participation [2].

The only curative treatment for PDAC is radical surgery, but potential cure is only possible with a microscopically negative resection margin (R0). Macroscopic (R2) and microscopic (R1) margin infiltration have survival trends similar to patients without surgery. R0 is a minimum >1 mm distance of viable tumor cells from the resection margin, R1 is ≤1 mm distance. A retrospective analysis of 44,852 patients with PDAC reported median survival of 19.7 months following R0, 14.3 months following R1, and 9.8 months with R2 resections compared with 10.3 months without surgery [100]. An incomplete tumor resection imposes morbidity risks without benefit to the patient, and the aim of resection is to obtain microscopically negative margins (R0) [101].

Tissue specimens obtained during resection are examined. During resection, lymphadenectomy is performed, including at least 15 lymph nodes, which are likewise examined as part of pathologic staging [16].

With surgical advances and greater use of adjuvant therapies, long-term cancer survival outcomes following resection were anticipated to improve over time [102]. However, in 1,147 pancreatic resections performed over three decades at the Memorial Sloan Kettering Cancer Center, a lack of progress in long-term survival was reported. Although patients treated between 2000 and 2009 had lower rates of operative mortality and greater one-year survival, for patients treated in the 1980s, 1990s, and 2000s, the median survival was 23.2, 25.6, and 24.5 months, respectively [103]. The five-year survival rates were 17%, 20%, and 8%, respectively. These data underscore the need for earlier detection and more effective systemic therapies [102].

Approaches

Pancreaticoduodenectomy (Whipple Procedure)

Used for tumors in the pancreatic head or periampullary region, the conventional Whipple procedure involves removal of the pancreatic head, duodenum, gallbladder, and the antrum of the stomach, with surgical drainage of the distal pancreatic duct and biliary system, usually through anastomosis to the jejunum. The primary reason for removing so much of the intra-abdominal structures is that they all share a common blood supply [24,102].

The former high morbidity and mortality rates of Whipple have declined with the greater experience of a more limited number of surgeons who regularly perform the procedure in high-volume centers [102]. Common morbidities include delayed gastric emptying in roughly 25% of patients, which may require nasogastric decompression and a longer hospital stay. Pancreatic anastomotic leak can be treated with adequate drainage. Postoperative abscesses are not uncommon [24].

With operative mortality associated with Whipple decreasing from around 25% in the 1970s to less than 2% at high-volume centers in the 2010s, the focus has shifted from surviving the operation to surviving the cancer [104].

Distal Pancreatectomy

Distal pancreatectomy is a procedure for tumors in the pancreatic body or tail. It has a lower mortality than standard Whipple, but its use in curative resection is limited; with tumors in this location seldom causing bile duct obstruction, most patients present at a later stage with unresectable disease. The procedure involves resection of the distal pancreas containing the tumor with splenectomy and over-sewing of the distal pancreatic duct. Complications involve pancreatic stump leak, hemorrhage, and endocrine insufficiency. Laparoscopic exploration should precede attempted resection, because occult peritoneal metastases are common [16,24].

Total Pancreatectomy

Total pancreatectomy, the least commonly performed procedure with the highest associated mortality (8.3%), may be needed to achieve an R0 resection margin for tumors in the neck of the pancreas, especially with extension into the body or tail, and in multifocal PDAC. Total pancreatectomy may be an option to pancreatic anastomosis in highly selected patients with a high-risk pancreas (small pancreatic duct) and obese patients with pancreatic fat infiltration. The metabolic consequences of permanent exocrine insufficiency and diabetes have a detrimental impact on quality of life and long-term survival [16,24,102].

Vascular Resection

Vascular involvement has traditionally been a formal contraindication to resection. With recent advances, venous resection and reconstruction can achieve R0 resection with similar overall survival and morbidity compared to surgery without venous resection. However, arterial resection during Whipple is associated with increased mortality and morbidity (bowel ischemia, hemorrhage, thrombosis) and is generally not recommended [16].

Progress in neoadjuvant therapies may downstage some tumors with arterial invasion to borderline resectable or resectable disease, making resection more achievable. Despite these advancements, it is currently accepted that arterial reconstruction is only appropriate in highly selected patients in high-volume centers with surgeons who are familiar with the advanced techniques required for reconstruction [16].

Total pancreatectomy should be considered in patients with locally advanced tumors who undergo pancreatectomy with arterial resection and reconstruction [16].

Biliary Drainage

In most patients with jaundice, early resection without biliary drainage is preferred. Preoperative drainage is indicated in patients with cholangitis or with obstructive jaundice scheduled for neoadjuvant therapy. Endoscopic retrograde placement of a fully covered metal stent is preferred. Endoscopic ultrasonography-guided stent placement is an effective and safe alternative [16].

CHEMOTHERAPIES IN PANCREATIC CANCER

As mentioned, the backbone of PDAC treatment is chemotherapy. Most patients present with advanced disease, and even those who undergo resection benefit from adjuvant chemotherapy. Chemotherapy is also used as neoadjuvant therapy and in metastatic disease with first-line or second-line indications [11].

Until recently, chemotherapies found effective in other GI cancers were applied to patients with advanced PDAC; the few agents showing any response became adjuvant therapies in localized PDAC. The near-futility in effective chemotherapy and redundancy in agents used in localized and metastatic PDAC reflects the pathologic complexity of this cancer and its profound resistance to cytotoxic therapies [2].

Since 2010, chemotherapy effectiveness has improved with the introduction of combination regimens, the identification of patients in whom mutational status conferred improved response to existing chemotherapies, and the introduction of novel compounds explicitly targeting mutational-related advanced PDAC.

FDA-Approved Chemotherapies in PDAC

Evidence Based Practice Recommendation

According to the American Society of Clinical Oncology, all patients with resected pancreatic adenocarcinoma who did not receive preoperative therapy should be offered six months of adjuvant chemotherapy in the absence of medical or surgical contraindications. The mFOLFIRINOX regimen is preferred in the absence of concerns for toxicity or tolerance.

https://ascopubs.org/doi/10.1200/JCO.19.00946

Last Accessed: August 27, 2024

Strength of Recommendation/Level of Evidence: Strong/high

In addition to single chemotherapy agents, the FDA has approved regimens of these agents, including FOLFIRINOX (consisting of folinic acid [also referred to as leucovorin], fluorouracil [5-FU], irinotecan [IRN], and oxaliplatin [OX]) (Table 9) [3,24,80,99]. Available chemotherapies are associated with acute and delayed toxicities, some of which can be dose-limiting (Table 10). Table 11 summarizes the 2021 NCCN guideline for chemotherapy and chemoradiotherapy in PDAC.

Table 9: CHEMOTHERAPY PROTOCOLS IN PANCREATIC CANCER

Drug

Dose and Route

Administration

Given on Days

Gemcitabine

Indication: Nonmetastatic PDAC

Cycle length: 4 weeks (once weekly for 3 weeks, then 1 week off)

Gemcitabine

1,000 mg/m^2 IV

Dilute in 250 mL NS (concentration ≤40 mg/mL), administered over 30 minutes.

Days 1, 8, and 15

Gemcitabine and capecitabine (GemCap)

Indication: Adjuvant therapy

Cycle length: 28 days

Duration: 6 months

Gemcitabine

1,000 mg/m^2 IV

Dilute in 250 mL NS (concentration ≤40 mg/mL), administered over 30 minutes.

Days 1, 8, and 15

Capecitabinea

830 mg/m^2 per dose oral

Twice daily (total 1,660 mg/m^2 per day), 12 hours apart. Swallow with water within 30 minutes post-meal.

Days 1 through 21

Modified FOLFIRINOX

Cycle length: 14 days

Oxaliplatinb

85 mg/m^2 IV

Dilute in 500 mL D5W, administer over 2 hours (before leucovorin). Shorter schedules (e.g., 1 mg/m^2 per minute) appear safe.

Day 1

Leucovorin

400 mg/m^2 IV

Dilute in 250 mL normal saline or D5W, administer over 2 hours (after oxaliplatin).

Day 1

Irinotecanc

150 mg/m^2 IV

Dilute in 500 mL normal saline or D5W, administer over 90 minutes concurrent with the last 90 mins of leucovorin infusion, in separate bags, using Y-line connection.

Day 1

Fluorouracil

2,400 mg/m^2 IV

Dilute in 500–1,000 mL 0.9% normal saline or D5W, administered as continuous IV infusion over 46 hours.d

Day 1

FOLFIRINOX

Indication: Metastatic PDAC

Cycle length: 14 days

Oxaliplatinb

85 mg/m^2 IV

Dilute in 500 mL D5W, administer over 2 hours (before leucovorin). Shorter schedules (e.g., 1 mg/m^2 per minute) appear safe.

Day 1

Leucovorin

400 mg/m^2 IV

Dilute in 250 mL normal saline or D5W, administer over 2 hours (after oxaliplatin).

Day 1

Irinotecanc

150 mg/m^2 IV

Dilute in 500 mL normal saline or D5W, administer over 90 minutes concurrent with the last 90 mins of leucovorin infusion, in separate bags, using Y-line connection.

Day 1

Fluorouracil

400 mg/m^2 IV bolus

Give undiluted (50 mg/mL) as a slow IV push over 5 minutes (immediately after leucovorin).

Day 1

Fluorouracil

2400 mg/m^2 IV

Dilute in 500–1,000 mL 0.9% normal saline or D5W, administer as continuous IV infusion over 46 hours (immediately after IV bolus).d

Day 1

aCapecitabine is contraindicated in patients with known DPD deficiency.

bMany centers routinely infuse oxaliplatin via central venous line because of local pain with infusion into a peripheral vein

cConsider a lower dose of irinotecan with poor performance status.

dTo accommodate an ambulatory pump for outpatients, can be administered undiluted (50 mg/mL) or the total dose diluted in 100–150 mL normal saline.

Source: [98,105]

Table 10: ACUTE AND DELAYED CHEMOTHERAPY TOXICITIESa

Agent

Acute Toxicities

Delayed Toxicities

Fluorouracil

Nausea and vomiting

Diarrhea

Oral and GI ulcers

Bone marrow depression

Diarrhea (especially with leucovorin)

Neurologic defects, usually cerebellar

Cardiac arrhythmias

Palmar-plantar erythrodysesthesia (hand-foot syndrome)

Capecitabine

Nausea and vomiting

Hand-foot syndrome

Diarrhea

Stomatitis

Dermatitis

Bone marrow depression

Hyperbilirubinemia

Gemcitabine

Fatigue

Nausea and vomiting

Fever

Bone marrow depression

Edema

Pulmonary toxicity

Irinotecan

Diarrhea

Diarrhea

Leukopenia

Oxaliplatin

Peripheral sensory neuropathy

Pharyngolaryngeal dysesthesias

Paresthesias

Bone marrow depression

Diarrhea

Persistent neuropathy

Paclitaxel

Hypersensitivity reactions

Bone marrow depression

Peripheral neuropathy

Alopecia

Arthralgias

aDose-limiting toxicities are bold-faced.

Source: [106,107]

Table 11: NCCN TREATMENT SUMMARY FOR PDAC

Strength of Recommendation/Evidence

Regimen

Notesa

Adjuvant stage 1 (resectable)

Category 1

Gemcitabine

Gemcitabine/capecitabine

5-FU/leucovorin

–

Category 2A

5-FU continuous infusion

Chemoradiation

Chemoradiation should follow induction chemotherapy, with or without subsequent chemotherapy

Category 2B

Capecitabine

–

Neoadjuvant stage 1/2 (resectable or borderline resectable)

Category 2A

Gemcitabine/paclitaxel NAB

–

Category 2B

Gemcitabine/cisplatinb

FOLFIRINOX

Chemoradiation

–

Stage 3 (locally advanced)

Category 1

Gemcitabine

Preferred for patients with poor ECOG PS (≥2)

Category 2A

Gemcitabine/paclitaxel NAB

Gemcitabine/erlotinib

Gemcitabine/cisplatinb

Gemcitabine/capecitabine

Gemcitabine fixed-dose rate

FOLFIRINOX

Chemoradiation

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Chemoradiation should follow induction chemotherapy, with or without subsequent chemotherapy

Category 2B

Gemcitabine/docetaxel/capecitabine Capecitabine

5-FU continuous infusion

FOLFOX

–

Stage 4 (metastatic)

Category 1

Gemcitabine

Gemcitabine/paclitaxel NAB (preferred)

Gemcitabine/erlotinib

FOLFIRINOX (preferred)

–

Category 2A

Gemcitabine/cisplatinb

Gemcitabine/capecitabine

Gemcitabine fixed-dose rate

Olaparib

Pembrolizumab (for MSI-H or dMMR tumors only)

Larotrectinib (for NTRK-positive only)

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Olaparib for maintenance therapy only in BRCA1/2 or PALB2 mutated stage 4 disease without progression after 4 to 6 months of first-line platinum-based therapy

Category 2B

Gemcitabine/docetaxel/capecitabine

Capecitabinec

5-FU continuous infusionc

FOLFOX

Entrectinib (for NTRK-positive only)

–

Second-line therapy

Category 1

Gemcitabinec,d

5-FU/leucovorin/irinotecand

–

Category 2A

Gemcitabine fixed-dose rate

Fixed-dose rate gemcitabine is a category 2B recommendation for patients with poor ECOG PS (≥2)

Category 2B

Capecitabinec,e

5-FU continuous infusionc,e

–

Strength of Recommendation Definitions

Category

Definition

1

Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

2A

Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

2B

Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

aECOG performance status (PS) 0/1 only, unless noted.

bIn BRCA1/2 or PALB2 mutations only.

cPoor ECOG PS (≥2) only.

dIf prior non-gemcitabine-based therapy.

eIf prior gemcitabine-based therapy.

Source: [11,141]

Fluoropyrimidines

Fluorouracil is a fluorinated (fluoro)-pyrimidine antimetabolite that inhibits thymidylate synthase and interferes with RNA synthesis and function, with some effect on DNA.

Capecitabine is an oral fluoropyrimidine that undergoes hepatic hydrolysis to form fluorouracil. The final enzyme, thymidine phosphorylase, is present at higher levels in tumor tissue, providing better selectivity and tolerability.

Gemcitabine is a pyrimidine antimetabolite that inhibits DNA polymerase and ribonucleotide reductase, which in turn inhibit DNA synthesis, blocks DNA replication and several forms of DNA repair [3,24,80,99].

Erlotinib

Erlotinib is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. EGFR is expressed on the cell surface of normal cells and cancer cells. Erlotinib inhibits intracellular phosphorylation, which prevents further downstream signaling, resulting in cell death [3,24,80,99].

Paclitaxel

Paclitaxel protein bound is a microtubular inhibitor (albumin-conjugated formulation) and a natural taxane that prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition [3,24,80,99].

Irinotecan Liposomal

Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase-1 DNA complex and prevent re-ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. Irinotecan liposomal is used in combination with fluorouracil and leucovorin [3,24,80,99].

DNA Damage Repair Mutational Status and Targeted Therapies

Platinum agents (e.g., cisplatin, oxaliplatin) and olaparib are recommended in patients with mutation in DNA damage repair (DDR) genes by the NCCN. DDR mutations are present in up to 24% of PDACs, most commonly BRCA1/2 and PALB2. Germline BRCA1/2 mutations (gBRCAm) affect approximately 7% of patients with PDAC [108]. DDR genes encode for proteins in the homologous repair pathway and DNA double-stranded break repair; thus, mutations may be more sensitive to further DNA damage [99].

Cisplatin inhibits DNA synthesis by the formation of DNA cross-links; denatures the double helix; covalently binds to DNA bases; and disrupts DNA function. Oxaliplatin is an alkylating agent. Following intracellular hydrolysis, the compound binds to DNA, forming cross-links that inhibit DNA replication and transcription, resulting in cell death [24,99].

PDACs with DDR mutations demonstrate improved responses to platinum-based therapies, and patients with advanced PDAC showed significantly improved median overall survival (22 months vs. 9 months) compared with nonplatinum therapy [96].

Poly (ADP-ribose) polymerase (PARP) inhibition has been posited to act synergistically with BRCA1/2 mutations by inhibiting single-stranded break repair, causing an accumulation of DNA damage and tumor-cell death [99,109]. Olaparib is a PARP inhibitor FDA-approved for PDAC with gBRCAm as maintenance therapy to sustain a progression-free state during platinum-based chemotherapy in metastatic PDAC [96].

The NCCN expands the use of olaparib to PDAC with gPALB2m. There are calls to expand these agents to PDACs with somatic DDR mutations [108].

Other FDA-Approved Targeted Therapies

The approved indications for the following agents are biomarker-defined, rather than by tumor site (e.g., pancreatic).

Pembrolizumab

Pembrolizumab is indicated in patients with microsatellite-instability-high (MSI-H) or dMMR mutations. Immune checkpoint inhibitors (ICIs) have efficacy in solid tumors with a high tumor mutational burden, and MSI-H or dMMR mutation solid tumors are associated with high tumor mutational burden. The ICI pembrolizumab is an anti-programmed death receptor-1 antibody that releases inhibition of the immune response, improving antitumor immunity [11,96].

Pembrolizumab is approved for any solid tumor with MSI-H or dMMR mutation that progresses during treatment without any satisfactory alternative treatment options [11,96]. This agent represented the first FDA approval (in 2017) with a biomarker-defined indication (i.e., agnostic of cancer site) [107]. Although this mutation is present in only about 1% of PDAC tumors, up to 83% of patients with dMMR PDAC respond to pembrolizumab [110].

Larotrectinib and Entrectinib

Larotrectinib and Entrectinib are neurotrophin receptor kinase (NTRK) inhibitors approved (in 2018 and 2019) for advanced, morbid, or unresectable solid tumors with NTRK fusion mutations, found in less than 1% of PDCAs [96].

The mutation product, TRK fusion protein, activates mitogen activated protein kinase-extracellular regulated kinase and phosphoinositide3 kinase-serine threonine signaling pathways, implicated in the oncogenesis of pancreatic cancer [96]. The NCCN recommends larotrectinib and entrectinib as first-line and subsequent treatment options for patients with NTRK gene fusion-positive locally advanced or metastatic PDAC [11].

Chemotherapy Efficacy: Localized Disease

A variety of data on chemotherapy efficacy are available, allowing for comparison of available agents in specific patient populations (Table 12). However, the terminology used can be confusing. Disease-free survival and progression-free survival are synonymous terms, and choice of the term used in this section will reflect the reference material. This is also the case with median survival and median overall survival. Unless noted otherwise, all patient outcomes are reported as median figures.

Table 12: ADJUVANT CHEMOTHERAPY TRIALS IN RESECTABLE PDAC

Phase III trial (Year)

Chemotherapy Comparison

Median Survival (Months)

ESPAC-1 (2004)

5-FU vs. observation

21 vs. 15.5

CONKO-001 (2013)

Gemcitabine vs. observation

22.8 vs. 20.2

ESPAC-3 (2012)

Gemcitabine vs. 5-FU/leucovorin

46 vs. 39

ESPAC-4 (2017)

Gemcitabine/capecitabine vs. gemcitabine alone

28 vs. 25.5

PRODIGE 24 (2018)

Modified FOLFIRINOX vs. gemcitabine

54.4 vs. 35

APACT (2019)

Gemcitabine/paclitaxel vs. gemcitabine alone

40.5 vs. 36.2

5-FU = 5-fluorouracil.

Source: [2]

The CONKO-001 trial established gemcitabine as standard adjuvant chemotherapy. In this study, 354 patients were randomized to receive gemcitabine or observation after resection and followed a median 136 months. Gemcitabine led to a 24% improvement in overall survival, a 10.3% absolute improvement in 5-year survival (20.7% vs. 10.4%), and a 4.5% improvement in 10-year survival (12.2% vs. 7.7%), compared to observation [111,112].

The ESPAC-3 trial showed the importance of completing the full post-resection adjuvant chemotherapy course (six cycles) in extending median overall survival of these patients compared with those not completing chemotherapy (28.0 months vs. 14.6 months) [96].

A continuation, ESPAC-4, found adding another fluoropyrimidine-based agent (capecitabine) to gemcitabine was superior to gemcitabine alone in median survival (28.0 months vs. 25.5 months) and five-year survival (28.8% vs 16.3%). A synergistic effect between gemcitabine and capecitabine on the DNA thymidylate enzyme was suggested [96].

PRODIGE-24 randomized 493 patients (ECOG performance status ≤1) with resected PDAC to modified FOLFIRINOX or gemcitabine for 24 weeks. At median 33.6 month follow-up, the disease-free survival with modified FOLFIRINOX was 21.6 months, compared with 12.8 months with gemcitabine [113]. Grade 3/4 toxicities were more frequent with mFOLFIRINOX (75.9%) than gemcitabine (52.9%). Nonetheless, the median 54.4-month overall survival with resection followed by mFOLFIRINOX is the longest survival reported to date with phase III results [5,114]. Thus, modified FOLFIRINOX is recommended as standard adjuvant chemotherapy in patients with excellent functional status; either gemcitabine/capecitabine or gemcitabine alone should be considered for individuals with poorer functional status [134].

Tolerance of adjuvant therapy remains a limitation, and patients commonly receive less than 50% of the planned dose, reflecting exposure to significant chemotherapy-related toxicity in patients experiencing substantial post-resection morbidity [2].

Chemotherapy Efficacy: Advanced/Metastatic Disease

First-Line Chemotherapy in Metastatic PDAC

5-FU has been used in pancreatic cancer treatment since the 1950s. Patients with advanced PDAC typically show response rates greater than 20% and median survival of 2.5 to 6 months [24,80].

In 1997, gemcitabine replaced 5-FU as first-line treatment in metastatic PDAC by improving one-year survival rates (18% vs. 2%) and median overall survival (5.65 months vs. 4.41 months) [32]. Subsequently, numerous attempts to improve gemcitabine efficacy in metastatic PDAC have involved adding another cytotoxic drug [2,96]. Some show marginal but statistically significant improvements in median survival over gemcitabine alone (Table 13).

Table 13: FIRST-LINE CHEMOTHERAPY TRIALS IN METASTATIC PDAC

Phase III Trial (Year)

Chemotherapy Comparison

Median Survival (Months)

Cullinan (1985)

5-FU vs. 5-FU/doxorubicin vs.

5-FU/doxorubicin/mitomycin

5.5 vs. 5.5 vs. 4.5

Burris (1997)

5-FU vs. gemcitabine

4.4 vs. 5.6

Tempero (2003)

Gemcitabine vs. gemcitabine fixed dose rate

5 vs. 8

Heinemann (2006)

Gemcitabine ± cisplatin

6.0 vs. 7.5

NCIC-CTG PA.3 (2007)

Gemcitabine ± erlotinib

5.9 vs. 6.2

Cunningham (2009)

Gemcitabine ± capecitabine

6.2 vs. 7.1

CALGB 80303 (2010)

Gemcitabine ± bevacizumab

5.9 vs. 5.8

SWOG S0205 (2010)

Gemcitabine ± cetuximab

5.9 vs. 6.3

PRODIGE 4 (2011)

Gemcitabine vs. FOLFIRINOX

6.8 vs. 11.1

MPACT (2013)

Gemcitabine ± nab-paclitaxel

6.7 vs. 8.5

NAPOLI 3 (2023)

Gemcitabine + nab-paclitaxel vs. NALIRIFOX

9.2 vs. 11.1

Source: [2,140]

The NCIC CTG PA.3 trial found a nonmeaningful clinical improvement with gemcitabine/erlotinib over gemcitabine alone in median overall survival (6.24 months vs. 5.91 months). Despite FDA approval for locally advanced/metastatic PDAC, the clinical impact of this modest gain with increased toxicity can be questioned [32,96].

PRODIGE 4/ACCORD 11 demonstrated that patients with advanced PDAC and ECOG performance status ≤1 had better outcomes with FOLFIRINOX than gemcitabine in median overall survival (11.1 months vs. 6.8 months) and progression-free survival (6.4 months vs. 3.3 months). Following these findings, FOLFIRINOX became standard first-line therapy for candidate patients [2].

FOLFIRINOX was associated with more toxicities, but the six-month degradation in quality of life was better in FOLFIRINOX than gemcitabine (31% vs. 66%). Improved cancer control with FOLFIRINOX may be due to the inclusion of irinotecan, which has activity against PDAC and synergistic activity when given prior to 5-FU [96].

The MPACT study demonstrated an improvement of 1.8 months in both median overall survival and median progression-free survival with gemcitabine plus nab-paclitaxel versus gemcitabine alone, leading to another first-line option for metastatic PDAC [96].

In February 2024, the FDA approved irinotecan liposome with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX), for first-line treatment of metastatic pancreatic adenocarcinoma [140]. Efficacy was demonstrated in NAPOLI 3, a randomized, multicenter trial comparing NALIRIFOX with gemcitabine plus nab-paclitaxel in 770 patients previously untreated in the metastatic stage of disease. Treatment efficacy was superior in the NALIRIFOX arm for overall survival (11.1 months vs. 9.2 months) and for progression-free survival (7.4 months vs. 5.6 months) [140]. The most common adverse reactions of NALIRIFOX therapy (occurring n at least 20% of patients) were diarrhea, fatigue, nausea, vomiting, decreased appetite, abdominal discomfort, mucosal inflammation, and pancytopenia. NCCN guidelines now include NALIRIFOX in its list of preferred regimens for treatment of patients with metastatic pancreatic cancer [141].

The NAPOLI 3 trial results suggest that NALIRIFOX may have advantages over FOLFIRINOX for treatment of metastatic PDAC. The median progression-free survival was one month longer than that reported for FOLFIRINOX in the 2011 PRODEDGE 4 trial. A systematic review and analysis of seven clinical trials (2,581 patients) testing first-line therapy for metastatic pancreatic cancer found that therapeutic efficacy (progression-free and overall survival) was similar for NALIRIFOX and FOLFIRINOX, although both were superior to gemcitabine/nab-paclitaxel [142]. NALIRIFOX was associated with higher rates of severe diarrhea but less hematologic toxicity and lower incidence of peripheral neuropathy. No clinical trial directly comparing FOLFIRINOX to NALIRIFOX have been reported. The liposomal form of irinotecan in the NALIRIFOX regimen makes it considerably more expensive than FOLFIRINOX.

Second-Line Chemotherapy in Metastatic PDAC

Second-line therapy primarily consists of doublet therapy using the alternative pyrimidine backbone to what was used in the first-line setting. In 2016, the NAPOLI-1 trial demonstrated that after progression on a first-line gemcitabine-containing regimen for metastatic PDAC, 5-FU/leucovorin plus nanoliposomal irinotecan improved overall survival from 4.2 months (with 5-FU/leucovorin alone) to 6.1 months. As with nab-paclitaxel, improving the delivery of traditional chemotherapies may lead to more effective treatments for individuals with pancreatic cancer [32].

The POLO trial examined targeted maintenance therapy in a biomarker-selected population. In patients with metastatic PDAC harboring germline BRCA1/2 mutations who had not progressed on first-line platinum-based chemotherapy, those randomized to olaparib had improved median progression-free survival (7.4 months compared with 3.8 months with placebo), but olaparib did not improve median overall survival [109]. The median duration of response to olaparib was 6 months but was more than 24 months in a subset of patients (23%), which is exceptional in metastatic PDAC [108].

In second-line chemotherapy after progression on a first-line regimen, there is considerable heterogeneity in the survival of patients, and predicting which patients will benefit is not established. The decision to pursue second-line chemotherapy should be individualized and based on the patient's goals and preferences. Factors influencing the choice of second-line therapy include the regimen used for first-line therapy, performance status and comorbidity, and mutation status [106].

RADIATION THERAPY FOR PANCREATIC CANCER

In addition to resection and chemotherapy, treatment of patients with PDAC may include radiation therapy or chemoradiotherapy. Unlike chemotherapy, the role of radiation therapy in the treatment of PDAC is uncertain. Radiation therapy is not a stand-alone treatment in local PDAC but is sequenced with chemotherapy as chemoradiotherapy.

Earlier adjuvant radiation therapy trials demonstrated an overall survival and disease-free survival benefit, but subsequent European chemoradiation studies showed negative findings [12]. Technical advances suggest increasing promise with radiation therapy, but multi-institutional randomized trials in PDAC have lagged [12].

Stereotactic body radiation therapy has promising local control and quality of life and is being evaluated for locally advanced and borderline resectable PDAC. However, adjuvant stereotactic body radiation therapy remains investigational with high toxicity risk and is only recommended as part of a clinical trial [12].

In the absence of phase 3 trials directly comparing neoadjuvant treatment approaches with or without radiation, adjuvant and neoadjuvant chemoradiation in PDAC awaits definitive evidence. Several such trials are in progress [2,12]. In particular, RTOG 0848 is expected to definitively clarify the role of post-resection radiotherapy [115].

Evidence Based Practice Recommendation

Following surgical resection of pancreatic cancer, adjuvant conventionally fractionated radiotherapy with chemotherapy in select high-risk patients (i.e., positive lymph nodes and margins regardless of tumor location within the pancreas) is conditionally recommended by the American Society for Radiation Oncology.

https://www.practicalradonc.org/cms/10.1016/j.prro.2019.06.016/attachment/0e8abbe7-fcc6-4c5d-8b46-e81e636ce080/mmc1.pdf

Last Accessed: August 27, 2024

Strength of Recommendation/Level of Evidence: Conditional/low

Nonetheless, the prospective cohort and retrospective evidence suggestive of decreased local recurrence and disease progression is sufficient for ASTRO, the NCCN and ASCO to recommend radiation therapy. Standard radiation prescriptions in the neoadjuvant setting consist of daily treatments over the course of five or six weeks to a total dose of 50–54 gray (Gy) [2].

The type and duration of chemotherapy given with radiation therapy for pancreatic cancer depends on the clinical stage, setting (neoadjuvant or adjuvant), performance status, and comorbidities. Patients with favorable performance status (0 or 1) are typically offered FOLFIRINOX prior to radiation therapy. Patients who are elderly or have a poor performance status (≥2) are typically offered gemcitabine or gemcitabine/nab-paclitaxel prior to radiation therapy. The duration (two to six months or longer) depends on patient tolerance and tumor response (i.e., no evidence of progression on chemotherapy). Common dose-limiting toxicities are diarrhea, neuropathy, and hematologic [12].

NEOADJUVANT THERAPY

Preoperative, or neoadjuvant, therapy is a major paradigm shift in treatment for patients with localized PDAC that offers the potential to lengthen survival while sparing patients unnecessary treatment-related morbidity using available treatments [116]. The purpose of neoadjuvant therapy differs somewhat in relation to disease stage and clinical features. Multiple prospective clinical trials have shown that neoadjuvant therapy eradicates occult metastatic disease, facilitates margin-negative surgical resection, and increases the number of patients eligible to receive postoperative adjutant chemotherapy [134].

Neoadjuvant therapy is recommended in upfront resectable disease with high-risk features of dissemination. This includes tumors in pancreas body and tail or >3–4 cm, ascites, large regional lymph nodes, CA19-9 levels >1,000 U/mL, severe weight loss, and extreme pain. For these patients, staging laparoscopy is recommended to identify liver and peritoneal metastases missed by MDCT in assessing resectability, with endoscopic ultrasonography-guided biopsy [7,11,15]. The next step is systemic neoadjuvant therapy (i.e., chemotherapy), post-neoadjuvant therapy CA19-9, and MDCT with contrast to reassess resectability (with some limitations). If R0 resection is feasible and there is no evidence of metastatic disease, surgery should be attempted [7,11,15].

In general, neoadjuvant therapy for patients who are candidates for resection is controversial [116]. Some oncology groups do not recommend neoadjuvant therapy in upfront resectable disease (except with high-risk features) until better evidence is available, but this stance has become less tenable as additional evidence supporting efficacy becomes available [7,13,15].

Even in patients with anatomically localized disease based on imaging and after complete resection with R0 margins, the high rates of distant failure after surgery for resectable PDAC indicates most patients already have systemic disease at the time of diagnosis. Current imaging fails to accurately assess the true burden of disease, missing occult metastases and under-staging patients [116].

Given this reality, systemic therapy is crucial, but many patients do not receive adjuvant therapy after resection. The high complication rates and potentially prolonged recovery with resection results in 25% to 50% of patients not receiving postoperative therapy [116]. However, systemic neoadjuvant therapy allows patients to receive therapy when they have better performance status and before the potential development of postoperative complications [116].

Neoadjuvant therapy also tests the tumor biology. Patients with aggressive tumors that progress and/or metastasize during neoadjuvant therapy are spared a futile operation. Due to their performance status, patients who do poorly on systemic neoadjuvant therapy would likely do poorly with surgery, resulting in mortality or serious perioperative morbidity precluding adjuvant therapy. Neoadjuvant therapy allows patients with resectable tumors who are poor surgical candidates time to medically and/or physically optimize before surgery.

Neoadjuvant therapy is not without its drawbacks. Eligibility for neoadjuvant therapy requires a tissue diagnosis, but the dense PDAC tumor stroma impedes tissue confirmation in approximately 15% of patients [116]. Further, neoadjuvant therapy means delaying surgery, with the possibility for local progression during neoadjuvant therapy into unresectable PDAC [15]. However, local progression almost always occurs concomitantly with development of systemic disease [116]. Essentially, better evidence is needed. Until phase III results are available, the poor outcomes of conventional treatment sequencing argue for the need for neoadjuvant therapy.

Borderline resectable pancreatic cancer is a recognized indication for neoadjuvant therapy, as this approach may shrink and make tumors more amenable for surgical resection with fewer complications and increased chance of R0 resection. Neoadjuvant therapy may minimize early non-detectable microscopic metastases, decrease lymph node involvement, and improve overall survival and outcomes [96].

Upfront Resectable/Borderline Resectable Tumor and Neoadjuvant Therapy

The NCCN recommends neoadjuvant therapy for patients with resectable or borderline resectable tumors. Treatment at or coordinated through a high-volume center is preferred, when feasible, and participation in a clinical trial is encouraged. The preferred neoadjuvant options are FOLFIRINOX with or without subsequent chemoradiation, or gemcitabine plus albumin-bound paclitaxel with or without subsequent chemoradiation [11]. For patients with BRCA/PALB2 mutations, the preferred regimen is gemcitabine plus cisplatin (two to six cycles) with or without subsequent chemoradiation [11].

ASTRO guidelines for neoadjuvant chemoradiation specify a radiation dose of 4,500–5,040 cGy in 180–200 cGy fractions [12]. They recommend delivery of radiation therapy following two to six months of chemotherapy.

Locally Advanced Pancreatic Cancer and Neoadjuvant Therapy

Locally advanced pancreatic cancer accounts for 30% of newly diagnosed cases. With local involvement of adjacent critical blood vessels and presence of occult micrometastatic disease, locally advanced pancreatic cancer is generally considered surgically unresectable and incurable, and the standard of care is as for metastatic disease [2].

However, the increased use of preoperative multiagent chemotherapy followed by chemoradiation has significantly expanded the pool of patients with locally advanced pancreatic cancer eligible for resection with curative intent, significantly improving the resectability and overall survival of these patients [117].

In a single-institution phase II trial, 49 patients with locally advanced pancreatic cancer received eight cycles of FOLFIRINOX followed by 50.4 Gy of photon radiation with capecitabine and losartan. Of these patients, 39 were brought to the operating room, 34 (69%) had their cancer removed, and of these, 30 patients (88%) had an R0 resection. Among patients who underwent resection, median progression-free survival and overall survival were 21.3 and 33 months, respectively, versus the 11- to 12-month historical overall survival [118].

Neoadjuvant therapy is associated with a downstaging-to-resection rate of greater than 30% in selected patients with locally advanced pancreatic cancer, with survival comparable to or better than initially resectable disease. For patients with arterial involvement, arterial divestment shows a lower morbidity and mortality rate than arterial resection and reconstruction [117].

Post-Neoadjuvant Therapy Restaging Evaluation of Resectability

Following neoadjuvant therapy, a restaging evaluation with pancreatic protocol MDCT is required to image tumor shrinkage and rule out local progression for resectability. However, post-neoadjuvant therapy imaging is not a reliable indicator of resectability due to its inability to distinguish post-treatment fibrosis from residual viable tumor [117]. Post-neoadjuvant therapy CA19-9 levels are predictive of tumor regression and should be used to guide decisions about suitability for surgical exploration for resection. Diagnostic laparoscopy should be routinely used to minimize nontherapeutic surgery rates [117].

Adjuvant Chemotherapy in Patients with Resected PDAC After Neoadjuvant Therapy

After resection of pancreatic cancer following neoadjuvant FOLFIRINOX, the benefit of adjuvant chemotherapy on overall survival is unclear. Although randomized controlled trial confirmation is needed, a 2020 multicenter, retrospective study provided informative results [119]. Of 520 patients (median age: 61 years; 53.7% male) who received a median of six neoadjuvant cycles of FOLFIRINOX, 343 (66.0%) received adjuvant chemotherapy. Adjuvant chemotherapy was FOLFIRINOX for 68 patients (19.8%), gemcitabine-based chemotherapy for 201 (58.6%), capecitabine for 14 (4.1%), a combination or other agents for 45 (13.1%), and unknown for 15 patients (4.4%). The median overall survival was 38 months after diagnosis and 31 months after surgery. No survival difference was found for patients who received adjuvant chemotherapy compared with those who did not (29 months in both groups).

In multivariable analysis, the interaction of lymph node stage with adjuvant therapy was statistically significant. In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved overall survival (26 months vs. 13 months). For those with node-negative disease, adjuvant chemotherapy was not associated with improved survival (38 months vs. 54 months). These results suggest that adjuvant chemotherapy after neoadjuvant therapy FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease [119].

LOCALLY ADVANCED PANCREATIC CANCER

Neoadjuvant therapy increasingly shows the ability to downstage locally advanced pancreatic cancer into resectable tumor, but until such approaches are employed beyond specialized PDAC research centers, most of these patients will remain unresectable [2].

Chemotherapy selection for patients with locally advanced pancreatic cancer is largely based on extrapolation from studies in metastatic PDAC. However, the natural history of locally advanced pancreatic cancer is less predictable than metastatic disease [120]. In an important autopsy study, 28% of patients with locally advanced pancreatic cancer at initial diagnosis died with localized disease only, from complications of locally destructive tumor growth [120]. Also noted, not all isolated metastases at initial diagnosis are harbingers of widespread metastatic disease, nor the greatest threat to patient survival compared with the primary tumor or cachexia [17].

In patients with locally advanced pancreatic cancer, even with progression, treatment should not simply mirror that in metastatic disease. Rather, it should be based on the pattern of progression (locoregional vs. disseminated), prior chemotherapy and/or radiation, and sequence of therapy (as well as performance status and comorbidity). For example, if a patient with locally advanced pancreatic cancer and a history of only chemotherapy as prior treatment later develops locoregional progression, radiation may be the appropriate modality [8].

Fluoropyrimidines and gemcitabine are the most used agents in adjuvant chemoradiotherapy trials of locally advanced pancreatic cancer. These studies suggest that as a radiosensitizer, capecitabine is a well-tolerated regimen with comparable or superior outcomes compared with low-dose gemcitabine [8].

There is a potential role for maintenance capecitabine or gemcitabine-based chemoradiotherapy in improving quality of life for patients with locally advanced pancreatic cancer and stable disease after 12 weeks of induction gemcitabine/capecitabine chemotherapy [8].

In contrast to conventionally fractionated chemoradiotherapy, there is growing interest in using induction chemotherapy for systemic control, followed by a short course of stereotactic body radiotherapy early during treatment with minimum disruption to systemic therapy. This could be particularly beneficial to patients with predominant local symptoms [8].

The ASCO guidelines for patients with locally advanced pancreatic cancer include several strong recommendations related to chemoradiotherapy or stereotactic body radiation therapy [2,8]. Specifically, it states that chemoradiotherapy or stereotactic body radiation therapy may be offered upfront rather than chemotherapy [8]. This approach is recommended for patients with local progression but no metastases, performance status ≤2, and favorable comorbid profile. It should also be offered to patients with response to an initial six months of chemotherapy or with stable disease who develop chemotherapy toxicities that are intolerable or cause a decline in performance status [8]. If patients respond or their disease has at least stabilized after six months of induction chemotherapy, chemoradiotherapy or stereotactic body radiation therapy may be offered as an alternative to continuing chemotherapy alone [8].

For patients with unresectable or locally advanced pancreatic cancer, definitive conventionally fractionated or dose-escalated radiation therapy with chemotherapy is used. For patients without systemic progression after four to six months (or longer) of chemotherapy, ASTRO recommends definitive radiation therapy [12]. The preferred dose is 5,040–5,600 cGy in 175–220 cGy fractions.

Local Ablative Radiation

With surgical resection considered the only potentially curative option but most patients harboring unresectable PDAC tumor, nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses delivered in patients with inoperable disease [121].

In one 2021 report, patients with locally advanced pancreatic cancer were treated with hypofractionated ablative radiation therapy, using respiratory gating, soft tissue image guidance, and other methods to address organ motion and limit the dose to surrounding luminal organs [121]. At baseline, 119 patients with locally advanced pancreatic cancer and median CA19-9 level >167 U/mL received four months of induction chemotherapy, followed by ablative radiation therapy. The median overall survival from diagnosis and ablative radiation therapy were 26.8 and 18.4 months. The 12- and 24-month overall survival following therapy were 74% and 38%, and the 12- and 24-month cumulative incidence of locoregional failure were 17.6% and 32.8% [121]. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper GI bleeding occurred in 10 patients (8%), with no grade 4 to 5 events. This cohort study of patients with inoperable locally advanced pancreatic cancer found that ablative radiation therapy following multiagent induction therapy was associated with durable locoregional tumor control and favorable survival [121].

METASTATIC DISEASE

Systemic chemotherapy can benefit patients with metastatic PDAC by improving disease-related symptoms and survival compared with best supportive care alone, but patients should understand that chemotherapy is palliative and not curative [80].

First-line chemotherapy for metastatic PDAC is consistent across clinical practice guidelines from ASCO, NCCN and ESMO. The preferred regimens are gemcitabine/albumin-bound paclitaxel, FOLFIRINOX, mFOLFIRINOX, and NALIRIFOX. Treatment selection is based on PDAC mutation status, serum total bilirubin level, ECOG performance status, comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

The initial chemotherapy selection for germline or somatic HRR gene mutation is a platinum-based chemotherapy regimen. For those with performance status ≤1 and serum bilirubin less than 1.5 times upper limit of normal, FOLFIRINOX or mFOLFIRINOX is preferred. Gemcitabine plus cisplatin can be used and probably has similar benefit. For patients with performance status 2, comorbidity that precludes intensive therapy, or a serum bilirubin more than 1.5 times upper limit of normal despite stenting, FOLFOX is preferred over FOLFIRINOX.

After at least 16 weeks of initial platinum-based chemotherapy without disease progression, chemotherapy should be discontinued and maintenance therapy with olaparib initiated for those with germline BRCA or PALB2 mutation. For advanced PDAC with somatic (i.e., non-germline) BRCA or PALB2 mutation, the benefit of olaparib maintenance therapy is not known and is under investigation.

For patients with an unknown (pending) HRR status, waiting until the germline or somatic mutation status is known is not recommend, given the rapidity of progression in most patients with newly diagnosed metastatic PDAC. These patients should be treated like HRR mutation carriers until results of genetic testing are available [80].

Patients with performance status ≤1, serum bilirubin less than 1.5 times upper limit of normal, and favorable comorbidity, FOLFIRINOX or NALIRIFOX is preferred, with gemcitabine plus nabpaclitaxel a potentially less toxic alternative. Patients with serum bilirubin more than 1.5 times upper limit of normal despite placement of a stent should receive FOLFOX rather than a gemcitabine-containing regimen, because gemcitabine is hepatically metabolized and associated with greater toxicity with hepatic impairment. For patients with performance status 2, favorable/adequate comorbidity, and serum bilirubin level less than 1.5 times upper limit of normal, gemcitabine monotherapy is suggested; gemcitabine/capecitabine is another option.

Highly selected patients with performance status 2 due to heavy tumor burden should be treated with gemcitabine plus nabpaclitaxel, owing to its higher response rate. Dose and schedule adjustments should be made to minimize toxicities. In patients with performance status ≥3 or poorly controlled comorbidity (regardless of histology or BRCA/PALB2 mutation status), systemic chemotherapy should only be offered on an individualized, case-by-case basis; supportive care should be emphasized.

8. PALLIATION AND SYMPTOMATIC MANAGEMENT

At diagnosis, the median survival for patients with locally advanced, unresectable pancreatic cancer is 8 to 12 months; with metastatic disease, this decreases to 3 to 6 months. For patients with locally advanced and metastatic disease, systemic chemotherapy can improve survival. In the best outcomes to date, FOLFIRINOX demonstrated an 11.1-month median survival [122].

Patients receiving chemotherapy often report better overall quality of life, but extended survival with chemotherapy may not reduce symptom burden. Because the pancreas is located deep in the central abdomen at the root of the mesentery and adjacent to the biliary and gastrointestinal tracts, most patients suffer a varied and serious symptom burden, frequently requiring medical attention and hospitalization for effective management. The common symptoms experienced by patients with PDAC are pain, abdominal distension/bloating, anorexia, constipation, anxiety, and depression. Diarrhea and steatorrhea are also common. Most patients experience significant weight loss and become cachectic, which further reduces quality of life, treatment response, and length of survival. Other intercurrent complications include biliary obstruction, gastric outlet obstruction, ascites, and venous thromboembolism [122,143].

All patients with newly diagnosed PDAC should have a full assessment of symptom burden, psychological status, and social supports as early as possible. Regardless of cancer stage and patient prognosis, early introduction to expert palliative and supportive care improves the social, psychological, and physical well-being of patients; decreases the intensity of medical interventions at the end of life; and ultimately improves survival [2].

Palliative care is an interdisciplinary specialty that is focused on preventing and relieving suffering and supporting the best possible quality of life for patients and their families facing serious illness, such as pancreatic cancer. Palliative care specialist clinicians provide in-depth pain and symptom management, communication regarding goals of care, and coordinated care across settings and over time. Palliative care aims to relieve suffering in all stages of disease and can be provided in tandem with curative or life-prolonging treatments [122].

When initiated early in the disease course, palliative care improves clinical, quality of care, and survival outcomes. Furthermore, multiple studies have shown that palliative care services improve patients' symptoms, allow patients to avoid hospitalization and to remain safely and adequately cared for at home, lead to better patient and family satisfaction, and significantly reduce prolonged grief and post-traumatic stress disorder among bereaved family members. Palliative care also lowers costs and reduces rates of unnecessary hospitalizations, diagnostic and treatment interventions, and nonbeneficial intensive care when patients are near the end of life [122].

VENOUS THROMBOEMBOLISM PROPHYLAXIS

Acquired hypercoagulability is a common feature of pancreatic cancer, which is one of the highest-risk malignancies for venous thromboembolism (VTE), including deep venous thrombosis (DVT), pulmonary embolism, and visceral portal or superior mesenteric vein thrombi. The reported incidence of VTE in patients with advanced PDAC is greater than 25%, which is four- to seven-fold higher than any other malignancy and fifty times higher than the average adult [143]. The risk is highest in the first three months after diagnosis; chemotherapy further increases the risk. In PDAC, VTE is strongly associated with higher short- and long-term mortality and high risk of recurrent VTE [122].

All patients should be educated about warning signs and symptoms of VTE. Physical examination of the legs for asymmetric pitting edema, erythema, and warmth is crucial in each office visit, and the threshold to perform a CT angiogram with tachycardia or pleuritic chest pain present should be extremely low [122].

Routine anticoagulation for primary VTE prevention is not indicated in ambulatory outpatients with pancreatic cancer and no other VTE risk factors [122]. In a patient with PDAC and documented VTE (symptomatic or incidentally found), early initiation of anticoagulation is the standard approach, and lifelong therapy should be considered. The decision to continue anticoagulation should be balanced against bleeding risk, cost of therapy, quality of life, life expectancy, and patient preference. Low-molecular-weight heparin or oral rivaroxaban, apixaban, or edoxaban is preferred to vitamin K antagonist or unfractionated heparin for long-term anticoagulation [122].

PERI-PANCREATIC COMPLICATIONS

Bile Duct Obstruction

Symptomatic biliary obstruction develops in approximately 80% of patients with carcinoma of the head of the pancreas [143]. Biliary stents relieve troublesome pruritis and may be used to improve liver function sufficiently to permit safe administration of cancer treatment. Endoscopic retrograde stenting is superior to surgical or percutaneous approaches to address bile duct obstruction because of a more favorable adverse event rate. Successful biliary stent placement can be achieved in more than 90% of patients, with potential post-procedure complications of pancreatitis, bleeding, or cholangitis in 5% of cases [143]. Self-expandable metal stents are preferred over plastic stents in patients with a life expectancy of more than three months in terms of patency duration, less therapeutic failure and need for reintervention, lower cholangitis incidence, and better patient quality of life. Patency rates between covered and uncovered metal stents are not significantly different [16]. Endoscopic ultrasonography-guided biliary drainage is an alternative if endoscopic biliary stent placement is unsuccessful or technically not feasible.

Gastric Outlet Obstruction

Pancreatic cancer invasion into the duodenum can lead to secondary gastric outlet obstruction and intractable nausea and vomiting. The choice of treatment intervention depends on the functional status and patient's predicted length of survival [143]. In patients with gastric outlet obstruction, endoscopic duodenal stenting allows a quick resumption of oral intake, with a low complication rate and a short recovery period. However, the need for reintervention is higher after duodenal stenting compared with that of palliative surgery. Endoscopic ultrasonography-guided gastrojejunostomy is an effective and safe alternative to surgery [16].

Ascites

Ascites in patients with metastatic PDAC may be due to peritoneal metastases. In patients with locally advanced tumors, ascites may be caused by portal vein thrombus if the tumor compresses the portal vein locally [122].

Patients with malignant ascites from pancreatic cancer can experience abdominal discomfort, nausea, vomiting, and dyspnea from the pressure of the fluid against the anterior abdominal wall and diaphragm. For most patients, survival is short, and the focus is symptom control. Symptom relief from intermittent paracentesis tends to be short-lived, and the procedure must be repeated for symptom relief. If reaccumulation requires more than once-weekly paracentesis, placement of a long-term drainage catheter is an option; complication rates are higher with indwelling catheters. Diuretics such as spironolactone and furosemide decrease the absorption of water and sodium in the kidneys and may provide some symptomatic relief [122].

PAIN CONTROL INTERVENTIONS

Evidence Based Practice Recommendation

The ASCO recommends that patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and symptoms of the cancer and/or the cancer-directed therapy.

https://ascopubs.org/doi/10.1200/JCO.20.01364

Last Accessed: August 27, 2024

Strength of Recommendation/Level of Evidence: Strong/intermediate

Pancreatic cancer is one of the most painful malignancies [85]. All patients with locally advanced and metastatic pancreatic cancer should be offered aggressive treatment of pain [8]. Adequate control of pain may be unsatisfactory due to significant variation in local practice [123].

Abdominal and/or back pain is often the major presenting symptom of the disease and can be a significant feature of advanced pancreatic cancer. Patients describe a gnawing mid-epigastric pain, which radiates bilaterally under the ribs and into the mid-back, owing to the proximity of pancreatic tumors to the celiac plexus. All patients should have the level of pain and degree of pain relief from analgesics addressed at every visit [122].

Pharmacotherapy

The mainstay of pain management is opioid therapy, and palliation of pain can often be successfully achieved by opioid analgesics alone [122]. The core principle is a "pain/analgesia ladder," with escalation in management based on symptom severity. Initial treatment may consist of non-opioid medications (e.g., non-steroidal anti-inflammatory drugs [NSAIDs]), followed by mild/moderate opioids (e.g., tramadol, codeine), then stronger opioids (e.g., morphine, oxycodone, fentanyl) for unremitting and severe pain. At each level of pain management, adjunctive therapy (e.g., cannabinoid, ketamine, clonidine, benzodiazepine, gabapentin, pregabalin, nortriptyline, duloxetine) can be incorporated for potential additive effect [122,143].

Patients with moderate-to-severe pain should receive doses adequate to provide relief. Concern about addiction should not be a barrier to effective pain control; even with dose escalation, addiction is seldom a problem in patients with PDAC and the risk is lower than generally assumed in non-malignant pain [81,123]. Given the ongoing concerns regarding opioid misuse in the United States, drug diversion may be a consideration.

For patients with persistent nausea and vomiting for whom taking oral medications is difficult, pain control may be achieved using transdermal patches when adipose tissue is sufficient for transdermal absorption [122]. When pain is constant rather than intermittent, long-acting oral (e.g., morphine, oxycodone, oxymorphone) or transdermal (e.g., fentanyl, buprenorphine) preparations may work better [81]. Breakthrough pain can be treated with rapid-onset transmucosal or intranasal fentanyl formulations. Methadone may be advantageous in many patients and can be used in small doses as add-on to existing opioid treatment. Methadone should only by prescribed by clinicians who are familiar with the complex pharmacology and adverse effect profile of this opioid [123].

Laxatives should be considered for all patients on opioid analgesia for PDAC pain, because constipation is a nearly universal side effect. There is considerable individual variation in both efficacy and side effects. Not all patients benefit from or tolerate opioids. A trial of an alternative opioid may also be indicated. Cases of poor pain control or intolerable pain may benefit from continuous opioid infusion via epidural or intrathecal catheters [81,123].

Near the end of life, pain management for advanced and terminal PDAC can become very challenging, and an interdisciplinary approach including palliative care specialists is needed. It is important wherever possible to consider the preferences of the patient. A range of supportive care measures can be offered, including intensive home support, home care with parenteral opioids, patient-controlled analgesia, and palliative sedation [123].

Celiac plexus neurolysis offers medium-term relief, but other procedures (e.g., splanchnicectomy) are also available. Adjunctive treatments for pain, depression, and anxiety as well as radiotherapy, endoscopic therapy, and neuromodulation may be required. Palliative chemotherapy may provide pain relief as a collateral benefit [123].

Celiac Plexus Neurolysis

Interventional therapies may be beneficial for severe pain refractory to opioids. A celiac plexus block uses a local injection of corticosteroids or a long-acting analgesic to reduce pain by disrupting visceral pain afferent pathways from the pancreas and surrounding structures. A celiac plexus neurolysis is permanent destruction of the plexus, equally effective and preferable for patients with a short life expectancy as it may provide symptomatic relief for three to six months [143].

The celiac plexus is a dense network of nerves that innervates the upper abdominal organs. Pain may be relieved by inhibiting synaptic pathways within the plexus by chemical destruction of the pathways and ganglia using dehydrated alcohol. Celiac plexus neurolysis is performed under endoscopic ultrasonography guidance [122].

Celiac plexus neurolysis improves analgesia and quality of life and decreases opioid requirements. The analgesic effect seems to vanish after eight weeks, and in most patients, pain recurs after three months. Repeated celiac plexus neurolysis benefits about 30% of patients and is normally not offered [123].

Splanchnic Nerve Neurolysis

Splanchnicectomy may disrupt more nerve pathways than celiac plexus neurolysis and is a better option when there is a large mass in the region of the celiac plexus. Splanchnicectomy is seldom performed in patients with PDAC despite some evidence of long-lasting pain relief and few complications in observational series, possibly because the expertise is not widely available [123].

Radiation Therapy

External beam radiation therapy with or without concomitant chemotherapy may also significantly alleviate pain due to local invasion of pancreatic cancer, frequently with improvement in cachexia and obstructive symptoms. However, it may take several weeks to achieve its maximal effect. When pain is caused by liver or bone metastases, patients may benefit from radiation therapy [16,122].

CACHEXIA, WEIGHT LOSS, AND NUTRITIONAL COMPROMISE

Nutritional compromise in PDAC is common, but the underlying pathologies are diverse [2]. Nausea, caused both by the primary disease process and its associated chemotherapy, is most effectively treated with serotonin-3 receptor antagonists and atypical antipsychotics (e.g., olanzapine), with some emerging evidence suggesting efficacy with cannabinoids. Loss of appetite, even in the absence of overt nausea, is frequently reported by patients, and this symptom is driven by central pathways that are largely distinct from those that produce nausea.

Malabsorption secondary to pancreatic exocrine deficiency degrades nutritional status. Pancreatic enzyme-replacement therapy helps to stabilize weight loss and also improves quality of life by decreasing gastrointestinal symptoms. Malabsorption from biliary obstruction is a complication found in up to 90% of patients with PDAC. Similar to the replacement of pancreatic enzymes, the treatment of biliary obstruction improves symptoms beyond its effects on digestion, including anorexia, pruritus, and fatigue.

Collectively, careful attention to the nutritional status of patients with PDAC improves both their survival and quality of life. Early and regular involvement of nutrition experts in their care is recommended [2,124].

Cancer-Related Anorexia/Cachexia Syndrome (CACS)

A constellation of disproportionate loss of lean body mass, weight loss, muscle wasting, adipose tissue reprogramming, and anorexia, cancer-related anorexia/cachexia syndrome (CACS) is more frequent in patients with PDAC than in any other malignancy due to the complex metabolic profile of pancreatic cancer [2]. In a study of 390 patients with advanced cancers, the rate of cachexia was highest in PDAC (89%), followed by gastric cancer (76%) and esophageal cancer (53%) [125].

Unlike simple starvation, which is characterized by a caloric deficiency that can be reversed with appropriate feeding, the weight loss of cachexia cannot be adequately treated with aggressive feeding [126]. The physical impact of CACS contributes to decreased patient quality of life, treatment response, and survival due to gross alterations in protein metabolism, increased oxidative stress, and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families [125].

In CACS, an abnormally accelerated resting energy expenditure increases muscle protein breakdown and lipolysis, which seems related to activation of cytokines (e.g., tumor necrosis factor-alpha, interleukin 6 and 1 beta), and tumor-derived, potentially cachexia-inducing factors that target skeletal muscle gene products [122,126].

Potentially Beneficial Agents

Cachexia does not respond to nutritional support. There are no FDA-approved medications for treatment of CACS, and positive pharmacotherapy response in patients with anorexia associated with non-malignant disease has been difficult to translate into benefit for patients with cancer [127,128].

Many agents have been evaluated for the treatment of CACS, but only corticosteroids (e.g., dexamethasone) and progesterone analogs (e.g., megestrol acetate) have a proven benefit in the anorexia associated with this syndrome [122]. Selection is based on life expectancy and assessment of risks versus benefits. Dexamethasone is suggested for patients for whom only weeks of therapy are anticipated, while megestrol acetate or medroxyprogesterone acetate (another progesterone analog) are suggested for patients with longer life expectancies [126].

A phase III study randomized 190 patients with advanced cancer and anorexia to megestrol acetate (480 mg/day), dexamethasone (4 mg/day), or placebo for up to four weeks. Differences in primary endpoint (at least 25% improvement in appetite) between megestrol (79.3%), dexamethasone (65.5%), and placebo (58.5%) were non-significant. Hyperglycemia and deep vein thromboses were more frequent with dexamethasone than megestrol or placebo. No other differences from placebo were found [127].

In this trial, the higher rate of deep vein thromboses with dexamethasone was unexpected. Megestrol acetate is associated with thromboembolic events and is contraindicated in patients with VTE. Dexamethasone has the potential to reduce cancer-related fatigue and elevate mood, at the significant cost of accelerating catabolic effects on muscle [127]. The primary benefits associated with these drugs are increased appetite and weight gain, not improved survival, and both drugs are associated with potential harms [122].

Mirtazapine is well-known for promoting weight gain. A placebo-controlled randomized trial found that appetite scores increased similarly with mirtazapine (15 mg at night) and placebo during the 28-day study. Mirtazapine was associated with significantly less increase in depressive symptoms and higher prevalence of somnolence than placebo, but no other differences were found [128].

The evidence of benefit in patients with CACS is inconclusive for androgens and selective androgen receptor modulators, anamorelin, cyproheptadine, long-chain omega-3 fatty acids, vitamins, minerals, and other dietary supplements, nonsteroidal anti-inflammatory drugs (NSAIDs), thalidomide, and combination approaches [126]. However, a trial of low-dose olanzapine (5 mg/day) is reasonable, particularly for patients who have concurrent nausea and/or vomiting unrelated to chemotherapy or radiation therapy [126].

Cannabis and Cannabinoids

In the cannabis plant, delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best-characterized therapeutic constituents. Pharmaceutical cannabinoid products containing THC (dronabinol), a THC analog (nabilone), or THC:CBD in an oromucosal spray (nabiximols, investigational) were examined for efficacy in CACS and palliative care in two meta-analyses [126].

Unfortunately, no benefit beyond placebo was found for pharmaceutical cannabinoid products in CACS, despite their superior weight gain and appetite effects in patients with advanced HIV [129]. Cancer patients with more than 30% decrease in pain with cannabinoids compared with placebo approached significance [129].

In both meta-analyses, available studies of smoked cannabis in CACS did not meet evidence thresholds and were excluded. This limits the ability to inform real-world clinical practice, where patient preference, self-titration to tolerability/effect, access, and other factors favor smoked/vaped cannabis over single-molecule pharmaceutical cannabinoids [130].

Counseling and Support

The substantial loss of body mass can cause significant distress to patients. Although advanced cachexia is irreversible, palliating anorexia in patients with advanced cancer is best approached by focusing on stimulating appetite, supporting each person's food preferences, and avoiding prescriptive dietary advice [127].

Providing education to patients and their caregivers is crucial. The objective is to promote a shared understanding about changed goals of care, and to help reduce the distress caused by reduced oral intake [127].

Counselling of family members regarding what to expect with disease progression is important—it can alleviate distress that leads to well-meaning but futile attempts to pressure or coerce the patient into increased feeding. Key points to discuss with patients and their family members, related to interactions about nutrition and eating near the end of life, include the following [131]:

- Loss of appetite is common in patients with advanced cancer and may be the result of the cancer process itself.

- Trying to force a patient to eat is usually counterproductive, potentially leading to increased nausea/vomiting.

- In most patients with advanced cancer and cachexia, providing additional calories by feeding tubes and/or intravenously does not improve outcomes.

- Trying to make a patient eat, when they have marked appetite loss, can lead to decreased social interactions and increased patient distress regarding interactions with caregivers (including stories of patients, in their dying days, pretending to be asleep when relatives visit, so that the relatives do not try to make them eat something).

Caregivers should be advised that it may be best to listen to and support the patient in a variety of other ways (such as giving the patient a massage or applying a lip moisturizer) instead of trying to talk them into eating more. Referral to a registered dietitian may provide patients and caregivers with additional opportunities to discuss concerns and challenges related to nutrition, appetite, and meal planning.

Diabetes Mellitus in PDAC

The presence of diabetes has been associated with higher mortality in patients with PDAC; corticosteroids can induce or exacerbate diabetes in these patients. For patients with PDAC-related diabetes, nutritional management by an experienced dietitian is essential [16]. Metformin or insulin is used as a first-line therapy. Insulin is often the preferred agent because of its efficacy, flexibility, and safety.

Careful monitoring of plasma glucose levels two hours after meals is widely recommended. The limited literature on this topic recommends maintaining blood glucose levels to avoid hypoglycemia and reduce symptoms of hyperglycemia.

Pancreatic Exocrine Insufficiency and Pancreatic Enzyme Replacement Therapy (PERT)

A contributory factor to extreme weight loss may be pancreatic exocrine insufficiency, which leads to maldigestion, fat malabsorption, and steatorrhea. This complication may be caused by gradual tumor encroachment on pancreatic parenchyma or obstruction of the main pancreatic duct, or as a complication of surgery and/or irradiation. The main clinical manifestation is weight loss and malnutrition, and nonspecific symptoms such as abdominal cramping, flatulence, and urgency to defecate. Fat malabsorption does not become evident until pancreatic lipase secretion falls below 10% of normal levels [122]. The characteristic fatty stools associated with steatorrhea (loose, greasy, foul-smelling) may not be evident because patients tend to limit fat ingestion.

Pancreatic exocrine insufficiency is very frequent (>90% with tumors in the pancreatic head), and is associated with higher mortality in patients with unresectable PDAC. Pancreatic enzyme replacement therapy (PERT) improves survival in these patients [16]. Given its high incidence, diagnostic testing is not necessary. Patients suspected of fat malabsorption should be treated empirically with oral PERT [122].

The classical approach to patients with pancreatic exocrine insufficiency was restricting fat intake (<20 gm/day) to reduce steatorrhea. However, this further restricts the intake of fat-soluble vitamins, which are already malabsorbed in patients with pancreatic exocrine insufficiency and is not recommended. Frequent low-volume meals and avoidance of foods that are difficult to digest (e.g., legumes) are generally recommended [122].

Pancreatic exocrine insufficiency is treated with capsules of porcine pancreatic enzymes (pancrelipase). There are several commercial products available, and the amount of enzyme per capsule varies [81]. Doses are in United States Pharmacopeia (USP) units or International Units (IU); 90,000 USP is equivalent to 30,000 IU [122]. A healthy pancreas produces about 900,000 USP of lipase in response to a meal. Sufficient fat absorption can be maintained at around 10% of normal capacity; thus, roughly 90,000 USP per meal is needed. Because non-resected patients retain some pancreatic function, a starting dose of 75,000 USP with main meals and 25,000 with snacks should suffice in reducing steatorrhea and preventing weight loss. Enzymes are most effective when taken across the course of a meal. Following Whipple, patients will require 90,000 USP with meals and 45,000 USP with snacks [124].

Acidic gastric pH is normally neutralized by pancreatic bicarbonate secretion, which is absent in many patients with PDAC, especially following Whipple resection. Acid-suppressing therapy with a proton pump inhibitor is often required, as failure to neutralize gastric acid inactivates the enzymes [16,124].

Despite recommendation from expert groups, including the NCCN, evidence suggests PERT is underutilized. This was examined in a large commercially insured U.S. population from 2001–2013. Among patients with PDAC (32,461), 1.9% had diagnostic testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose (defined as ≥120,000 USP lipase daily) [132].

Testing and appropriate dosing is infrequent and inconsistent in an insured U.S. population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients [132].

9. CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For patients who are not proficient in English, it is important that information regarding all aspects of their care (including diagnostic procedures and treatment options) and palliative care resources be provided in their native language, if possible. 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. Interpreters can be 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 treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

10. CONCLUSION

PDAC is the most lethal solid malignancy, predicted to become the second leading cause of cancer death in the United States by 2030. The complexity of this aggressive cancer has been vexing to investigators and tragic for patients and their families. Major research efforts over the past 50 years have improved the five-year survival rate from 6% to 12.8%. The greatest gains—from resection of early-stage tumors—are the least likely to present at diagnosis. There is an urgent need to reduce PDAC incidence through primary and secondary prevention, and mortality by accelerating therapeutic development [133].

Until diagnostic or therapeutics breakthroughs arrive, novel uses of standard treatments (i.e., neoadjuvant therapy) show survival advantages for a greater number of patients. The longest survival reported by a phase III trial was published in 2018—a median 54.4 months in patients who received resection followed by mFOLFIRINOX [113]. Many novel treatments are in phase III trials. Additional approaches to manage morbidities and provide better palliative care are also needed. Cancer anorexia/cachexia is a high-priority area.

It is now clear that even early-stage PDAC is a systemic disease and that new-onset metabolic (e.g., diabetes, anorexia/cachexia, hyperglycemia) and neuropsychiatric (e.g., depression, fatigue) symptoms/syndromes are prodromal rather than comorbid or secondary. This recognition has also called for a re-thinking of pancreatic cancer from a more integrative, multi-system perspective [2].

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Evidence-Based Practice Recommendations Citations

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3. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020;38(27):3217-3230. Available at https://ascopubs.org/doi/10.1200/JCO.20.01364. Last accessed August 27, 2024.

35270 • Multimodal Pharmacotherapy for Pain Management

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired)

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

Techniques to ameliorate pain have been actively sought since the earliest recorded history of science and medicine. Although opioids are generally effective, the associated risks and side effects make their use undesirable in many patients. In an effort to decrease the use of opioids, it is vital for clinicians to first consider other agents to control pain. Combining various classes of drugs, in lower doses, can help control pain while decreasing side effects. This course will focus on the science behind multimodal pharmacologic pain management and its efficacy.

Table of Contents

35270 • Multimodal Pharmacotherapy for Pain Management

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. THE PHYSIOLOGY OF PAIN

ACTION POTENTIAL

FREE NERVE ENDINGS AND FIBER TYPES

PAIN PATHWAYS: GETTING THE INFORMATION FROM THE SITE OF PAIN TO THE CENTRAL NERVOUS SYSTEM

3. TYPES OF PAIN

ACUTE PAIN

CHRONIC PAIN

4. ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT

OPIOIDS

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

LOCAL ANESTHETICS

CALCIUM CHANNEL BLOCKERS

ALPHA-ADRENERGIC AGONISTS

ANESTHETIC DRUGS

ANTIDEPRESSANTS

5. USING MULTIMODAL PAIN THERAPY: EXAMPLES FROM THE PROFESSIONAL LITERATURE

EXAMPLE 1

EXAMPLE 2

6. CASE STUDIES

CASE STUDY 1

CASE STUDY 2

CASE STUDY 3

7. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

35270 • Multimodal Pharmacotherapy for Pain Management

Education Category. Pharmacology

Release Date. 11/01/2022

Expiration Date. 10/31/2025

Course Overview

Techniques to ameliorate pain have been actively sought since the earliest recorded history of science and medicine. Although opioids are generally effective, the associated risks and side effects make their use undesirable in many patients. In an effort to decrease the use of opioids, it is vital for clinicians to first consider other agents to control pain. Combining various classes of drugs, in lower doses, can help control pain while decreasing side effects. This course will focus on the science behind multimodal pharmacologic pain management and its efficacy.

Audience

This course is designed for nurses involved in the care of patients with pain.

Course Objective

The purpose of this course is to provide healthcare providers with a clear understanding of the concept of multimodal pharmacotherapy for pain relief, including available classes of analgesics.

Learning Objectives

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

1. Describe the underlying pathophysiology of pain.

2. Outline the different types of pain.

3. Discuss the mechanism of action and clinical use of opioids in the management of pain.

4. Compare and contrast other analgesic agents that can be used in a multimodal approach to pain management, including nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, and local anesthetics.

5. Analyze approaches to multimodal pharmacotherapy for pain management.

Faculty

Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), is a retired nurse anesthetist and prehospital registered nurse (instructor) who has published extensively in various areas of healthcare research while providing clinical care in arenas ranging from academic medical centers to austere environments in the third world during both wartime and peacetime. He has a bachelor’s degree in nursing from Georgetown University, Master’s degrees in education (Boston University) and nursing specializing in anesthesia (State University of New York in Buffalo and U.S. Army), and a PhD from the University of South Carolina. He is a retired lieutenant colonel in the U.S. Army Nurse Corps. He has taught nursing anesthesia, pharmacology, and physiology; mentored students in doctoral programs; and used advanced patient simulation to train students. Dr. Haas has worked in clinical, administrative, education, and research roles. He continues to work as an independent consultant, while taking more time to enjoy life with his wife of nearly 50 years and their children and grandchildren.

Faculty Disclosure

Contributing faculty, Richard E. Haas, BSN, MSN, EdM, PhD, CRNA, LTC US Army Nurse Corps (Retired), has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Sharon Cannon, RN, EdD, ANEF

Division Planner Disclosure

The division planner has 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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Pain is one of the most potent safeguards to homeostasis. Experiencing pain allows humans to learn which activities or substances might cause irreparable damage to the body, and thus avoid engaging in those activities or ingesting those substances. However, this system is not perfect. Techniques to ameliorate pain have been actively sought since the earliest recorded history of science and medicine. Opioids, alcohol, mandrakes, and cannabis have all been used through the years in an attempt to mitigate pain [1].

From the 1860s until the 1950s, morphine was the pre-eminent opioid used for the control of pain. It was easily produced, especially as the pharmacotherapeutic industry became increasingly more refined and developed. In the 1950s, researcher Paul Janssen began his work on the synthesis of a new opioid called fentanyl [2]. In 1960, fentanyl was synthesized, and its use became widespread as a result of its safety and efficacy. Two derivatives of fentanyl followed in the 1970s: alfentanil (with a more rapid offset) and sufentanil (with increased potency) [2]. Opioids continue to be the mainstay of severe pain relief.

Even as researchers have lauded the effects of opioids for pain relief, they decried the problems with the use of opioids, particularly the risks of abuse and addiction. In the decade following their widespread use in the Civil War, physicians began to refer to opioid use disorder as the "soldier's disease" [3]. Unfortunately, knowledge of the problem has not led to an immediate solution. Problems with opioid abuse, including use disorder and diversion for illicit use, continue. At the same time, opioids (including fentanyl and its congeners) are widely used for the control of severe pain. There is evidence that even appropriate use of opioids may lead to use disorders and diversion in a subset of patients [4].

In an effort to decrease the use of opioids, it is vital for clinicians to first consider other agents to control pain. Combining various classes of drugs, in lower doses, can help control pain while decreasing side effects. One large dose of an opioid may be effective, but the preferred approach may be to use less or no opioid and to combine other agents, including anti-inflammatories, local anesthetics, alpha-2 receptor agonists, and others, to attain pain relief without the risks associated with opioids. This course will focus on the science behind multimodal pharmacologic pain management and its efficacy.

2. THE PHYSIOLOGY OF PAIN

Management of pain is a highly complex and patient-centered specialty. Clear understanding of the underlying anatomy and physiology is required to make the correct selection of pharmacologic interventions.

The human body has a number of specialized receptors in the skin, viscera, and periosteum of the bones that send impulses to the spinal cord and brain reporting the presence of pain (Table 1) [5]. Of particular interest to those treating pain is the free nerve ending (FNE) (Figure 1). There are several types of these unmyelinated nerve endings, and the ones most related to pain and tissue damage information processing are type IVa [6]. FNEs can send an impulse in the form of an action potential into the pain pathways as the result of tissue damage (secondary to trauma or heat) or tissue deformity (severe pressure resulting in tissue destruction). It is helpful to briefly review the concept of the action potential before moving on to an examination of the FNE.

Table 1: TYPES OF SENSORY RECEPTORS

Type

Function

Location

Free nerve ending

Transmit pain and temperature

Skin, periosteum, arterial walls, joint surfaces

Pacinian (lamellar) corpuscle

Pressure

Skin

Meissner (tactile) corpuscle

Touch

Skin

Muscle spindle

Stretch and pressure

Skeletal muscle

Golgi tendon apparatus

Stretch and pressure

Tendons

Kinesthetic receptor

Three-dimensional location (proprioception)

Joints

Source: Compiled by Author

Figure 1: FREE NERVE ENDING

Source: Reprinted from Blausen.com staff (2014). Medical gallery of Blausen Medical 2014. WikiJournal of Medicine 1 (2).

ACTION POTENTIAL

Action potentials are changes in polarity along a nerve based on ion flow into and out of the nerve cell. As the action potential travels down the length of the cell, it will end at a point in the nervous system that results in some form of output, either physical (muscle movement) or experiential (pain). Figure 2 shows some of the details of an action potential and provides an extended explanation of their formation. Of particular importance is the quantity of ions moving at any specific time. The primary ions moving after stimulation and reaching threshold are Na+ (sodium, into the cell), K+ (potassium, out of the cell), and Cl- (chloride, into the cell). After the nerve has fired, the sodium/potassium adenosine triphosphate (ATP)-ase pump works to move sodium out of the cell and potassium back into the cell. A pump is needed because the ions are moving against their gradients, and energy is required in the form of ATP to power the pump.

Figure 2: ION MOVEMENT IN ACTION POTENTIAL FORMATION

Point A above shows the resting membrane potential of the nerve. At rest, a certain degree of leakage of both the sodium (Na+) into the cell and potassium (K+) out of the cell occurs. When a painful stimulus is experienced in the periphery, impulses will arrive at some point along a secondary nerve. Note the gradual upslope of the potential within the cell (the section between points A and B). In this example, painful impulses are coming into a section of nerve tissue from a free nerve ending, resulting in opening voltage-gated Na+ channels, resulting in an influx of Na+ that is faster than the outward leakage of K+, leading to an increasing membrane potential. Once membrane potential reaches threshold (point B), a large number of voltage-gated Na+ channels open, resulting in a large shift of Na+ ions from the extracellular fluid to the intracellular fluid, causing the initiation of an action potential (shaded area 1). Voltage-gated K+ and chloride (Cl-) channels then open, allowing K+ efflux and Cl- influx, dropping membrane potential (shaded area 2). The movement of K+ and Cl- is so great that an overshoot occurs, and the nerve hyperpolarizes (or falls below resting membrane potential, point D and shaded area 3). The Na+/K+ ATP-ase pump begins to work (shaded area 3) and equalizes Na+ and K+ gradients to result in a return to normal resting membrane potential.

Source: [7]

A variable but set amount of nervous action potential impulses is required to reach threshold. The nerve must receive a sufficient number of input signals (or stimuli) to move its membrane potential above threshold and fire an impulse, sending, in this case, a message of pain along a nerve pathway. Understanding the science behind the action potential and its formation is crucial for the healthcare provider, as many analgesic drugs work by altering the transmissibility of signals sent along the nerve. If the action potential formed in the FNE can be blocked or altered, painful sensations can be mitigated or eliminated.

FREE NERVE ENDINGS AND FIBER TYPES

The FNEs are one of the sets of tissue receptors that can be stimulated to send impulses (action potentials) along the length of the nerve for further interpretation either in the spinal cord or various sections of the brain. Despite the study of FNEs over the past decade, the exact mechanism of action is still unknown. There are several postulations about how stimuli cause the firing of FNEs, initiating action potentials and resulting in the experience of pain. FNEs are also referred to as nociceptors. While nociceptors are often described as pain receptors, the purpose of the nociceptor is to alert the body to the presence of tissue damage [8]. FNEs are small structures, with a thin layer of Schwann cells surrounding them. They are branched in appearance and have small varicosities containing mitochondria, vesicles, and an axonal reticulum (analogous to the sarcoplasmic reticulum or endoplasmic reticulum in other cell types) [5,9]. The vesicles contain numerous neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), both of which are crucial in spreading action potentials during conditions of tissue destruction resulting in pain [9]. Figure 2 illustrates varicosities in the distal ends of the FNE, but these structures are present throughout the FNEs until they reach larger nerves.

There are two primary types of nerves that carry pain data elicited by stimulation of an FNE: type Aδ or myelinated (fast) nerve fibers and type C or unmyelinated (slow) nerve fibers [5,8]. Myelinated fibers are insulated with Schwann cells, but with gaps (nodes of Ranvier) in which the nerve fiber is exposed to the environment of the extracellular fluid. The myelinated fibers are also referred to as fast fibers because the action potentials can skip between the nodes of Ranvier in a process called saltatory conduction (rather than traveling the entire length of the axon). Sharp or acute pain, especially from traumatic injury, is usually processed in this fashion.

Type C fibers move impulses more slowly. While myelinated fibers can carry action potential impulses at speeds of 5–30 meters per second, unmyelinated fibers have speeds of 0.4–1.4 meters per second [8]. Most individuals have experienced this type of pain differential speed in their own lives: an acute accidental injury such as cutting one's finger while cooking results in an immediate response followed by an aching sensation. This is because both type A and type C nerve fibers travel in bundles together, and the stimulation of one nerve makes the stimulation of a nearby nerve easier. An example of this phenomenon is seen in Figure 3. The solid line represents an unmyelinated nerve (type C), while the line with nodes represents a myelinated nerve (type Aδ). If the nerves travel together from the site of injury, the patient experiences two waves of pain. Myelinated fibers carrying information about pain tend to be highly localized, dependent on the density of FNEs in the area of injury. Unmyelinated fibers tend to carry information related to aching or less acute or localized pain. A significant amount of visceral pain tends to be carried by unmyelinated fibers, making diagnoses of this type of pain difficult.

Figure 3: SIMPLIFIED PAIN PATHWAY

Source: Bettina Guebeli, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

PAIN PATHWAYS: GETTING THE INFORMATION FROM THE SITE OF PAIN TO THE CENTRAL NERVOUS SYSTEM

Pain pathways are complex routes over which action potentials are sent from the peripheral nerves to the central nervous system (CNS). An interruption of the pathway at any point tends to mitigate the degree of pain felt by the patient and, in some cases, may alleviate pain entirely. This can be accomplished by blocking some part of the pathway with a local anesthetic or by administering an agent(s) that drives the resting membrane potentials of neurons in a more negative fashion or interrupts the pathway within the brain. One of the key aspects of multimodal pharmacologic pain relief is to use smaller doses of various agents that work at different points along the pathway, minimizing adverse side effects while maximizing the number of sites of action.

Pain and other impulses originate in the peripheral nervous system (PNS), enter the dorsal horn of the vertebra, and then ascend to the brain along the spinothalamic tract. This is a three-neuron pathway containing first-, second-, and third-order neurons. In Figure 4, the spinothalamic tract can be traced from the primary afferent nerve (receiving the pain signals at the site of injury) to the spinal cord, entering via the dorsal root of the cord. At this point, the first-order neuron synapses with a second-order neuron. Upon entry into the cord, the second-order neuron crosses from the right to the left (or left to right, if it enters the left dorsal root). This is referred to as decussation. The second-order neuron then rises up the cord in either the anterior or later spinothalamic tract, synapsing with a third-order neuron in the thalamus. This neuron leads to the sensory cortex in the brain, which in turn interprets the exact location and degree of pain.

Figure 4: FAST VS. SLOW PAIN TRANSMISSION

Source: Bettina Guebeli, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

Local Changes and Injured Tissue

Because pain is adaptive in nature, it is important that signals are sent to the central nervous system to ensure the body responds to maintain homeostasis. As discussed, FNEs exposed to noxious stimuli send action potentials down a specific pain receptor pathway to insure its arrival in the central nervous system [9,10,11,12]. Recall also that action potential generation is dependent upon the release of neurotransmitters, which in turn raise the nerve's membrane potential above threshold. While many neurotransmitters do this, a significant number function to lower resting membrane potential. This environment, in the presence of injury, has been referred to as "inflammatory soup," as a representation of the numerous and diverse substances involved in responses to pain [7].Table 2 provides a synopsis of most of these substances, focusing on those with the greatest impact in pain management. For nearly every substance, there is some form of pharmacologic antagonist available or in development to nullify its excitatory effect. While Table 2 provides a brief glimpse at how neurons can be excited by local peptides and neurotransmitters, the actual mechanisms by which these changes are made are incredibly complex.

Table 2: SUBSTANCES AFFECTING THE TRANSMISSION OF IMPULSES IN FREE NERVE ENDINGS AND SOMATIC NERVES

Substance

Description

Bradykinin

Bradykinin is a vasodilator that increases capillary permeability, increases migration of white blood cells, and increases free radicals in inflamed tissue and significantly excites pain receptors.

Calcitonin gene-related peptide (CGRP)

Stimulation of the free nerve endings results in the release of CGRP from the neuron, sensitizing it to stimuli and making the neuron hyperactive.

Norepinephrine

Pain stimulates the sympathetic nervous system, leading to the release of norepinephrine, which has an excitatory effect on the neuron.

Glutamate

Glutamate is an endogenous and highly excitatory neurotransmitter that binds at both the NMDA and AMPA receptors to excite the neuron and facilitate pain transmission.

Histamine

A ubiquitous substance throughout the body, histamine is released by mast cells and binds with excitatory receptors on the neurons and other cells.

Tachykinin

Tachykinins are a broad family of neuropeptides, including substance P, neurokinin A, and neurokinin B, released in response to pain or inflammation. They bind with neurokinin receptors, resulting in increasing excitatory stimulation of the neuron.

Serotonin (5-HT)

During inflammation, 5-HT is released from platelets in the area of injury. In turn, these bind with 5-HT2A and 5-HT3 receptors, resulting in excitation of the nerve.

Prostaglandin

One of the most crucial substances in pain management, prostaglandin sensitizes all aspects of excitatory phenomena in neurons. They are produced from the cell's arachidonic acid supply via the cyclo-oxygenase and lipoxygenase pathways.

Cytokine

Cytokines increase synaptic excitatory transmission in neurons and are represented by such substances as TNF and interleukins (e.g., IL-1b, IL-6).

AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA = N-methyl-D-aspartate, TNF = tumor necrosis factor.

Source: [5,10,11,12,13,14,15]

There is a large number of receptors on the neuron's cell membrane, most of which can bind with a specific molecular neurotransmitter. Nearly every drug administered in multimodal pain therapy interacts with one or more of these receptors.

Complex Ascending Pain Pathways

Figure 5 is a complex diagram of the ascending pain pathways. Starting in the lower left corner (with the stimulus), the pain pathway can be seen tracking along both Ad and C fibers and entering the dorsal root of the spinal cord. The peripheral nerve synapses with a second-order nerve (Box 1) that decussates across the spinal cord; activating or inhibiting the interneurons in the lamina of the dorsal root can stop the impulse from propagating. The pain pathway then begins to ascend the anterior and lateral spinothalamic tracts toward the brain (Box 2). In the neck area of the diagram, the spinothalamic tract has been highlighted (Box 3), and it continues to ascend into the thalamus in the brain. The second-order neurons synapse in a special area of the thalamus called the ventrobasal complex (Box 4) [5]. The thalamus, when activated, is thought to cause the conscious perception of pain and provides an anatomic location for the cell bodies of the third-order neurons [5]. The third-order neurons then ascend to the somatosensory cortex, allowing the patient to localize and quantify the painful stimulus (Box 5).

Figure 5: ASCENDING PAIN PATHWAYS

This is a cross-sectional view looking from the top of the head down toward the feet. As indicated by the box labeled abdomen, the patient is lying face down.

Source: Richard Lennertz, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

The thalamus also has neuronal branches that help to stimulate the reticular activating system, the portion of the brain responsible for sleep and waking [5]. The thalamus has numerous projections into other areas of the brain, including the prefrontal cortex and the amygdala, the latter of which is part of the limbic system [16,17]. The projections of the neurons into the limbic system account for the suffering aspect of pain, where the sensation is overlaid with an emotional experience. As pain is important in preventing homeostasis damage, including an emotional response to pain (in addition to a sensory response) helps ensure the person experiencing pain will avoid the stimulus that led to the pain.

The hippocampus is another area that receives neuronal impulses during painful stimuli [17]. Previous studies have linked decreases in hippocampal volume to major depression; however, the hippocampus also helps process and modify nociceptive stimulation [18,19]. Further, the hippocampus is the primary site for implanting memories [17].

Patients who are exposed to chronic pain or chronic stress may develop severe pain syndromes refractory to usual treatment. These pain syndromes have been associated with increased production of tumor necrosis factor-alpha (TNFα), a proinflammatory cytokine that sensitizes the patient to increased levels of pain secondary to local inflammation [19]. These inflammatory processes also atrophy the hippocampus, which has been associated with major depressive disorder [20]. It is not unusual, therefore, for unremitted or inadequately treated pain to co-occur with severe depressive disorders [21,22].

Wide-Dynamic-Range (WDR) Neurons

At this point, it is appropriate to discuss the case of the wide-dynamic-range (WDR) neuron, a self-stimulating type of interneuron. As discussed, interneurons are found in the dorsal horn of the spinal cord and may act to facilitate or inhibit the transmission of nerve impulses, depending upon the receptors and neurotransmitters present. WDR neurons are associated with chronic pain states and are triggered by glutamate and glycine (excitatory neurotransmitters), which in turn activate N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors [5,12,23,24]. The NMDA receptor is a channel between the extracellular fluid and intracellular fluid embedded in the cell membrane. The dorsal horn of the spine has many glutamate- and glycine-releasing interneurons, and in an excitatory state, large numbers of glutamate and glycine neurotransmitters are released from neurons [25]. They have binding sites on NMDA receptors, which allows the movement of both Na+ and Ca2+ into cells, while a comparatively small amount of K+ exits [23,25]. The NMDA receptor cannot open, even in the presence of glutamate and glycine, without first having the magnesium ion (Mg2+) blocker removed from the center of the channel. The interneurons containing the NMDA receptors, however, have other receptors, allowing them to become excited and fire an impulse. When the initial depolarization occurs, the Mg2+ obstruction is removed from the channel, and the rich environment of glycine and glutamate allows the membrane to continually depolarize. This increases the excitability of the second-order neuron, facilitating the passage of painful stimuli to the brain. As the nervous tissue becomes increasingly excited, further releases of glutamate and glycine occur, prompting more NMDA receptor opening in a positive feedback loop. This is called a windup phenomenon [26]. In other words, the area of injury becomes so excited that hyperalgesia sets in, and, in this state, even the smallest stimulus may result in severe pain. Wind-up phenomena result in a continual stimulation of neurons within the cord, with information processed there being sent to the brain. This is referred to as long-term potentiation and is quite difficult to treat [23,24].

Knowledge of these pain pathways is necessary to achieve a sense of the many sites in the central and peripheral nervous systems where pain can be treated. As specific drug classes are described, one may return to these sections for a better these diagrams to understand how and where they act in the body.

3. TYPES OF PAIN

ACUTE PAIN

Pain pathways stimulate many areas of the brain. The brain responds by the release of many neurotransmitters and other hormones to provide a systemic response [10]. As discussed, pain impulses activate the amygdala, which triggers a sympathetic nervous system response, sometimes referred to as the "fight-or-flight" response. The release of norepinephrine and epinephrine results in, among other things, tachycardia, hypertension, and elevated blood glucose levels. Additionally, the local response to the stimulus produces the release of local neurotransmitters, such as substance P, glutamate, CGRP, and brain-derived neurotrophic factor (BDNF) [10,11]. Of perhaps greater concern is the release of cytokines, which results in a profound inflammatory response. The inflammatory response is usually highlighted by hyperalgesia (exaggerated painful response to a painful stimulus) and allodynia (painful response from a non-pain-inducing stimulus). Take the example of a minor sunburn. If the skin is reddened and inflamed, a pat on the back becomes inordinately painful (hyperalgesia) and simply wearing a shirt may be intolerable (allodynia). In addition to these responses, untreated acute pain may lead to the expression of additional FNEs and nociceptors.

Acute pain usually has an easily recognized proximate cause and can be well-localized. The possible exception is intra-abdominal or pelvic pain, in which unmyelinated nerves are responsible for most nerve impulse propagation. However, even this hard-to-localize pain is often characterized to a general area ("My stomach hurts") rather than being poorly defined ("Everything aches").

In some cases, acute pain is associated with a medical procedure, such as routine surgery. For these patients, it is possible to visualize precisely where tissues have been manipulated and thus the location of the pain. The advantage of treating this form of acute pain is that treatment can be pre-emptive, with the administration of analgesics as part of the overall management plan [27].

CHRONIC PAIN

Chronic pain is experienced by nearly one-third of the adult population of the United States and is associated with costs of more than $600 billion per year [11]. It can result in physical and emotional disability. It has become clear that chronic pain is far different from acute pain in its experience and treatment. While acute pain is related to a specific injury site, chronic pain is often centrally mediated and can therefore occur without the stimulation of a peripheral nerve [7,11,28]. Unfortunately, while acute pain can serve some adaptive purpose in protecting the person from harm, chronic pain is maladaptive in nature and typically has no beneficial biologic or systemic significance [11].

Historically, the initial approach to diagnosis and management of pain emphasized the identification of disease, lesion, or anatomic site of the pain, without reference to the underlying neural mechanisms or the application of this to treatment considerations [29]. Evidence now strongly supports combining the conventional etiology-based approach with a mechanism-based approach that classifies pain syndromes by the type of maladaptive nervous system alteration that has developed in reaction to the original insult. This approach provides a comprehensive dual therapeutic focus that targets the pathologic sustaining mechanism of the pain as well as the original disease, lesion, or tissue injury that has been the traditional focus of pain management [29,30]. Such an approach is believed to optimize pain diagnosis and treatment by avoiding the limitations associated with the traditional etiology-based approach [31,32,33,34,35,36].

Most pain syndromes involve multiple, often overlapping, neurobiologic mechanisms determined by the stage of the disease process. Current concepts of pain classify these into four main categories: nociceptive, inflammatory, neuropathic, and centralized [37].

Nociceptive pain is a physiologic response to tissue injury, the perception that arises from intense stimulation of specialized peripheral sensory neurons (nociceptors) that respond only to noxious (pain) stimuli. Nociceptive pain is subgrouped by location of involved tissues into somatic pain (muscle or connective tissue) and visceral pain (visceral structures) [38]. Nociceptive pain is considered adaptive during tissue healing but maladaptive and pathologic when it persists after healing has occurred.

Inflammatory pain occurs in response to tissue injury or infection that activates peripheral nociceptors and initiates the immune response. While the resultant production and recruitment of pro-inflammatory mediators to the injury site may serve to perpetuate discomfort, it also facilitates tissue repair; thus, this is considered an adaptive pain mechanism.

Neuropathic pain originates from peripheral or central nervous system injury. Unlike nociceptive and inflammatory pain, the mechanism of neuropathic pain has no adaptive function and is strictly pathologic [32,39]. Acute pain from somatosensory damage is termed "acute neural injury." The term "neuropathic pain" implies pain that persists beyond the period of expected or actual tissue healing, and the underlying mechanism involves a maladaptive alteration in somatosensory nervous system function [35].

Centralized pain results from heightened nociceptive sensitivity in the absence of detectable peripheral stimulus and with negligible peripheral inflammatory pathology. The mechanism is poorly understood and is regarded as strictly pathologic as it lacks any evident adaptive function. Centralized pain disorders include conditions such as fibromyalgia, tension headache, and irritable bowel syndrome [32,38,40].

The persistence of acute nociceptive, inflammatory, or neural injury pain beyond tissue healing or repair reflects ongoing nociceptive activity that has become dissociated from peripheral nociceptive input to become maladaptive. Regardless of whether acute pain originates from tissue injury, tissue infection, or peripheral nerve injury, a similar process occurs by which nociceptive, inflammatory, and neuropathic pain signals are relayed from tissue injury site to the brain. This highly intense or prolonged pain signaling can lead to profound alteration in neuronal pathways that are further "upstream" from the peripheral tissue pain origin. Among these are increased ascending pathway signaling to the brain, reduced descending inhibitory signaling, expansion of pain receptive field, and induction of spontaneous and widespread pain. The resulting peripheral and central pathway hypersensitivity represents a state of abnormal nervous system function, amplified central nervous system sensory signaling, and abnormally low threshold pain response. The pain is no longer a symptom of peripheral insult, but a disease state of the nervous system [35]. This transition from acute to chronic pain occurs in discrete pathophysiologic steps involving multiple signaling pathways [41].

4. ANALGESIC AGENTS EMPLOYED IN MULTIMODAL PAIN MANAGEMENT

Figure 6 illustrates some of the sites and agents useful in the management of pain. Note that some agents act at more than one site along the pain pathway, and some of the agents enhance the utility of the endogenous descending pain pathways.

Figure 6: SITES AND AGENTS FOR MULTIMODAL ANALGESIA

Source: Bettina Guebeli, licensed under a Creative Commons Attribution-Share Alike 4.0 International license. Modified by author.

OPIOIDS

Evidence Based Practice Recommendation

According to the Institute for Clinical Systems Improvement, there needs to be shared decision-making with the patient about reducing or eliminating opioids to avoid unnecessary complications from long-term opioid use. This involves following and re-evaluating the patient closely, with dose reduction or discontinuation as needed.

https://www.icsi.org/wp-content/uploads/2020/01/PalliativeCare_6th-Ed_2020_v2.pdf

Last Accessed: October 20, 2022

Level of Evidence: Expert Opinion/Consensus Statement

Opioid analgesics produce therapeutic and side effects by mimicking endogenous opioid activity, although some opioids produce analgesia by activity outside the opioid receptor complex. Opioids widely differ in levels of affinity and activation of opioid receptor subtypes. In addition, inter-individual variation in analgesic response and side effects is significant, largely driven by genetic factors [42]. The complex interaction between unique opioid properties and individual patient characteristics dictates that a patient-tailored approach is required for opioid selection, dose initiation, and titration to optimize safety, analgesia, and tolerability.

Naturally occurring opioid compounds are produced in plants (e.g., opium, morphine) and in the body (the endogenous opioids) [43]. Endogenous opioids are peptides that bind opioid receptors, function as neurotransmitters, and help regulate analgesia, hormone secretion, thermoregulation, and cardiovascular function. The three primary endogenous opioid peptide families are the endorphins, enkephalins, and dynorphins, and the three primary opioid receptor types are mu, kappa, and delta [44,45]. A quick overview of this complex pain modulation system is helpful in understanding how opioid analgesics work.

Endogenous Opioid Peptides

Endogenous opioid peptides are neurotransmitter molecules in the opioid receptor complex that produce specific physiologic effects determined by neuronal distributions of the activated opioid receptor type [46]. The endogenous opioid peptides are cleaved from the pro-hormone precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. The endogenous delta opioid receptor peptides are met-enkephalin and leu-enkephalin, cleaved from proenkephalin. Prodynorphin gives rise to kappa opioid receptor agonists dynorphin A and B. Pro-opiomelanocortin encodes the peptide beta-endorphin, which has agonist activity at all three classical opioid receptors. Some endogenous opioid ligands lack specificity for opioid receptor subtypes, such as b-endorphin and the enkephalins [47,48].

Endorphins

Endorphins are synthesized in the hypothalamus and the pituitary gland. Pain, strenuous exercise, excitement, and orgasm stimulate their release, binding, and activation. Endorphins are popularized as the "natural pain killers" from their ability to induce analgesia and a general feeling of well-being. They are thought to largely mediate analgesia from acupuncture, massage, hydrotherapy, and transcutaneous electrical nerve stimulation therapy [49].

Dynorphins

Dynorphin peptides are synthesized from the precursor pro-dynorphin and have primary affinity and binding at the kappa opioid receptor. Dynorphins are distributed throughout the CNS, with highest concentrations in the brain stem, hypothalamus, and spinal cord. Their physiologic actions are diverse, and their primary function is the modulation of pain response, appetite and weight, circadian rhythm, and body temperature. Dynorphins are linked to stress-induced depression and drug-seeking behavior, and drugs that inhibit dynorphin release are under evaluation for possible use in the treatment of depression related to drug addiction [49].

Enkephalins

Enkephalin peptides, derived from pro-enkephalin, are located throughout the brain and spinal cord and are involved in regulating nociception. Enkephalins inhibit neurotransmission in pain perception pathways, reducing the emotional and physical impact of pain. Enkephalins also reside in the gastrointestinal (GI) tract, where they help regulate pancreatic enzyme secretion and carbohydrate metabolism [49].

Opioid Receptors

Opioid receptors are expressed throughout the CNS and PNS on key nodes within the pain pathway and are highly concentrated in areas involved with integrating pain information [50]. Opioids vary greatly by receptor affinity, binding, and activity and can bind to produce agonist, partial agonist, or antagonist receptor activity [44]. As noted, the analgesic activity and the side effects result from mimicry of endogenous opioids, achieved by the beta-phenylethylamine group moiety shared by endogenous and exogenous opioid receptor ligands that facilitate opioid receptor binding [51].

Mu Opioid Receptors

Mu receptors are the primary mediators of analgesia produced by opioid analgesics in clinical use. Their greatest CNS concentration is in the thalamus, medulla, periaqueductal gray area, neocortex, amygdala, dorsal horn, inferior and superior colliculi, and brain stem [44,49,52]. PNS occupancy includes the peripheral sensory neuron dorsal root ganglion, stomach, duodenum, jejunum, ileum, and proximal and distal colon. Mu receptors in non-neural tissue are found in the vascular and cardiac epithelium, keratinocytes, vas deferens, and Sertoli cells [53].

Mu opioid receptors in the amygdala and nucleus accumbens mediate opioid reward response (e.g., euphoria). In this brain region, opioids bind to and activate mu receptors, which inhibit gamma-aminobutyric acid (GABA) to increase dopamine transmission [50]. Mu opioid receptors broadly distributed in the limbic system mediate emotional response to pain and analgesia. In the medial thalamic nuclei, they relay spinothalamic inputs from the spinal cord to the cingulate gyrus and limbic structures [54].

Kappa Opioid Receptors

Kappa opioid receptors bind dynorphin as the primary endogenous ligand. In the CNS, they are highly concentrated in the caudate-putamen, nucleus accumbens, amygdala, brain stem, neural lobe of the pituitary gland, and hypothalamus. In the PNS, these receptors are found in the sensory neuron dorsal root ganglion, stomach, duodenum, jejunum, ileum, and proximal and distal colon. They are primarily found in the limbic system, brain stem, and spinal cord. Their major effects include spinal analgesia, sedation, dyspnea and respiratory depression, dependence, and dysphoria [53]. The kappa opioid receptor subtype k3 is considered the primary analgesic mediator [55].

Delta Opioid Receptors

Delta receptors are mostly confined to CNS structures of the pontine nuclei, amygdala, olfactory bulbs, and deep cortex, but are also found in the GI tract and the lungs. They mediate spinal and supraspinal analgesia and the psychomimetic and dysphoric effects of opioid analgesics [49,56].

Other Potential Opioid Receptors

Other opioid-like receptors have been identified in the CNS, including the opioid receptor like-1 (ORL-1). In contrast to the classic opioid receptors, the ORL-1 receptor is insensitive to the opioid antagonist naloxone. Opioids can bind to and activate the toll-like receptor 4 (TLR4), an innate immune pattern-recognition receptor [50].

Opioid Analgesic Mechanism

Opioid analgesia results from a complex series of neuronal interactions, largely mediated by the high density of opioid receptors in the dorsal horn of the spinal cord and in subcortical regions of the brain [46]. The analgesic effects of opioids result from two general processes: 1) direct inhibition of ascending transmission of pain signaling from the dorsal horn of the spinal cord, and 2) activation of descending pain control circuits from the midbrain to the dorsal horn of the spinal cord [49]. All three opioid receptor types mediate spinal analgesia. Supraspinal analgesia is primarily mediated by mu opioid receptor subtype 1. Opioid receptors are coupled to the superfamily of inhibitory G proteins. Receptor activation inhibits adenylate cyclase, reducing generation of cyclic adenosine 3,5 monophosphate and other second messengers. Potassium conduction is activated, inhibiting calcium influx to hyperpolarized target cells and reducing their response to depolarizing pulses. Neurotransmitter release is inhibited, and generation of postsynaptic impulses is decreased [46,50].

Although drugs such as morphine are highly selective for mu opioid receptor and bind multiple mu receptor subtypes, mu opioid agonists greatly differ by interaction with different receptor variants and other opioid and non-opioid receptors [45]. A pharmacologically and clinically relevant classification approach is classifying opioid agents by functional interaction as mu receptor agonists, partial agonists, mixed agonists-antagonists, or antagonists (Table 3).

Table 3: COMMONLY USED OPIOIDS

Drug

Functional Category

Route(s)

Comparison to Morphinea

Morphine

Mu receptor agonist

IM, IV, PO, inhaled vapors

1

Hydromorphone (Dilaudid)

Mu receptor agonist

PO, SQ, IM, IV

10

Fentanyl (Actiq, Sublimaze)

Mu receptor agonist

PO, IV, buccal film, transdermal patch

100

Oxycodone (Roxicodone, OxyContin)

Mu receptor agonist

PO

1.5

Tramadol (Ultram, ConZip)

Mu receptor agonist

PO, IV

0.1

Hydrocodone (Hysingla ER)

Mu receptor agonist

PO

1

Oxymorphone (Numorphan)

Mu receptor agonist

PO, SQ, IM, IV

0.3

Meperidine (Demerol)

Mu receptor agonist

PO, IM, IV

0.1

Methadone (Methadose)

Mu receptor agonist

PO, SQ, IM, IV

Dose dependent

Codeine (Codeine)

Mu receptor agonist

PO

0.17

Buprenorphine (Belbuca, Butrans, Sublocade)

Partial mu receptor agonist

PO, buccal film, transdermal patch, IM, IV

30

Butorphanol (Stadol)

Mixed agonist/antagonist

Nasal spray, IM, IV

2

Nalbuphine (Nubain)

Mixed agonist/antagonist

SQ, IM, IV

1

Sufentanil (Dsuvia)

Mu receptor agonist

IV

1,000

Naloxone (Narcan)

Antagonist

IV, IM, SQ, nasal spray

--

aAssuming the pain relief value of morphine is 1, this is the comparative pain relief value of each agent.

IM = intramuscular, IV = intravascular, PO = oral, SQ = subcutaneous.

Source: [57,58]

Spinal Level

The spinal cord dorsal horn is a primary analgesic site of opioids and is densely populated with mu (70%), delta (20%), and kappa (10%) opioid receptors. Opioid receptors are localized on presynaptic afferent fibers, interneurons, and postsynaptic projection neurons [50]. Opioids bind to and activate mu receptors, which inhibit the release of pain mediators such as substance P, glutamate, and nitric oxide from nociceptive afferent neurons. Spinal level analgesia appears to elevate pain thresholds [46].

Supraspinal Level

At supraspinal levels, opioids produce analgesia by attenuation of the subjective evaluation of pain. After morphine is given for severe pain, patients report pain but without the associated anguish and distress. Conscious awareness and pain response are retained but modified by changes in emotional response to pain, mediated in part through opioid receptors in the limbic system [46].

Opioid receptors are highly concentrated in the medial thalamus, where incoming sensory information associated with intense and deep pain is filtered and then relayed to the cerebral cortex. This opioid effect on medial thalamus pain signal filtering greatly contributes to analgesia [46].

Opioid receptors are highly localized in subcortical brain regions where descending pain-modulating pathways originate. Normally, these pathways are inhibited by GABAergic neurons that project to descending inhibitory neurons of the brain stem. Opioid analgesics bind to and activate mu receptors on GABAergic neurons; this inhibits GABA to activate descending pain-modulating pathways [46,50]. In addition, opioids activate ascending serotonin/norepinephrine pathways that project to forebrain centers to regulate the emotional response to pain [44].

The greatest factor that contributes to opioid analgesia is concentration of the drug on the mu receptor, which can be altered by pharmacokinetic processes that influence plasma concentration of the opioid by impacting its absorption, distribution, metabolism, or excretion. Intrinsic properties of the opioid, such as lipid solubility, also contribute to opioid receptor concentration [59].

Neuropathic Pain

Opioid analgesics have historically been considered less effective in neuropathic pain, but more recent evidence provides some support for their use. The extent of neuropathic pain reduction correlates with the duration of opioid therapy, possibly accounting for the mixed results in short-term studies [60,61]. A 2011 study discovered previously unknown mu and kappa receptor expression on numerous peripheral tissues, immune cells, and joint capsules/synovium. The administration of opioids by injection into painful peripheral tissue sites results in pain relief in the absence of CNS activity, which supports the existence of localized peripheral opioid receptors [62].

Opioid effectiveness in neuropathic pain may be influenced by the capacity to inhibit voltage-gated sodium channels and individual channel type. Buprenorphine is more effective in blocking sodium channels than meperidine, lidocaine, and bupivacaine, possibly from greater lipophilicity, as this is a major factor in local anesthetic potency [61]. Sufentanil, fentanyl, and tramadol, but not morphine, are effective in blocking neuronal Nav 1.2 and may have greater clinical effect in some forms of neuropathic pain [63].

Inflammation enhances opioid anti-nociceptive action by peripheral mechanisms that activate during later (but not early-stage) inflammation, suggesting that timing of opioid administration contributes to analgesic efficacy in inflammatory pain [62]. Opioids are also effective in reducing the "air hunger" of dyspnea in patients suffering from cancer or respiratory or cardiovascular insufficiency [44].

Opioid Antagonists

A fourth group of opioids, opioid antagonists, bind and inactivate opioid receptors. Naltrexone and naloxone have traditionally been used to reverse potentially fatal overdose from opioid receptor agonists such as morphine or heroin. Opioid agonist molecules on mu opioid receptor are displaced, agonist effects on mu opioid receptor are abruptly halted, and opioid-dependent patients rapidly experience full alertness, analgesic loss, and opioid withdrawal [64].

Clinical trials with low-dose naltrexone have found unexpected and paradoxical enhancement rather than blockade of analgesia when co-administered with morphine and other opioid agonists in postoperative pain or severe intractable pain. Other evidence suggests analgesic efficacy as monotherapy in Crohn disease, irritable bowel syndrome, and fibromyalgia [65]. These findings led to the development and introduction of the peripheral-acting mu receptor antagonists alvimopan, methylnaltrexone, and naloxegol for severe opioid-induced constipation [66,67].

In addition to opioid-induced constipation, opioid antagonists are U.S. Food and Drug Administration (FDA)-approved for the treatment of alcohol and opioid use disorder (naltrexone 50–100 mg/day oral) and opioid overdose (naloxone 0.4–1.0 mg/dose IV or IM). In pain medicine, the dose ranges of naltrexone and naloxone are substantially lower. Of the two, naltrexone is much more widely used, and published pain medicine studies have used dose ranges of 1–5 mg (termed "low-dose") or <1 mg in microgram amounts (termed "ultra-low-dose") [65]. For example, case studies have reported dramatic improvement in refractory pain with intrathecal administration of an opioid agonist combined with ultra-low-dose naloxone in the low nanogram range [68].

The mechanism of low-dose and ultra-low-dose opioid antagonists is not fully known and is the subject of investigation [65]. One explanation describes a sequential action, whereby binding and inhibition first occurs at excitatory receptors, followed by binding at inhibitory receptors. This decrease in excitation facilitates a broader clinical expression of inhibitory function, which potentiates analgesia and reduces adverse effects. For example, with opioid-induced hyperalgesia, ultra-low-dose naltrexone appears to act through excitatory blockade to promote analgesia and tolerability [69,70].

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

NSAIDs alleviate pain by inhibiting the conversion of arachidonic acid to prostaglandins catalyzed by COX isozymes. Nonselective NSAIDs inhibit COX-1 and COX-2 and include ibuprofen, aspirin, and naproxen. The nonselective action inhibits the formation of both gastroprotective-mediating prostaglandins and pain-promoting prostaglandins, increasing the risk of serious toxicities such as GI ulceration and bleeding. This prompted the development of selective COX-2 inhibitors, which produce fewer GI side effects but are linked with an increased risk of cardio-renal morbidities [71]. To mitigate risk of GI adverse events, proton pump inhibitors are recommended for use in some patients using NSAIDs [72].

Acetaminophen is available over the counter and is also included in combination with many prescription opioids. Analgesia is achieved through central but not peripheral inhibition of prostaglandin. Although effective in mild pain, acetaminophen is not anti-inflammatory. The side-effect profile is relatively benign with intermittent use at recommended labeled dosing, but long-term or high-dose use can be hepatotoxic, and the daily dose should never exceed 4 g. Acetaminophen is recommended over NSAIDs as an analgesic in patients with GI, renal, or cardiovascular comorbidity [73].

While beneficial in the management of pain, some patients with reactive airway disease may develop bronchospasm, although this adverse effect is rare [5]. In addition, prostaglandins are vasodilators. A constitutive level of circulating prostaglandin is necessary to maintain adequate vasodilation in the afferent limb of the glomerulus to assure renal blood flow in the kidney. Overuse of NSAIDs may result in decreased glomerular blood flow, resulting in decreased elimination of toxins from the body and, in especially severe states, renal failure [5]. The most commonly used NSAIDs are listed in Table 4 [74,75].

Table 4: COMMONLY USED NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) AND ACETAMINOPHEN

Drug

Route(s)

Meloxicam (Anjeso)

IV, PO

Ketorolac (Toradol)

PO, IM, IV, eye drops, nasal spray

Ibuprofen (Motrin, Advil)

PO, IV

Diclofenac (Cataflam, Voltaren)

PO, IM, IV, eye drops, topical gel

Acetaminophen (Tylenol)

PO, IV, rectal

Naproxen (Aleve, Anaprox)

PO

Celecoxib (Celebrex, Elyxyb)

PO

Aspirin

PO

Source: [74,75]

LOCAL ANESTHETICS

Local anesthetics prevent the generation and propagation of nerve impulses in response to painful stimuli. The basic chemical structure of a local anesthetic consists of an aromatic ring (which enhances lipid solubility) and an intermediate ester or an amide chain and a terminal amine [8]. As such, all of these agents are classified as either an ester type or an amide type. The type of anesthetic used and the inclusion of a vasoconstrictor (e.g., epinephrine) will influence the duration of action. Certain factors, such as the presence of active infection in the area to be anesthetized, heightened patient anxiety, or inaccurate deposition of the agent, may affect the ability of a local anesthetic to achieve the appropriate level of anesthesia.

The local anesthetics lidocaine and bupivacaine block Na+ influx of voltage-gated ion channels in afferent neuron terminals, inhibiting depolarization and generation of action potentials, resulting in the transmission of fewer nociceptive impulses to the spinal cord. In clinical application, topical lidocaine is used for neuropathic pain to block hyperactive sodium ions in damaged peripheral nerves and inhibit transmission of ectopic impulses to the dorsal horn. This action interferes with peripheral and central sensitization and maladaptive neuroplasticity [71,76].

Capsaicin defunctionalizes nerve fiber terminals through multiple mechanisms to produce analgesia. The initial reduction in neuronal excitability and responsiveness result from inactivation of voltage-gated sodium channels and direct desensitization of plasma membrane TRPV1 receptors. This is followed by extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm the TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [77,78]. The persistent effect involves extracellular Ca2+ entry of TRPV1 and release from intracellular stores to overwhelm TRPV1 receptor intracellular Ca2+ buffering capacity, subsequent activation of calcium-dependent proteases, and cytoskeleton breakdown [77,78]. Capsaicin is available as a high-potency (8%) patch and as a lower-concentration cream. A single 60-minute application may provide up to 12 weeks of analgesia [76]. Capsaicin may initially cause pain because substance P is released from nociceptive terminals to initiate nociceptive firing. The analgesic response follows as nociceptive terminals desensitize to elevate pain threshold [79].

The use of local anesthesia has become more popular and may be more precisely administered being guided by ultrasonography. Ultrasound technology allows for optimized needle placement, resulting in fewer failed blocks and lower doses. These blocks can be performed before having a procedure performed. When administered before surgery, local anesthetic blocks allow for lower doses of anesthetic agent, along with prolonged postoperative pain relief. In one study, when a local anesthetic block was provided in addition typical analgesic therapy following total knee replacement, morphine doses, pain scores, and nausea were all significantly decreased compared with those who received usual treatment [80].

However, local anesthetics are not without drawbacks, and overdose resulting in local anesthetic systemic toxicity (LAST) is a concern [81]. Because local anesthetics are designed to cross phospholipid membranes, they easily enter the brain and heart, where the blockade of ion channels can have adverse effects. Normally, the first symptoms in patients who are conscious are a metallic taste and/or ringing in their ears (tinnitus). If left untreated, this can progress to excitatory symptoms, followed by drowsiness, coma, and even death [81,82]. Table 5 provides key information about commonly used local anesthetics, including maximum doses.

Table 5: MAXIMUM DOSES OF LOCAL ANESTHETICa

Local Anesthetic

Ester or Amide

Maximum Dose Per Kilogram Plain

Maximum Dose Plainb

Maximum Dose Per Kilogram with Epinephrine

Maximum Dose with Epinephrineb

Bupivacaine (Marcaine)

Amide

2 mg/kg

175 mg

3 mg/kg

225 mg

Levobupivacaine (Chirocaine)

Amide

2 mg/kg

200 mg

3 mg/kg

225 mg

Lidocaine (Xylocaine)

Amide

5 mg/kg

350 mg

7 mg/kg

500 mg

Mepivacaine (Carbocaine)

Amide

5 mg/kg

350 mg

7 mg/kg

500 mg

Ropivacaine (Naropin)

Amide

3 mg/kg

200 mg

3 mg/kg

500 mg

Prilocaine (Citanest)

Amide

6 mg/kg

400 mg

8 mg/kg

250 mg

Procaine (Novocaine)

Ester

7 mg/kg

1,000 mg

10 mg/kg

600 mg

Tetracaine (Amethocaine)

Ester

0.2 mg/kg

20 mg

N/A

1,000 mg

aDoses vary by country and institution, familiarize yourself with your local policies regarding maximum doses before administering

bIf administering a local anesthetic to a large patient, stop at the maximum dose, even if the mg/kg dose would exceed it.

Source: [82,83,84]

The closer to the vasculature the site of injection is, the more likely that the local anesthetic will undergo rapid vascular uptake and result in adverse effects. Mixing the agent with epinephrine, a vasoconstrictor, decreases uptake, thus prolonging the anesthetic effect and decreasing the likelihood of complications. As this is the case, it is possible to give more local anesthetic when it is mixed with epinephrine [82,83,84].

In the event of an accidental overdose, there is a specific protocol for treatment [81,82]. As soon as LAST is detected, the patient should be administered an IV bolus injection of 20% lipid emulsion 1.5 mL/kg-1 over one minute. An infusion of 20% lipid emulsion should be started at a dose of 15 mL/kg-1/hour. If after five minutes cardiovascular stability is not restored or the patient further deteriorates, a maximum of two repeat boluses may be administered, with five minutes between injections. At the same time, the infusion rate may be doubled. The infusion should continue until the patient has stabilized or the maximum dose of emulsion (12 mL/kg-1) has been given. The use of lipids to rescue these patients is a relatively new development, so review is important for those in clinical areas with high use of local anesthetics [85].

CALCIUM CHANNEL BLOCKERS

The gabapentinoids, gabapentin and pregabalin, are widely used in the management of both postoperative and chronic pain relief. Their names may give the impression they interact with gamma-amino butyric acid (GABA), but this is not the case [86,87]. Gabapentin and pregabalin are anticonvulsants that are also effective in a wide range of neuropathic pain conditions. Their mechanism of action involves selective binding to and blockade of the α2δ1 subunit of voltage-gated calcium channel in various brain regions and the superficial dorsal spine. This inhibits the release of glutamate, norepinephrine, and substance P to decrease spinal cord levels of neurotransmitters and neuropeptides [76,88,89]. The binding affinity of pregabalin for the calcium channel α2δ1 subunit is six times greater than gabapentin, which is reflected in the greater efficacy of pregabalin at lower doses. Because gabapentin possesses a shorter half-life and nonlinear absorption, pregabalin is easier to titrate and better tolerated [89].

While having a long history in the treatment of chronic pain, the use of these agents to prevent postsurgical pain is relatively new. In one study of 90 women scheduled for abdominal hysterectomy, a control group was compared to groups receiving either 300 mg pregabalin or 900 mg gabapentin administered one to two hours prior to surgery [86]. The average time until first request for analgesia was 31 minutes in the pregabalin group, 16 minutes in the gabapentin group, and 7 minutes in the control group. There was no difference in demographic variables, including length of surgery, across the three groups. In this case, preoperative administration of a gabapentinoid was shown effective in lengthening the duration of analgesia [86].

The locus coeruleus is activated during normal responses to painful stimuli. However, in patients with chronic pain, stimuli inhibit rather than activating the locus coeruleus, dampening analgesic response [90]. When gabapentin is administered to these patients, glutamate is released in the brain, which in turn stimulates the locus coeruleus, restoring its analgesic function [91].

ALPHA-ADRENERGIC AGONISTS

While more commonly associated with the autonomic nervous system and its functions, alpha-adrenergic agonists can also function in the relief of pain, as well as decreasing the sympathetic side effects which accompany pain, including hypertension and tachycardia. Antinociceptive activity of the α-2 adrenoceptor agonists clonidine and tizanidine includes modulating dorsal horn neuron function and norepinephrine and 5-HT release, potentiating mu-opioid receptors, and decreasing neuron excitability through calcium channel modulation [92]. Clonidine is available as a transdermal patch for use in neuropathic pain states. Local use enhances release of endogenous enkephalin-like substances. Intrathecal or epidural administration with opioids and/or local anesthetics is favored in treating neuropathic pain because the synergistic effect improves pain control. Tizanidine is used as a muscle relaxant and antispasticity agent; its use in the management of musculoskeletal pain is off label [76,79].

Dexmedetomidine was originally approved as a short-term sedative analgesic for mechanically ventilated patients in the intensive care unit [93]. Dexmedetomidine is far more selective as an alpha-adrenergic agonist and has the same central action around the locus coeruleus [93]. As time passed since its introduction, the use of dexmedetomidine has increased, especially among patients with comorbidities (e.g., heart and vascular disease, morbid obesity). Its cardiovascular stability, along with its minimal effect on respiratory drive after the infusion is terminated, have made this agent popular in both the intensive care unit and the operating room. Aside from its use as a sedative or aesthetic agent, use of dexmedetomidine has been explored in patients with refractory end-of-life pain. In a case study, a male patient, 58 years of age, with chronic pancreatitis secondary to alcoholism reported inadequate pain relief despite receiving a combination of oxycodone, nortriptyline, and lorazepam. Increased inpatient intravenous opioids and ketamine still brought the patient no relief, and dexmedetomidine was attempted as a last resort. An infusion of dexmedetomidine brought the patient's pain under greater control, to the extent that he was able to sit in a recliner and visit with family [94]. Based on this and other reports, dexmedetomidine is being explored as a possible option in palliative care.

Alpha-adrenergic agonists are also found in the area of the brain where projections from the locus coeruleus inhibit an inhibitory portion of the brain responsible for arousal. When alpha-adrenergic agonists act in this area of the brain, they block the ability of the nerves projecting from the locus coeruleus to inhibit the second-order neuron. Thus, these agents, in sufficient doses, render the patient somewhat drowsy [95]. This is important to remember, as the drowsiness associated with the original alpha-adrenergic agonists made their use problematic.

ANESTHETIC DRUGS

Anesthetics are powerful agents typically used in the operating room to reduce the capacity for consciousness and diminish the pain associated with surgery. Two examples are ketamine and nitrous oxide. These agents are quite different; the first is an injectable dissociative anesthetic with variable effects depending on the dose, and the second is an inhaled vapor with profound analgesic effects [18,96,97].

Ketamine

Ketamine is a phencyclidine anesthetic given parenterally, neuraxially, nasally, transdermally or orally in subanesthetic doses to alleviate a variety of pain conditions, including severe acute pain, chronic or neuropathic pain, and opioid tolerance [79]. The mechanism of analgesic effect primarily involves NMDA receptor inhibition. Thus, patients with NMDA-mediated central sensitization are likely to realize significant benefit from treatment with ketamine. Ketamine also has activity on nicotinic, muscarinic, and opioid receptors and exerts both anti-nociceptive and anti-hyperalgesic effects, with the latter produced at lower dose ranges [98].

Evidence Based Practice Recommendation

The American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists recommend that subanesthetic ketamine infusions be considered for patients undergoing painful surgery and patients undergoing surgery who are opioid-dependent or opioid-tolerant.

https://rapm.bmj.com/content/rapm/43/5/456.full.pdf

Last Accessed: October 20, 2022

Strength of Recommendation: B (There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial.)

Ketamine is one of very few therapies demonstrating substantial and durable pain reduction of treatment-refractory chronic regional pain syndrome [99]. Potentially distressing adverse reactions (e.g., hallucinations, disturbing dreams, out-of-body experiences) and unwanted changes in mood, perception, and intellectual performance have limited its clinical use in pain control. However, trials have effectively controlled these side effects with high-dose co-administration of midazolam or lorazepam combined with either clonidine or ondansetron [100,101].

Ketamine, however, also has its down sides. One of the most concerning is the formation of psychotomimetic behaviors, and the presence of hallucinatory phenomena after its administration. Fortunately, these are dose dependent in nature and rarely occur at the doses required to treat pain [102,103]. It has also become a drug of abuse and misuse. Most notoriously, ketamine became known as a "date-rape drug," because it was administered in drinks to unknowing victims who were subsequently sexually assaulted by their predators. Because ketamine causes amnesia, victims have little or no memory of what occurred to them, although they often experienced after-effects, such as pain. As a result of this growing criminal use, Congress passed the Drug-Induced Rape Prevention and Punishment Act of 1996. During this period and the decade following, there was increased awareness of the dangers of ketamine and other drugs that were used in a similar manner, such as flunitrazepam (Rohypnol) and gamma hydroxybutyric acid (GHB) [104]. As a result, ketamine developed a stigma, and this negative view may persist in many minds.

Today, ketamine is increasingly being used to treat patients with treatment-refractory major depressive disorder, which frequently co-occurs in those with chronic pain. The agent appears to actually increase the size and volume of the hippocampus, thus treating the cause of depression [18,105]. In patients who are imminently suicidal, short-duration doses have been found to significantly reduce suicidal ideation [106].

Nitrous Oxide

Nitrous oxide (chemical formula N_2O) is a component familiar to many, as it is commonly used today to facilitate comfort and address anxiety in dental settings. Historically, it has been used in both dental and medical interventions. Nitrous oxide is a compressed gas and is one of the oldest anesthetic agents in use, with its origins dating back to 1772 [96]. Unlike the inhaled hydrocarbons commonly used as part of a general anesthetic, nitrous oxide has potent analgesic properties. It is thought that nitrous oxide works to enhance the endogenous descending pathways to the alpha-2 and GABA-A neurons in the spinal cord, decreasing the ability of the second-order neurons to depolarize and carry painful stimuli to the brain. When administering nitrous oxide, it is crucial to ensure that oxygen is added to prevent the administration of 100% nitrous oxide to the patient, which would rapidly result in hypoxia and death. All certified nitrous oxide delivery devices have lockout systems to preclude this from happening.

Nitrous oxide is given as a percentage of total inhaled gas flow. The route of administration is inhalation via a mask secured to the patient's nose. For analgesic purposes, the concentration is typically 50% to 70% nitrous oxide with oxygen. Onset of action can occur in as quickly as 30 seconds, with the peak effects seen in five minutes or less. Nitrous oxide diffuses into the alveolus very quickly, accounting for its rapid uptake and circulation to the brain. Nitrous oxide is not metabolized in the body. It is eliminated via respiration within minutes after 100% oxygen is inhaled at the conclusion of the intervention [107].

Repeated doses can be problematic, as extended use of nitrous oxide has been linked to vitamin B12 deficiency [108]. As such, serum vitamin B12 level may need to be measured before and after treatment. Of more concern is the continuous exposure of hospital or clinic staff to chronic low doses of nitrous oxide [96]. Limits of nitrous oxide in the ambient environment are strict and tightly regulated by the by the National Institute for Occupational Safety and Health (NIOSH) [109]. The maximum recommended level of exposure is 25 parts per million per procedure over an eight-hour period [109]. Sufficient fresh air flow in the procedural area is required, along with a secure fitting of the delivery mask. Nitrous is highly diffusible and will enter into closed spaces very easily.

For a short period, prehospital paramedics were using 50% nitrous oxide as an analgesic during stabilization and transport of patients to the hospital; however, this use did not gain traction, and nitrous oxide is not a universal requirement for emergency medical vehicles [110].

As with other analgesics, nitrous oxide tanks should be secured, as there is a potential for abuse and diversion, particularly in locations in which small tanks are used and can easily be removed and transported. Nitrous oxide also enhances combustion, so care should be taken when using it around lasers and electric cautery. This agent is associated with increased rates of postoperative nausea and vomiting, but the risk decreases with the duration of administration.

ANTIDEPRESSANTS

Antidepressants, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs), are now a mainstay of pain management. Each of these agents increases the circulating level of neurotransmitters (e.g., norepinephrine, serotonin, dopamine, acetylcholine) in the brain [111]. Note that while these agents have been used for pain management in some cases for decades, this use is often still considered to be off label [111].

Antidepressants act in the brain at the periaqueductal grey, the amygdala, the prefrontal cortex, the thalamus, and the somatosensory cortex, among other places [112]. However, they also work in the periphery, primarily by blocking voltage-gated Ca2+ channels, especially in the dorsal horn of the spinal cord. As discussed, when Ca2+ cannot enter a neuron, then exocytosis of neurotransmitters onto the receptors of the next order neuron cannot take place. This, in turn, blocks the transmission of the action potential and thus the painful stimulus [112]. Antidepressants also increase the effectiveness of endogenous GABA, an inhibitory neurotransmitter. The various antidepressant classes have different effects on pain pathways.

Tricyclic Antidepressants

TCAs are widely used in neuropathic pain. A TCA's mechanism involves blocking pre-synaptic reuptake of norepinephrine and serotonin; inhibition of neuronal membrane ion channels by reducing neuronal influx of calcium or sodium ions; and activity with adenosine and NMDA receptors [79]. A primary site of analgesic action is the descending modulatory pathway, where monoamine reuptake inhibition elevates norepinephrine and serotonin levels to enhance endogenous nociceptive inhibition. The secondary amines nortriptyline and desipramine are favored over the tertiary amines amitriptyline and imipramine due to more benign side effect profiles [113,114]. Amitriptyline is often the treatment of choice for neuropathic pain [79]. Unfortunately, TCAs have numerous side effects, including xerostomia (dry mouth), tachycardia, urinary retention, and drowsiness [111].

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs were designed to treat depression by increasing the amount of circulating serotonin in the brain. This increased amount of serotonin results in down-regulation (decreased number and density) of the 5-HT receptors, which allows for an increased firing of serotonergic neurons in the brain [111]. Compared with the other antidepressants, SSRIs have limited utility in treating pain and are seldom prescribed for this purpose.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

The dual serotonergic and noradrenergic re-uptake inhibitors (SNRIs) duloxetine, venlafaxine, and milnacipran are widely used in the treatment of neuropathic pain conditions. Duloxetine is used in painful diabetic neuropathy, with demonstrated efficacy at 60–120 mg/day. Venlafaxine behaves like a SSRI at doses of ≤150 mg/day and like an SNRI at doses >150 mg/day; a dose ≥150 mg/day is often necessary to achieve pain control [76]. Of the three available SNRIs, milnacipran has the greatest affinity for norepinephrine, duloxetine has the greatest potency in blocking serotonin, and venlafaxine selectively binds to the serotonin but not the norepinephrine transporter [115].

SNRIs are better tolerated than TCAs because they lack affinity for cholinergic, histaminic, and adrenergic receptors [89]. The anti-nociceptive effect of the SNRIs duloxetine and milnacipran primarily involves increasing serotonin and norepinephrine concentrations in descending inhibitory pain pathways, which enhances the suppression of afferent spinal inputs and reduce pain [113].

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs work by irreversibly degrading the monoamine oxidase enzymes responsible for degrading norepinephrine. These agents, however, have numerous side effects, including hypotension, dizziness, headache, xerostomia, palpitations, and weight gain [116]. One potential issue is the interaction of MAOIs with tyramine and tryptophan. With oral ingestion, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine (e.g., red wine, aged cheeses and meats, soy sauce, tap beer, smoked or pickled fish, sauerkraut) are consumed, the individual may suffer from hypertensive crisis. If foods containing tryptophan (e.g., milk, poultry, tofu, nuts, seeds) are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual and depends on the degree of inhibition, which in turn depends on dosage and selectivity. These side effects limit the utility of MAOIs in pain management [116,117].

5. USING MULTIMODAL PAIN THERAPY: EXAMPLES FROM THE PROFESSIONAL LITERATURE

Evidence Based Practice Recommendation

The Orthopaedic Trauma Association Musculoskeletal Pain Task Force recommends the use of multimodal analgesia (MMA) as opposed to opioid monotherapy for pain control. MMA may include NSAIDs, acetaminophen, gabapentinoids, and immediate-release opioids.

https://journals.lww.com/jorthotrauma/fulltext/2019/05000/clinical_practice_guidelines_for_pain_management.11.aspx

Last Accessed: October 20, 2022

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

With a clear understanding of the pharmacologic tools available to help manage pain, clinicians can begin the process of creating and supporting a pain management plan for each patient's unique needs. The World Health Organization (WHO) analgesic ladder, introduced in 1986 and disseminated worldwide, remains recognized as a useful educational tool but not as a strict protocol for the treatment of pain. It is intended to be used only as a general guide to pain management [118]. The three-step analgesic ladder originally intended for management of cancer-related pain designates the type of analgesic agent based on the severity of pain (Figure 7) [118]. Step 1 of the WHO ladder involves the use of nonopioid analgesics, with or without an adjuvant (co-analgesic) agent, for mild pain (pain that is rated 1 to 3 on a 10-point scale). Step 2 treatment, recommended for moderate pain (score of 4 to 6), calls for a weak opioid, which may be used in combination with a step 1 nonopioid analgesic for unrelieved pain. Step 3 treatment is reserved for severe pain (score of 7 to 10) or pain that persists after Step 2 treatment. Strong opioids are the optimum choice of drug at Step 3. At any step, nonopioids and/or adjuvant drugs may be helpful.

Figure 7: THE WORLD HEALTH ORGANIZATION'S THREE-STEP LADDER OF ANALGESIA

Source: [118]

The pharmacologic treatment of pain involves selecting the right drug(s) at the right dose, frequency, and route, and managing side effects As with any healthcare action, it is vital to assess patients and to attempt to identify underlying cause(s) prior to the initiation of treatment. Specific evaluative steps should be taken to determine the nature of a patient's pain and to assess the possibility and impact of adverse effects. The WHO ladder is also accompanied by guiding principles [118,119]:

- Believe the patient's report of pain. This sounds simple, but it can be difficult for clinicians to avoid becoming jaded over time, especially if they care for patients in drug-seeking environments.

- Initiate discussions of pain by asking specific questions and observing behaviors, such as groaning, a furrowed brow, and elevations in pulse or blood pressure.

- Get the facts about the pain. A helpful mnemonic taught to prehospital providers is OPQRST:

- Onset

- Provocation or palliation

- Quality

- Region (of the body) and radiation

- Severity

- Timing

- Evaluate the patient's psychological state.

- Perform a detailed physical assessment.

- Obtain further testing if one is not sure, including radiologic and laboratory tests.

With these data, the provider is now ready to plan and carry out multimodal analgesia. The following examples are presented as examples of the applicability and efficacy of multimodal approaches in research studies.

EXAMPLE 1

In one study, 150 patients were assessed for breakthrough pain following shoulder surgery [120]. The first group (75 patients) was given a standard course of opioid and acetaminophen combination (hydrocodone 10 mg/acetaminophen 325 mg) or 5–10 mg of oxycodone every 4 hours [120]. They also received a single-shot interscalene regional nerve block with 0.5% ropivacaine (local anesthetic). Finally, intravenous hydromorphone was also available as a rescue intervention. In the second multimodal group (75 patients), patients received preoperative 300 mg celecoxib, 600 mg gabapentin, and 1,000 mg acetaminophen. They also received the same regional nerve block. For postoperative pain, group 2 received naproxen 500 mg every 12 hours with food, gabapentin 300 mg every 8 hours, acetaminophen 1,000 mg orally or IV, followed by 500 mg orally every 6 hours. For breakthrough pain, this group could receive 5–10 mg of hydrocodone, as needed [120]. There were no differences in the demographic makeup of the two groups.

On postoperative day zero (the day of surgery), pain scores were significantly lower in group 2 when compared with the standard group [120]. On postoperative days 1 and 2, the multimodal group continued to have lower scores, but the differences were not statistically significant. Opioid consumption, measured in mg of morphine equivalent, were significantly decreased in the multimodal group on all three measurement days. The length of in-patient stay for the multimodal group was significantly lower (1.4 days +/- 0.7) compared with the opioid group (1.9 days +/- 1.1 days), resulting in an average cost savings of $1,000 for the multimodal group [120].

EXAMPLE 2

In this study, patients with unresectable hepatocellular carcinoma received transarterial chemoembolization, a primary palliative treatment [121]. This group of patients have chronic pain, and transarterial puncture is associated with a lower degree of surgical pain. In this example, patients are provided with a therapeutic procedure that can partially mitigate the pain and then supported with other analgesic agents. The study involved a total of 84 patients, with half assigned to the multimodal group and the other half assigned as a control group [121].

The multimodal group received 40 mg intravenous parecoxib sodium 30 minutes before the beginning of the procedure. In the control group, patients received 5 mg dezocine (an opioid) preintervention. All patients underwent a percutaneous puncture of the femoral artery after having the site numbed with 10 mL 2% lidocaine (total dose: 200 mg lidocaine). After the procedure, the multimodal group was provided with a patient-controlled analgesia pump; the intravenous pain solution was a combination of sufentanil 100 mcg and dexmedetomidine 200 mcg diluted in 100 mL normal saline. The pump was programmed to provide 2 mL of the solution (2 mcg of sufentanil and 4 mcg of dexmedetomidine) as a first dose, a background infusion rate of 2 mL/hour, and 2 mL bolus doses on demand with a lockout period of 5 minutes (maximum: about 12 doses per hour) [121]. This sufentanil dose is below the usual administered for general anesthesia. The dose of dexmedetomidine tracks closely to that needed for intensive care unit (ICU) sedation [122]. Using the two agents together provides central sedation via two routes (one from the opioid, the other from the alpha-2 agonist) while simultaneous providing pain relief throughout the spinal cord.

The control group received 100 mg flurbiprofen (an NSAID) every 12 hours for the first 48 hours postprocedure and 100 mg tramadol (a combination opioid agonist and SSRI) for breakthrough pain [121]. Mean visual analog scale (VAS) pain scores were measured at 0, 2, 4, 6, 12, 24, and 48 hours after the procedure. Patients in the multimodal group had statistically lower VAS pain scores at 0, 2, 4, 6, and 12 hours after the procedure. From a qualitative viewpoint, more than 95% of the multimodal patients reported good satisfaction with their pain control. In the control group, 69% reported good satisfaction, and 11.9% reported a "fairly bad experience" of pain control [121].

6. CASE STUDIES

The following case examples detail how specific patients were cared for and the logic behind analgesic decision-making. This should serve as a starting point that will result in further self-exploration.

CASE STUDY 1

Note that this first example is directed toward the management of acute pain, and the interventions take place in the hospital or surgical facility. Many people, however, suffer chronic pain and self-medicate to treat it. In either case, multimodal analgesic techniques may still be used.

Patient A is scheduled to receive a total knee replacement arthroplasty [123]. Preoperatively, the patient is counseled regarding what pain might be expected with this surgery and how it might be treated. After the patient has been worked up, she receives acetaminophen 1,000 mg and celecoxib 400 mg by mouth [123]. This is referred to as pre-emptive analgesia and is done to ensure that the processes needed to, in this case, block the inflammatory effects of prostaglandins released by surgery are beginning to function prior to initiation of surgery [124].

The patient is next taken to a block room and receives local anesthesia in the knee area. In other cases, surgeons may inject local anesthesia at the end of the case.

During surgery, the patient receives a spinal anesthetic with local anesthesia. The anesthetic is placed in the subarachnoid space with local anesthesia. Because the local anesthetic is deposited so close to the nerves, a very small dose can provide several hours of anesthesia.

After surgery, the patient begins to receive several pain management interventions almost immediately, the first of which is cryotherapy. Next, as the body is responding with an inflammatory process releasing prostaglandins and other neurotransmitters in response to an injury (albeit a therapeutic one), the patient receives 1,000 mg of acetaminophen every six hours around the clock [123]. This patient tolerated oral analgesics, but acetaminophen can be administered intravenously for those experiencing problems with postoperative nausea and vomiting. The patient is also started on celecoxib 200 mg twice per day for up to five days. At this point, Patient A begins to question the need for NSAIDs when she is "having no pain." The nurse describes the importance of reducing inflammation in simple terms. He also explains that the long-acting local anesthetics will wear off over time, and it is important to pre-emptively control pain. Despite these interventions, some patients will experience postoperative pain exceeding the ability of NSAIDs to mitigate. For these individuals, an opioid rescue (oxycodone tablet 5 mg and intravenous hydromorphone 0.2 mg) every four hours as needed will help bring most pain under control [123].

CASE STUDY 2

Patient B is an elderly man (85 years of age) with chronic and unremitting pain. Initial assessment of the patient's pain remains important. While Patient B is experiencing chronic pain, he may also have an unresolved injury or illness causing the pain. In such a case, treatment of the underlying pathology could result in mitigation of pain [125].

Therapeutic intervention for Patient B begins with the use of NSAIDs and COX-2 inhibitors, especially for a pathology such as osteoarthritis, which is quite common among the elderly. As part of the assessment in this example, remember that elderly patients tend to have less total body water, decreased muscle tone, increased fat stores, and normal age-related degeneration of the liver and kidneys [125]. Unless there are other factors (e.g., current opioid use disorder), the best approach is to start low and titrate slow—use the smallest dose possible and increase it incrementally in small doses. The elderly often experience depression as part of their chronic pain; this should not be surprising, as living with unresolved pain each day can be psychologically taxing. Antidepressant agents, such as an SNRI, may be added to the care plan, with the caveat that there is an increased risk of falling [126]. Gabapentinoids may replace the antidepressant if the pain is neuropathic in nature, and opioids can be added on an as needed basis, though it is crucial to start at the low end of the dosing scale [126]. This follows the WHO guidance of NSAIDs first and opioids last.

While it is fine to conduct mental exercises with imaginary patients, the guiding standard for the clinician is whether the analgesia works. This is an important question, so at this point a small number of studies will be presented for your review.

CASE STUDY 3

In this example, Patient C, a man 71 years of age, presents with a severe case of recurring right sciatic pain [127]. On history and examination, the patient describes persistent pain at a scale of 8 out of 10, starting in the lumbar area of his back and running down his right thigh. Further comorbidities include chronic obstructive pulmonary disease (COPD) and previous right-side neck surgery to remove a buccal tumor. An MRI is ordered, revealing spondylolisthesis, which causes pain in lower back or legs at L5–S1, and the patient was also identified as having degenerative disk disease at L5–S1, and disk herniations at L3–L4, L4–L5, and L5–S1 [127]. This patient is taking 20 mg oxycodone daily in an effort to mitigate his pain.

The pain control team begins to titrate back the patient's oxycodone with tramadol and offers surgical decompression. After the patient refuses surgical intervention, the team decides to administer an ultrasound-guided caudal epidural steroid injection of triamcinolone 40 mg and 2% lidocaine 20 mg (local anesthetic) mixed in 12 mL of normal saline [127]. The mixture of normal saline is necessary because epidural injections require a greater volume to ensure the nerve roots are all bathed in the solution.

After the injection, Patient C's walking distance increases from 20 meters to 200 meters, and his pain score reduces from 10 to 7. One month later, the patient remains improved, but the team decides to add 5 mg oxycodone (25% of the original dose) as needed back to the patient's regimen. By his third month post procedure, the patient's pain score has dropped to 2. The multimodal plan, when compared with the singular large dose opioid plan, proved to be life-changing for this patient [127].

7. CONCLUSION

It is important to remember that pain is an adaptive mechanism to protect the body from comprise and prevent future involvement with the pain-generating stimulus. Modern medicine has many options to identify causes of pain and to treat the underlying problem while providing relief from pain [27]. However, pain management is an elusive goal for many patients. In the 1990s and 2000s, in an effort to address this problem, opioids were prescribed more freely. Unfortunately, this corresponded with an increase in opioid misuse and use disorder. In order to both assure that patient pain is managed and reduce the risks associated with opioids, numerous types of analgesics and techniques can be carefully mixed to decrease side effects while optimizing pain control.

It is crucial for all practitioners to carefully evaluate patients who are in pain to determine the extent to which the pain can be repaired or relieved. All available tools should be explored to treat the causes of pain at the local peripheral levels, the spinal cord levels, and the brain processing level. Familiarity with the pathophysiology of pain can guide good pharmacologic decisions and restore the patient's quality of life.

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95. Brown E, Lydic R, Schiff N. General anesthesia, sleep and coma. N Engl J Med. 2010;363:2638-2650.

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98. Blonk MI, Koder BG, van den Bemt P, Huygen FJ. Use of oral ketamine in chronic pain management: a review. Eur J Pain. 2009;14(5):466-472.

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100. Patil S, Anitescu M. Efficacy of outpatient ketamine infusions in refractory chronic pain syndromes: a 5-year retrospective analysis. Pain Med. 2012;13(2):263-269.

101. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo-controlled study. Pain. 2009;147(1-3):107-115.

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105. Abdallah CG, Sanacora G, Duman RS, Krystal JH. The neurobiology of depression, ketamine and rapid-acting antidepressants: is it glutamate inhibition or activation? Pharmacol Ther. 2018;190:148-158.

106. Xiong J, Lipsitz O, Chen-Li D et al. The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: a systematic review and meta-analysis. J Psychiatr Res. 2021;134:57-68.

107. Silverman M, Hexem J. Nitrous oxide/oxygen sedation and the single-dose sedative. Inside Dentistry. 2011;42-54.

108. Whizar-Lugo VM, Heredia-Mota C, Camacho A. Back to the future: ketamine and nitrous oxide in major refractory depression.J Anesth Crit Care. 2017;9(3):1-5.

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Evidence-Based Practice Recommendations Citations

1. McCusker M, Jolkvosky M, Ruff R, et al. Palliative Care for Adults. 6th ed. Bloomington, MN: Institute for Clinical Systems Improvement; 2020. Available at https://www.icsi.org/wp-content/uploads/2020/01/PalliativeCare_6th-Ed_2020_v2.pdf. Last accessed October 20, 2022.

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38950 • Pathophysiology: Muscles, Joints, and Connective Tissues

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

www.netce.com

Copyright © 2022 NetCE, All rights reserved.

With knowledge of the structures and function of the muscles, joints, and connective tissue and the dynamic pathology that intrudes and impedes normal function, nurses can readily provide quality and often life-saving actions. An awareness of why symptoms appear leads to quicker reporting to physicians of changes in the patient's condition. Nurses can also perform immediate interventions based on standing orders and recognition of what needs to be done in order to provide safe quality care. This knowledge changes what could be only technical care to professional care through the use of decision-making skills built upon the knowledge of pathophysiology.

Table of Contents

38950 • Pathophysiology: Muscles, Joints, and Connective Tissues

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. MUSCLES, JOINTS, AND CONNECTIVE TISSUES: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

STRUCTURE AND FUNCTION OF SKELETAL MUSCLES

OTHER CONNECTIVE TISSUE STRUCTURES

3. THE PROCESS OF SKELETAL MUSCLE CONTRACTION

4. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

INFLAMMATION

DEGENERATIVE CHANGES

INFECTION

NEOPLASIA

TRAUMA

5. RELATED INFLUENCES AND EFFECTS

NEUROLOGIC AND VASCULAR PROBLEMS

OCCUPATION AND LIFESTYLE

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

SUBJECTIVE DATA

OBJECTIVE DATA

DIAGNOSTIC STUDIES

7. SPECIFIC DISORDERS OF CONNECTIVE TISSUE AND MUSCLES

GENETIC DISORDERS

INFLAMMATORY DISORDERS

IMMUNOLOGIC DISORDERS

TRAUMATIC DISORDERS

8. SPECIFIC DISORDERS OF THE JOINTS

DISORDERS OF MULTIFACTORIAL ORIGIN

DEGENERATIVE DISORDERS

IMMUNOLOGIC DISORDERS

INFECTIOUS DISORDERS

NEOPLASTIC DISORDERS

TRAUMATIC DISORDERS OF THE JOINT

9. CASE STUDIES

SYSTEMIC LUPUS ERYTHEMATOSUS

LOW BACK PAIN

RHEUMATOID ARTHRITIS

10. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

38950 • Pathophysiology: Muscles, Joints, and Connective Tissues

Education Category. Infection Control / Internal Medicine

Release Date. 10/01/2022

Expiration Date. 09/30/2025

Course Overview

With knowledge of the structures and function of the muscles, joints, and connective tissue and the dynamic pathology that intrudes and impedes normal function, nurses can readily provide quality and often life-saving actions. An awareness of why symptoms appear leads to quicker reporting to physicians of changes in the patient's condition. Nurses can also perform immediate interventions based on standing orders and recognition of what needs to be done in order to provide safe quality care. This knowledge changes what could be only technical care to professional care through the use of decision-making skills built upon the knowledge of pathophysiology.

Audience

This course is designed for nurses in all practice settings.

Course Objective

As health care becomes more complex, it is essential that the theoretical concepts of the basis of illness (pathophysiology) be well understood. The purpose of this course is to reinforce the scientific rationales for the interventions nurses perform and the decisions nurses make as patients move through the ever-changing struggle with their illness.

Learning Objectives

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

1. Describe the structure and function of the muscles, joints, and connective tissues.

2. Discuss the pathophysiologic influences that may affect the muscles, joints, and connective tissues.

3. Outline the role of subjective data in completing a full nursing assessment of the muscles, joints, and connective tissues.

4. Describe objective data compiled during a nursing assessment of the muscles, joints, and connective tissues.

5. Identify imaging and diagnostic studies used in the identification and classification of muscles, joints, and connective tissues.

6. Discuss genetic conditions manifesting in the muscles and connective tissues.

7. Evaluate the presentation and differential diagnosis of inflammatory muscle and connective tissue disorders.

8. Describe the clinical presentation and treatment of immunologic disorders of the muscles and connective tissues.

9. Review the assessment and treatment of traumatic conditions of the muscles and connective tissue.

10. Discuss disorders of the joints with multifactorial origin.

11. Analyze the manifestations and therapeutic approaches for degenerative joint diseases.

12. Outline the presentation, treatment, and nursing considerations for patients with immunologic joint conditions, such as rheumatoid arthritis.

13. Compare and contrast the various joint diseases with an infectious origin.

14. Describe cancers of the joints, muscle, and connective tissues.

15. Evaluate the appropriate assessment and management of traumatic joint injuries.

Faculty

Jane C. Norman, RN, MSN, CNE, PhD, received her undergraduate education at the University of Tennessee, Knoxville campus. There she completed a double major in Sociology and English. She completed an Associate of Science in Nursing at the University of Tennessee, Nashville campus and began her nursing career at Vanderbilt University Medical Center. Jane received her Masters in Medical-Surgical Nursing from Vanderbilt University. In 1978, she took her first faculty position and served as program director for an associate degree program. In 1982, she received her PhD in Higher Education Administration from Peabody College of Vanderbilt University. In 1988, Dr. Norman took a position at Tennessee State University. There she has achieved tenure and full professor status. She is a member of Sigma Theta Tau National Nursing Honors Society. In 2005, she began her current position as Director of the Masters of Science in Nursing Program.

Faculty Disclosure

Contributing faculty, Jane C. Norman, RN, MSN, CNE, PhD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

Sharon Cannon, RN, EdD, ANEF

Division Planner Disclosure

The division planner has 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.

Implicit Bias in Health Care

The role of implicit biases on healthcare outcomes has become a concern, as there is some evidence that implicit biases contribute to health disparities, professionals' attitudes toward and interactions with patients, quality of care, diagnoses, and treatment decisions. This may produce differences in help-seeking, diagnoses, and ultimately treatments and interventions. Implicit biases may also unwittingly produce professional behaviors, attitudes, and interactions that reduce patients' trust and comfort with their provider, leading to earlier termination of visits and/or reduced adherence and follow-up. Disadvantaged groups are marginalized in the healthcare system and vulnerable on multiple levels; health professionals' implicit biases can further exacerbate these existing disadvantages.

Interventions or strategies designed to reduce implicit bias may be categorized as change-based or control-based. Change-based interventions focus on reducing or changing cognitive associations underlying implicit biases. These interventions might include challenging stereotypes. Conversely, control-based interventions involve reducing the effects of the implicit bias on the individual's behaviors. These strategies include increasing awareness of biased thoughts and responses. The two types of interventions are not mutually exclusive and may be used synergistically.

1. INTRODUCTION

Along with the bones, muscles, ligaments, tendons, cartilage, and the joints provide the body with a supportive framework that allows flexibility of movement and protects the internal organs. These tissues also give shape to the body and act partially as a storage and supply area for minerals. When the tissues are unable to perform their usual functions because of trauma or rheumatic, inflammatory, or degenerative conditions, a person's physical support, protection, mobility, and ability to carry out activities of daily living are affected.

2. MUSCLES, JOINTS, AND CONNECTIVE TISSUES: STRUCTURAL AND FUNCTIONAL INTER-RELATIONSHIPS

The musculoskeletal system is composed of many anatomical structures that work together to produce movement, support, and protection of the body and its parts. These structures include the bones and joints of the skeletal system; the skeletal muscles; and the tendons, ligaments, and other elements that connect these tissues. This course will focus on the components of the system excluding the bones.

STRUCTURE AND FUNCTION OF SKELETAL MUSCLES

Contraction of skeletal muscle is its primary function, with the intent of moving the bones of the skeleton. Bone serves as a lever, the joint serves as a fulcrum upon which the bone pivots, and the muscle provides the force that moves the lever. A second function of skeletal muscles is maintenance of body posture. A residual amount of contraction in the muscles, known as muscle tone, serves to keep the body erect. A third function is heat production. To combat hypothermia, small, rapid contractions of skeletal muscle (shivering) produce body heat [1].

Producing Skeletal Movement

A typical skeletal muscle is anchored at each end to bone by a tendon. The muscle often stretches across a joint. The muscle's attachment to the less movable bone is called its origin, and its attachment to the more movable bone is called its insertion. When the muscle contracts, one bone remains more or less stationary, forcing the other bone to move [2].

Most skeletal muscles work in groups. The prime mover is the muscle that contracts to produce the movement. Synergists are muscles that work with prime movers to assist in performing the movement. Antagonists are muscles that work opposite prime movers by relaxing during their contraction or by producing an opposite effect. For example, the arm is flexed by contracting the biceps brachia, which acts as the prime mover; at the same time, the triceps brachii on the opposite side of the humerus relaxes, acting as the antagonist (Figure 1). When the arm is extended, the roles of the biceps and triceps are reversed. An isotonic contraction occurs when a muscle shortens during contraction. An isometric contraction occurs when a muscle becomes tense while remaining the same length [2].

Figure 1: MUSCLES OF THE UPPER EXTREMITY

Source: National Cancer Institute

Skeletal Muscle Structure

Muscle—skeletal, smooth, and cardiac—is made up of elongated cells called fibers (Figure 2). The fibers contain bands of contractile protein called myofibrils that extend the length of the cell. At the neuromuscular junction, the chemical acetylcholine creates the stimulus for muscle-nerve conduction of movement. Skeletal muscle fibers are multinucleated, and their myofibrils have striations: light and dark bands perpendicular to the long axis of the cell. The dark bands (anisotropic or A bands) are composed of the protein myosin, and the light bands (isotropic or I bands) contain the protein actin. A sense fibrous line called the Z line crosses the center of each I band and divides the myofibrils into a series of repeating units called sarcomeres. The bands are visible to the unaided eye and give skeletal muscle its alternate name: striated muscle. Smooth and cardiac muscles are made up of uninucleated cells. They further differ from skeletal muscle in that smooth muscle has tapered fibers with no striations and cardiac muscle has branched fibers [2].

Figure 2: STRUCTURE OF A SKELETAL MUSCLE

Source: National Cancer Institute

Muscle fibers are bound together by connective tissue into small bundles called fascicles, visible to the unaided eye. Fascicles are bound into larger bundles, which collectively form the muscle. The entire muscle is enclosed by a connective tissue covering called the epimysium, which is continuous with the connective tissue surrounding the fascicles and fibers. The epimysium is also continuous with the tendon or other connective tissue at attachment of muscle to bone. Thus, there is a continuous network of connective tissue extending from individual muscle fibers to the tendon. Blood vessels and nerves penetrate the connective tissue of the muscle, so muscle has sufficient blood supply to furnish nutrients and oxygen and to remove the waste products of muscular activity [2,3].

OTHER CONNECTIVE TISSUE STRUCTURES

Tendons are cords of connective tissue that attach muscles to the periosteum of the bones. During muscle contraction, the muscle pulls the tendon, which pulls the bone to which it is attached, producing movement. Flexion, extension, adduction, and abduction are normal movements of muscles and bones.

Ligaments, made of fibrous connective tissue, connect bones to one another. They have the ability to stretch while providing stability. The knee joint, for example, is stabilized by ligaments, such as the anterior and posterior cruciate ligaments, which bind the femur to the tibia within the joint capsule, and by the medial and lateral collateral ligaments outside the joint capsule [4].

A bursa is a fluid-filled sac that facilitates motion of structures that move against each other. It can be found between skin and bone, muscle and bone, tendons and bone, ligaments and bone, and between muscles. The bursae function as padding between structures to reduce friction caused by moving parts [4].

Connective tissue, in the broad sense of the term, include all tissues made up of cells in a matrix, including bone, cartilage, blood, and lymph. However, the term is used in a more limited sense when discussing diseases of the connective tissues. In this sense, connective tissue means the binding and covering tissues of the body, inducing tendons, ligaments, muscle fascia, and the deep layers of the skin. This kind of connective tissue (sometimes called "connective tissue proper") is essential in holding together all the components of the musculoskeletal system. Also included are intervertebral discs (or intervertebral fibrocartilage), which serve as "shock absorbers" to cushion the spine and help it move [4,5].

3. THE PROCESS OF SKELETAL MUSCLE CONTRACTION

Skeletal muscle contraction begins with the stimulus of a muscle fiber by a motor neuron. Every motor neuron ends in many fine branches, with each branch connecting with an individual muscle fiber. A group of muscle fibers activated by a single motor neuron is called a motor unit. Motor units range in size from a single muscle fiber in muscles controlling fine, skilled movements to over one hundred fibers in muscles involved in gross movements. All the fibers of a motor unit contract together when the neuron is stimulated [6]. There are two types of motor units in skeletal muscle, Type 1 and Type 2. Type 1 has a small cell diameter, with a high excitability and fast conduction velocity. It has an oxidative profile with moderate contraction velocity and low fatigability. There are few muscle fibers of this type. In contrast, Type 2 has a large cell diameter, with low excitability but a very fast conduction velocity. Type 2 fibers are numerous in quantity, with a glycolytic profile and high fatigability. The small motor units, with Type 1 (also known as "slow-twitch") fibers, are recruited first and are frequently active, while the large motor units, with Type 2 ("fast-twitch") fibers, are used infrequently, in forceful contractions. Maximal efforts, in which fast motor units are recruited, cannot be sustained because of the rapid depletion of glycogen.

When a nerve impulse reaches the end of a motor neuron, small vesicles in the ends of the nerve branches release acetylcholine, which increases the permeability of the muscle cell and causes an influx of calcium ions into the cell. The calcium ions cause structural changes in the myofilaments that allow them to slide past each other, causing contraction. The structural changes also allow breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) to provide energy for the contraction. The muscle relaxes as a result of the action of the enzyme cholinesterase, which breaks down acetylcholine, allowing the muscle to return to its resting state [6].

At the beginning of muscle contraction, ATP is formed from creatine phosphate stored in the muscle. The supply of creatine phosphate is limited, however, and even with mild muscle activity, additional ATP must be formed from ADP. The energy for forming this additional ATP is supplied by respiration. The first step in respiration is glycolysis, or anaerobic respiration, which produces lactic acid and small amounts of ATP. Under normal conditions, the lactic acid is broken down further by aerobic respiration, which requires an oxygen supply. The final products of aerobic respiration are carbon dioxide, water, and large amounts of ATP [6].

During sustained strenuous exercise, the blood cannot supply enough oxygen to keep pace with glycolysis, and lactic acid accumulates in the muscle, causing an oxygen debt. Muscle contractions continue for a short time using the small amount of ATP produced by glycolysis, but soon the demand exceeds the supply and the muscle is fatigued. The contractions decease in strength and then stop. The pain of muscle fatigue is the result of accumulated lactic acid. Oxidation of excess lactic acid occurs after exercise, when the person breathes deeply to pay off the oxygen debt [6].

The effects of exercise on the body's cells are significant. Physical activity increases the size and number of mitochondria, increases muscle's ability to use fat as a source of energy, increases the size of muscle fibers, and increases the content of myoglobin in muscle fibers. Exercise also results in increased fat oxidation. All of these increases lead to hypertrophy of the muscle, which leads to an increase in strength of the muscle. The wasting of muscle due to lack of use is assessed as atrophy

4. PATHOPHYSIOLOGIC INFLUENCES AND EFFECTS

The primary function of the musculature and connective tissues of the body is to provide body movement. When disease or trauma alters the system, the individual's ability to move and ambulate can be affected, which can profoundly affect a person's lifestyle. Movement is often still possible, but not without pain or difficulty [7].

INFLAMMATION

Inflammation may occur in muscle or connective structures as a result of excessive or repeated strain or pathogenic invasion. Restricted motion and pain usually result. One such example is rotator cuff injury, when the patient is unable to abduct the arm because of pain and muscle spasms. Other connective tissues of the body may be affected by inflammation, resulting in changes in other organs as well as the musculoskeletal system. Many of these connective tissue disorders are believed to be associated with immune processes [7].

DEGENERATIVE CHANGES

The joint is the musculoskeletal structure most frequently influenced by degenerative disease. Changes are most often associated with aging, excess weight, trauma, and inflammatory conditions. In the presence of these factors, articular cartilage softens, thins, and ulcerates, and the joint surfaces become rough. There may be a narrowing of the joint space and swelling of adjacent soft tissue. The normal smooth-gliding joint action is diminished, and the periosteum becomes irritated by friction, stimulating the growth of bone spurs at the joint margins. The effects of this destruction include joint pain, stiffness, and joint deformity, which can result in slight to moderate limitation of movement. Crunching or grating sounds, called crepitus, may be heard upon movement [8,9].

The intervertebral discs can also be affected by degeneration. The water content of the discs decreases with age, causing them to become thinner. The surrounding ligaments also change with age, so the disc becomes unstable. These changes along with increased bone resorption cause decreased height and painless restriction of spinal movement in the elderly. In some cases, the condition becomes more severe, with pressure on nerves causing pain and neurologic deficits [8,9].

Somewhat akin to degeneration is the process of atrophy. Muscle can atrophy as a result of disuse. As noted, the normal strain on muscles contributes to their development and to the maintenance of their size, shape, strength, and composition. Through disuse, muscle cells become reduced in size and weakened, and the muscle mass becomes more fibrous. Inactivity can also lead to joint contracture; the muscle fibers become shortened and fixed, and the joint's range of motion becomes limited. These conditions are reversible with the resumption of activity. However, contractures can progress to an irreversible state without treatment [8,9].

INFECTION

Musculoskeletal structures, such as joints and bursae, can be infected by pathogens entering from penetrating wounds or via the circulation. Pain and restricted motion are common in these cases [10].

NEOPLASIA

Malignant neoplasms of the bone, muscle, and cartilage are called sarcomas. Cancer affecting the muscle is called rhabdomyosarcoma; chondrosarcoma originates in the bones but can extend to the cartilage [11]. Depending on the specific cancer and location, patients may experience a temporary limitation in mobility (e.g., following surgery for tumor removal) or permanent limitation due to extensive surgical intervention, such as amputation [11].

TRAUMA

Skeletal muscle can be injured by trauma. Fortunately, skeletal muscle fibers can regenerate, but when the damage is extensive, the fibers are replaced by scar tissue. Trauma to the musculoskeletal structures supporting the joints is common. Muscle fibers may be injured due to overuse, overstretching, forcible twisting and other abnormal movement. The fibers may be torn, or stretched too far, and joint surfaces may dislocate, that is, separate partially or completely. Associated blood vessels and nerves may be damaged in the process. Pain and limited motion are the result [12].

Direct muscle trauma, overuse, or exposure to high temperatures can induce rhabdomyolysis. Rhabdomyolysis is a complex syndrome involving the rapid dissolution of damaged skeletal muscle, resulting in the leakage of intracellular contents to such an extent that it results in organ (particularly kidney) damage.

5. RELATED INFLUENCES AND EFFECTS

NEUROLOGIC AND VASCULAR PROBLEMS

Neurologic and vascular problems can cause or contribute to connective tissue and muscle disorders. Because muscle functioning is the result of the combined effect of muscle fibers and motor nerves, neurologic damage or interference can impair muscle functioning, causing atrophy and paralysis. Likewise, disruption of the vascular supply to these tissues can limit the nutrient and oxygen supply to cells and interfere with removal of cellular waste products. Prolonged interruption of circulation leads to necrosis [13,14].

Connective tissue disorders can also give rise to neurologic or vascular problems, which may in turn cause further musculoskeletal damage. Pressure from bandages, traction devices, tumor growth, and poor positioning are a few problems that can hinder nerve and blood vessel functioning. Trauma to muscles causes edema and hemorrhage in soft tissues, increasing the pressure within a confined space. Pressure on nerves and blood vessels in the area can become so great as to produce irreversible necrosis of the muscle tissue. A permanently disabling contracture of the limb may occur, as well as loss of motor and sensory functioning [13,14].

OCCUPATION AND LIFESTYLE

A person's occupation and lifestyle can contribute to alterations in the muscular and connective tissues. Interest in physical fitness has prompted many people to become active in athletic endeavors. Highly athletic activities, including weightlifting, distance running, and more intense sports, are associated with an increased risk for injury, particularly with improper conditioning and training [15].

Sport injuries can generally be categorized as acute or overuse. Acute injuries occur most often in contact sports and include strains, sprains, and dislocations. Overuse injuries are usually a result of repetitive motions or excessive intensity or duration of exercise. Acute injuries are typically traumatic (e.g., ligament tears), while the most common overuse injuries are tendinosis and osteoarthritis [15].

With muscle and connective tissue disorders, patients may be unable to continue their usual recreational activities. Further, roles within the family may change to accommodate impaired ability to conduct usual activities of daily living. Occasionally, it may be necessary to use assistive devices or to modify the environment, which requires a period of adjustment [15].

6. NURSING ASSESSMENT: ESTABLISHING THE DATA BASE

The nursing assessment of patients with muscle, joint, and/or connective tissue disorders requires special emphasis on the musculoskeletal, neurologic, and vascular systems [16].

SUBJECTIVE DATA

As part of any nurse assessment, patients should provide important information about what they are experiencing as a result of their conditions.

Pain

Pain, in some cases severe, is a common manifestation of joint, muscle, and connective tissue problems. Patients should be asked to describe their pain thoroughly, including location, intensity, quality, duration, radiation, precipitating factors, and successful relief measures. Some patients ache all over and should indicate each of the areas involved. Knowing the quality of pain may help pinpoint a specific problem, but the patient may require help in describing the pain. All these data are helpful in reaching a diagnosis [16].

Some patients experience pain so severe they cannot tolerate moving or being touched. Others have learned to live with chronic pain. It is important to pay attention to descriptions of pain that seem unusual or excessive for the patient's condition; such complaints warrant a thorough assessment. Changes in pain status may indicate a new or undiagnosed condition [16].

Paresthesia

Some patients with musculoskeletal conditions will experience paresthesia, such as tingling, numbness, and/or and diminished or absent sensation. The affected area should be defined as precisely as possible. Paresthesia is an indication of a neurologic problem and requires an in-depth assessment [16].

Changes in Activities of Daily Living and Mobility

Nurses can obtain additional subjective data by asking the patient how the problem affects activities of daily living and mobility. Changes in normal activities may be from pain alone or from other effects of their illness, including fatigue, weakness, stiffness, or decreased mobility of a particular body part. Some patients may have abandoned activities or made adjustments to maintain independence. Patients should be encouraged to discuss their view of the situation to bring insights and misconceptions to the surface [16].

Assistive Devices

Patients should be asked about any assistive devices used to help maintain independence, including aids for walking, eating, dressing, bathing, or toileting. These may not be devices designed specifically for the tasks; some are creative and adaptive in finding new ways to meet their daily needs [16].

History of the Injury

Subjective data are particularly helpful in the case of injury when the patient can describe the traumatic event and the action taken. This information can help the healthcare team determine what tissues and structures were inured as well as anticipate potential problems.

OBJECTIVE DATA

Physical Assessment

Objective data include the results of physical assessment and of laboratory and other diagnostic tests. When assessing patients with musculoskeletal disorders, vital signs, posture, muscle strength and tone, ability to ambulate, and neurologic status should all be included in the patient assessment [16].

Vital Signs

Assessment of vital signs is of particular importance in cases of musculoskeletal trauma. Hyperthermia may accompany inflammation and is common with an infection. Observing respiration is essential when injury occurs to the face, neck, or chest. Patients with spinal or chest changes may also have abnormal respirations [16].

Inflammation and Swelling

Inflammation is an immune response to infection, physical trauma, or autoimmune reaction. Swelling occurs as inflammatory exudate forms to defend the tissues from the injury. Edema may also be present. Inspection and palpation are used when assessing patients for swelling and inflammation and comparing one extremity to the other for size, warmth, and erythema. A joint will appear swollen when there is an increase in synovial fluid or when blood or purulent material is present in the joint capsule. This swelling is known as effusion. Effusion in the knee is detected by displacing the fluid with an upward stroke along the medial side of the knee and then pressing on the lateral side. The fluid will return and form a bulge (the bulge sign).

It is important to be gentle when assessing inflamed areas because they are usually tender. It is best to start palpating at the distance from the obvious tender area and work toward it, letting patients know when and where they will be touched and reassuring them that the touch will be gentle [16].

Skin Integrity

Injury or disease processes may cause changes in the skin. Discoloration results when trauma to soft tissues causes ecchymosis (bruising). The skin may be broken or torn as result of injury. Describe any lesions completely: include the occasion, length, depth, and appearance of the involved tissue. If there is any drainage, describe the amount, color, type, and odor [17,18].

Rashes are common in connective tissue disorders. Look for changes in the skin such as discoloration, dryness, scaliness, and lesions. With some types of arthritis, the hair, skin, and nails may show signs of changes. Discoloration, usually redness, may occur in the palms, over joints, and at the distal ends of the toes and fingers. Normal pigmentation may also be altered. Characteristic nodules may be noted when palpating and observing the skin [17,18].

Structural Changes

Joints may be assessed for changes by observation and palpation. Heberden nodes may be noted on the distal interphalangeal joint of patients with osteoarthritis. Likewise, rheumatoid nodules may be noted near the joints of patients with rheumatoid arthritis, even in the absence of other signs. Joints may be compared bilaterally to assess symmetry, position, and changes in alignment [17,19].

The curvature of the spine should be assessed to identify the presence of scoliosis (lateral curve), kyphosis (convex curve of the thoracic spine), or lordosis (concave curve of the lumbar spine). Patients with skeletal changes may shift another body part in the opposite direction to compensate for the imbalance; for example, the pelvis may tilt to compensate when one leg is shorter than the other [17,18].

Range of Motion

Range of motion can be measured with an instrument called a goniometer. Placing the arms of the goniometer parallel to the axis of the bones that form the joint, the examiner measures the angle for the typical positions of the joint. The elbow's normal flexion, for example, is 160o, whereas its normal extension is 0o. To determine what is normal for a patient, compare a joint with an apparently impaired range of motion to the corresponding joint in the other extremity, if possible. Patients can have differences in range of motion for a variety of reasons, particularly as they age, so it is vital to assess typical range of motion on an individualized basis. Dexterity is usually assessed by asking the patient to pick up an object from a flat surface [17,18].

If a patient is unable to move an extremity, range of motion may be determined through passive movement. Joints should not be moved beyond the point of comfort, and if possible, assessments should not include acutely inflamed joints, which may be tender [17,18].

During the assessment of range of motion, note joint stiffness, instability, and changes. Boney crepitation may be heard or felt during movement when there is a rough surface of the articular cartilage or when broken bone ends rub together. A limitation of motion may be due to a contracture. Early detection of signs movement limitation can allow for the implementation of measures to improve range of motion and prevent further limitations [17,18].

Posture

Observe the patient's standing posture for abnormalities. Posture can be affected by structural changes or differences, muscle weakness, or trauma. In addition, patients may hold themselves in positions that relieve or decrease pain. Patients should be observed for symmetry. Posture is also an indication of energy and muscle tone. Normally, posture is erect but not rigid [16].

Muscle Strength, Size, and Tone

Assessment of muscle strength, size, and tone can support the diagnostic process, but it can also provide information about the amount of assistance necessary for ambulation and participating in activities. Muscle strength is assessed by asking the patient to resist movements or to move against resistance [16].

Muscles should be observed and palpated bilaterally to check their size and asymmetry. If there seems to be a significant discrepancy in size, the limb circumferences should be measured [16].

Muscle tone is assessed by moving the extremities passively. While the patient is relaxed the examiner moves the extremity through the ranges of motion, noting resistance to movement. A muscle with diminished tone is described as flaccid. When the muscle is tight and tense from involuntary contraction, it is said to be spastic [16]. Function of the muscles depends on proper function of the nervous system. Muscle abnormalities noted during the assessment may be due to disorders of the nervous system rather than musculoskeletal disorders.

Ability to Ambulate

To assess the ability to ambulate, the patient should be asked to get up to walk across the room, turn around, and come back. Any difficulties rising to standing, starting or stopping walking, or turning should be noted. In a typical gait, the feet are 2–4 inches apart, and the body shifts from side to side about 1 inch. The posture is erect, with toes pointed straight ahead and shoulders in a straight line; the arms swing back and forth at the person's sides, and movement is smooth with good balance [16].

There can be a variety of irregularities in gait, with an equally diverse underlying etiology. A limp can occur from differences of leg length, joint motion, muscle strength, or other causes. The gait may appear stiff, unsteady, or wide-based; the feet may drag, or the steps may be very short. The body may lurch to the side as the individual shifts weight from one leg to the other. An irregular gait can cause fatigue because of the extra energy needed for walking. Ambulation may also be affected by pain, fear of falling, and loss of balance and coordination. As adults age, walking speed and balance may decrease. Steps may be short and shuffling, without the confidence and poise of youth [16].

DIAGNOSTIC STUDIES

Diagnostic studies provide information useful in diagnosing and following the course of the disease process.

Serum Enzyme Tests

Blood tests performed to detect presence of muscle disease measure levels of enzymes released when muscle tissues are destroyed or injured. These enzymes are creatine phosphokinase or creatine kinase, lactic dehydrogenase (LDH), and serum glutamic-oxaloacetic transaminase (SGOT), also known as aspartate amino-transaminase (AST). The same tests indicate cardiac muscle destruction in the patient with a myocardial infarction [20].

Serum Tests for Antibodies and Antigens

The antinuclear antibody (ANA) test is the most specific and sensitive test for lupus and is therefore the most commonly used autoantibody test. Ninety-seven percent of patients with lupus have a positive ANA blood test. The titer and patterns of the blood sample are reported. A titer greater than 1:80 is usually considered positive [21]. It is important to note that a positive ANA test is found in 97% of patients with lupus, but alone, it does not indicate a conclusive diagnosis of lupus [21]. A positive ANA test, although not always found, satisfies one of the four typical clinical characterizations required for a definitive diagnosis of lupus. ANA tests may also be positive in patients with other connective tissue diseases, chronic infectious diseases, and autoimmune diseases [21].

The 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) joint working group recommends several laboratory tests for the diagnosis of rheumatoid arthritis, including rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and anti-cyclic citrullinated peptide (anti-CCP) antibody [22]. A positive rheumatoid factor is the most specific and sensitive laboratory marker of rheumatoid arthritis, as it is seen in about 70% to 80% of patients [23,24,27]. It is also present in many healthy individuals, patients with other rheumatic diseases, and individuals with chronic infections [26]. The anti-CCP antibody test is a specific blood test available for diagnosing rheumatoid arthritis and distinguishing it from other types of arthritis [24,27]. The anti-CCP antibody test is a marker of anti-citrullinated protein antibody (ACPA) and is positive in about 80% to 90% of patients; it can also be present in other diseases, including active tuberculosis, and is especially useful in early synovitis. While rheumatoid arthritis differs from person to person, individuals with rheumatoid factor, the anti-CCP antibody, or subcutaneous nodules tend to have more severe forms of the disease [24,26,27]. However, biomarkers for the initial tissue processes that cause joint damage in rheumatoid arthritis lack prognostic accuracy and are therefore inadequate as stand-alone tests. As such, they are typically used to help rule out other causes of arthritis when a patient has clinical features of rheumatoid arthritis [28].

The presence of human lymphocyte antigen B27 (HLA-B27) is used to help diagnose or rule out ankylosing spondylitis and reactive arthritis. This antigen is present in 90% of those with these conditions, but it can also be found in those without pathology, so it is not diagnostic [20].

Serum Uric Acid

Serum uric acid is elevated during an acute episode of gout but may be normal during remission. Serum uric acid level is also used to assess kidney function [20].

Erythrocyte Sedimentation Rate and C-Reactive Protein

The ESR is a test in which the settling of red blood cells in uncoagulated blood is timed. This is a nonspecific test, and elevations in ESR are indicative of generalized inflammation. Changes in the ESR give an indication of improvement or worsening of the condition [20].

CRP is also associated with disease activity, and the CRP value over time correlates with radiographic progression in patients with rheumatoid arthritis [24,26,29]. ESR is typically ≥30 mm/hour, and CRP level is typically ≥0.7 pg/mL.

Synovial Fluid Analysis

In certain instances, clinicians may perform an arthrocentesis in order to differentiate rheumatoid arthritis from other arthropathies [30]. Findings from synovial fluid aspiration that support a diagnosis of rheumatoid arthritis include straw-colored fluid with a significant number of fibrin flecks, synovial fluid ability to clot at room temperature, and 5,000–25,000 white blood cells/mm3 (5–25 × 109/L) with 85% polymorphonuclear leukocytes [23,24]. In addition, bacterial cultures are negative, no crystals are present, and the synovial fluid glucose level is low [23,24].

X-ray

Evidence Based Practice Recommendation

For patients with chronic extremity joint pain and suspected rheumatoid arthritis, the American College of Radiology recommends x-ray as the imaging study of choice for evaluation.

https://acsearch.acr.org/docs/3097211/Narrative

Last Accessed: September 26, 2022

Strength of Recommendation: 9 (Usually appropriate)

Examination by x-ray helps diagnose joint problems; it also allows following of the progress of a condition and its response to treatment. X-rays are able to show joint changes, such as erosion of joint margins, joint space narrowing, bone spurs, loose bodies, and dislocation. Specific injuries to soft tissues such as tendons and ligaments do not show on x-rays, but soft tissue swelling may be obvious [20].

Magnetic Resonance Imaging (MRI)

Magnetic resonance imaging (MRI) can produce a detailed and highly useful image of the joints and soft tissues. As such, it is usually the best option when evaluating major joints, the spine and the muscles, tendons, and ligaments of the extremities. MRI has a role in the diagnosis of a variety of musculoskeletal disorders, including osteoarthritis, back pain, tears in the connective tissues of the joints, congenital disorders of the joints, and occupational/sports-related injuries [31].

Musculoskeletal Ultrasound

Because it is readily available and avoids the use of radiation, ultrasonography is often a good option in the assessment of musculoskeletal disorders and injuries. Ultrasound allows for the visualization of joints, tendons, muscles, bursae, ligaments, cartilage, nerves, fascia, and related soft tissue and can have a role in diagnosis and/or evaluation of disease progression for a variety of conditions. The American Academy of Physical Medicine and Rehabilitation indicates that ultrasound is an essential component in the diagnosis of tendinopathies/tendon tears, nerve entrapments (e.g., carpal tunnel syndrome), and acute or chronic muscle injury [32]. It may also be involved in the evaluation of ligamentous injury and joint instability syndromes, subluxations/dislocations, and fascia injury or inflammation. When joint aspiration is necessary, it may be guided by ultrasound, as may therapeutic injections.

Electromyogram

The electromyogram is a test to measure the electric currents produced by muscles, at rest and during contraction. Small needle electrodes are inserted into the muscle being tested and then connected by wires to an electromyography machine. Changes in muscle electrical activity may be helpful in diagnosing neuromuscular disease, and the test is particularly useful in differentiating muscular disease from neurologic disease [20].

Biopsy

Various biopsies may be performed on the musculoskeletal system. Skin samples, obtained by a punch biopsy, may be examined to diagnose certain connective tissue disorders. Muscle biopsies are usually operative procedures done to evaluate muscle disease. The synovial membrane can be biopsied, and analysis can be useful in diagnosing different types of arthritis. Buccal mucosa may be biopsied to help diagnose Sjögren syndrome, and the temporal artery may be biopsied to diagnose temporal arteritis [20].

7. SPECIFIC DISORDERS OF CONNECTIVE TISSUE AND MUSCLES

Injury to connective tissue and muscle may arise from congenital or acquired disease or from trauma. Diagnosis and treatment/management of these conditions are specific to the disorder.

GENETIC DISORDERS

Genetic disorders of connective tissue are structural connective tissue changes present at birth. Most of these disorders are transmitted by a single autosomal dominant gene. Although there are many congenital connective tissue disorders, most are rare; two more widely known conditions are Marfan syndrome and Ehlers-Danlos syndrome. The obvious manifestations of these disorders may not appear until the second decade of life or later [33].

Both syndromes are serious and require collaborative assessment and treatment by the entire healthcare team. Healthcare providers should gather careful family histories detailing the patterns of disease transmission so families can see the degree of risk [33].

Marfan Syndrome

Marfan syndrome is one of the most common inherited (autosomal dominant) disorders of connective tissue, occurring in 1 in every 10,000 to 20,000 individuals [34]. It is the result of mutations in the FBN1 gene. FBN1 mutations are associated with a broad continuum of physical features ranging from isolated features of Marfan syndrome to a severe and rapidly progressive form in newborns.

Clinical Manifestations

There is wide variability in clinical symptoms in Marfan syndrome, with the most notable occurring in eye, skeleton, connective tissue, and cardiovascular systems. The most common symptom is myopia. Ocular problems are a result of defective supporting tissue of the lens, which can cause bilateral subluxation or total dislocation of the lens. The dislocation is usually upward, but slit-lamp examination is done to detect more subtle variations. Complications such as reduced visual acuity, uveitis, glaucoma, cataracts, and retinal detachment may also occur [33].

Cardiovascular complications of Marfan syndrome are potentially life-threatening and commonly involve the aorta. Marfan syndrome causes degeneration of the elastic fibers of the aortic media, which can lead to dissecting aneurysm. Aortic regurgitating may occur, producing a diastolic murmur. Mitral valve prolapse, thickening of the coronary arteries, conduction system abnormalities, and aortic coarctation have also been associated with this condition [33].

Echocardiogram is useful in following aortic and mitral valve abnormalities. Patients with valve involvement are at risk for endocarditis. These patients should be prescribed antibiotic prophylaxis for any dental work causing bleeding or for any other invasive procedures, to prevent bacteremia [33].

The most obvious skeletal manifestations in patients with Marfan syndrome are extreme height and long extremities. These patients are usually much taller than other members of their families and have excessively long arms and legs in relation to their bodies. The measurement from fingertip to fingertip with the arms outstretched is typically greater than the body height. Arachnodactyly (extremely long fingers) is commonly noted. The sternum may bulge outward (pectus carinatum, or pigeon breast), or it may be depressed (pectus excavatum, or funnel breast). If the chest differences are extreme, the echocardiogram becomes unreliable [33].

Kyphoscoliosis may be quite severe because of the weakness of the ligaments and other supporting connective tissues. Other skeletal manifestations include a long and narrow skull, with a high, arched palate, and flat feet. Joints and ligaments are hyperextensive, leading to recurrent dislocations of the knees and hips [33].

Therapeutic Measures

Therapeutic approaches in Marfan syndrome are directed toward the specific manifestations. Corrective lenses are almost universally necessary, and yearly ophthalmologic examinations aid in early detection of retinal detachment and lens dislocation [33].

Because cardiovascular problems are the major cause of mortality, most diagnostic and treatment efforts are directed here. Echocardiograms are done yearly, unless the diameter of the aorta exceeds the upper limits by 50%, in which case echocardiogram is performed every six months [33]. Beta blockers are used to decrease the stress on the aorta at the time of diagnosis or when there is progressive aortic dilatation. There is some evidence that angiotensin receptor blockers may be used, and clinical trials are underway to evaluate this use. Surgery to repair the aorta is done when the aortic diameter is greater than 5 cm in adults and older children, when the aortic diameter increases by 1.0 cm per year, or when there is progressive aortic regurgitation [34].

Kyphoscoliosis is the most deforming and disabling skeletal manifestation of Marfan syndrome. Patients should be examined biannually, and therapy (e.g., bracing, physical therapy, spinal fusion) should be initiated as soon as possible to prevent or slow further changes [33]. In more severe cases, the thoracic cavity in patients with kyphoscoliosis can be so reduced that cardiac and respiratory function are compromised. These patients are particularly susceptible to upper respiratory infections and should be treated aggressively if an infection occurs [33].

Prepubertal girls are often given estrogen and prepubertal boys given androgens to decrease height and help prevent kyphoscoliosis. While these hormones induce early epiphyseal closure, they also trigger the physical and psychosocial changes of puberty, which can create additional psychosocial stresses.

While Marfan syndrome is not always inherited, it is always heritable. Approximately 75% of cases are inherited, and the offspring of patients with Marfan syndrome have a 50% chance of developing the syndrome. In addition, patients with Marfan syndrome who become pregnant are at risk for potentially dangerous aortic changes resulting from cardiovascular overload and increased intra-abdominal pressure [33].

Specific Nursing Measures

The health history is extremely important in patients with congenital disorders such as Marfan syndrome. Particular attention should be paid to the patient's coping abilities in terms of living with a chronic disease that involves numerous changes in body image [7,35].

At each visit, the patient should be thoroughly assessed, with particularly attention to the eyes, cardiovascular system, and musculoskeletal system [7,35]. When examining the patient's eyes, look for tremor of the iris as it is moved horizontally. This is an indication of subluxation of the lenses. These patients may also have myopia and blue sclera (due to the presence of thin sclera through which the vessel-rich choroid can be seen).

Patients may display early diastolic murmurs of aortic regurgitation. This consists of a high-pitched blowing sound, heard best with the stethoscope over the second right or third left intercostal space. Increased pulse pressure and collapsing (water-hammer) pulse may also be evident. Occasionally, a midsystolic click indicative of mitral valve prolapse may be auscultated.

Nursing interventions for these patients will focus on supportive symptomatic care and education needs. The nurse should be prepared to discuss the nature and course of the disease and the importance of genetic and pregnancy counseling. The patient should be urged to keep current with biannual exams. Patients should also be counseled to avoid trauma, including contact sports, and invasive surgical procedures (when possible) [7,35]. They are also advised to avoid medications and foods that can lead to chronic increases in blood pressure and stretch the connective tissue in the cardiovascular system.

Ehlers-Danlos Syndromes

Ehlers-Danlos syndromes are a group of rare genetic disorders of connective tissue that affect the skin, joint, and hematopoietic systems. It is usually transmitted by an autosomal dominate gene, but it may also be recessive or an X-linked recessive gene [33].

Clinical Manifestations

The major manifestations of Ehlers-Danlos syndromes are fragile and increased elasticity of skin, hyperextensible joints, and fragility of blood vessel walls [33]. In the 2017 classification system, 13 types of Ehlers-Danlos syndrome were identified, including rarer forms [36]. They are generally organized according to the dominant system(s) involved, severity, and mode of transmission.

The skin of most patients with an Ehlers-Danlos syndrome is very smooth and hyperextensible; it can be pulled away from the body but returns to its original shape. Fragility and bruising are often evident. Minor cuts cause gaping wounds with little bleeding. Even the slightest trauma may cause purpura or hematomas that calcify, particularly over pressure points such as knees and elbows [33].

An unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Dislocations, effusion, and hemarthrosis of the hip, patella, and shoulders may occur. Kyphoscoliosis, flat feet, and hyperextensible knees are often present. Thoracic changes are not as common but do sometimes occur, as does a forward slipping of the lower lunar vertebrae (spondylolisthesis) [33].

The patient may have episodes of bleeding, including spontaneous epistaxis; bleeding into the joints (hemarthrosis); blood in the sputum (hemoptysis); dark, tarry stools (melena) indicating bleeding in the digestive tract; and bleeding gums. It is not known whether the abnormal bleeding is from weakness in blood vessel walls or abnormal interactions of platelets with collagen [33]. Patients with Ehlers-Danlos syndrome who become pregnant are at risk for uterine rupture.

Abnormalities of the heart and blood vessels occur in patients with the cardiac-valvular type. These include mitral valve prolapse, right bundle branch block, and other conduction abnormalities. Patients with this type of Ehlers-Danlos syndrome have friable arteries, increasing the risk for adverse events during invasive angiography [33].

Other manifestations of Ehlers-Danlos syndrome can include spontaneous bowel rupture, pneumothorax, and diaphragmatic hernias or diverticula. In rare instances, a patient may have glaucoma, retinal detachment, or corneal abnormalities [33].

Specific Nursing Measures

Care for patients with an Ehlers-Danlos syndrome is limited to symptomatic treatment and support; there is no curative treatment. The main concern is to protect the patient's skin and joints from cuts, bruises, and dislocations. At each visit, the patient should be assessed for bleeding gums, melena, hemoptysis, and nosebleeds. Inadequate wound healing or wound dehiscence after a surgical procedure should be noted. Assessment of the lungs for pneumothorax, particularly following surgery, is important [35].

As with any chronic condition, the nurse needs to teach patients and their families about the nature and course of the disease. The patient should also be referred to a genetic counselor, as there are varying modes of heritability. A patient with Ehlers-Danlos syndrome who becomes pregnant is at risk for abortion, preterm birth, exacerbation of joint problems, increased bruisablity, abdominal hernia, and varicosities. Serious complications may arise with cesarean deliveries, because sutures do not hold well and wound dehiscence may result [7].

INFLAMMATORY DISORDERS

Many pathologic conditions involve inflammation of connective tissue. In this section, most of the inflammatory conditions are related to alterations in the immune system [37].

Bursitis, Tendinitis, and Tendinosis

Bursitis is an inflammation of the synovial membrane lining a bursa; tendinitis is an inflammation of a tendon. These inflammations may result from trauma, or they may be secondary to disease. Although both conditions are usually acute, they can become chronic and disabling with repeated injury or inadequate care [37]. Note that tendinitis is distinct from tendinosis, which is the result of a noninflammatory condition characterized by degeneration of the tendon in response to chronic overuse.

Bursitis and tendinosis develop from prolonged overuse of a particular muscle group that can eventually damage a bursa or tendon. Overuse may be due to repetitive work movements or to a sports activity. Because the vascular supply of tendons is poor, their healing is limited and inflammation can become chronic, resulting in tissue damage and persistent pain. Often, the patient becomes unable to continue performing the movements that led to the condition, potentially impairing their ability to continue working.

Calcium deposits in tendons or bursae may also be the cause of inflammation. Tendon sheaths may become inflamed secondarily to systemic disease, such as gout, rheumatoid arthritis, or scleroderma [37].

Clinical Manifestations

The major symptom of bursitis/tendinitis/tendinosis is pain, often so severe that the patient is unwilling to move the affected part. Swelling may be present, and this alone may keep the patient from moving the joint. Any of the body's many bursae and tendons can become inflamed, but some joint areas are more commonly affected than others. Differential diagnosis of acute pain and erythema in joint areas should include infection, gout, and rheumatoid arthritis [37].

Bursitis and tendinitis/tendinosis of the shoulder involve the subacromial and subdeltoid bursa (different sections of the same large bursa) and the tendon of the supraspinatus muscle. The onset of bursitis or tendinitis in the shoulder usually follows activities involving repetitive movements of the whole arm, such as sanding, painting, sawing, throwing, or repeated lifting. Pain in the deltoid area increases when the patient lies on the shoulder or actively abducts the arm. A classic sign of bursitis/tendinitis/tendinosis of the shoulder is the "painful arc" between 80o and 120o of active arm abduction. The patient is often unable to support the weight of the arm at these angles. Further abduction causes no pain, and the examiner can perform assisted range of motion. If passive range of motion causes pain, capsulitis, rather than a periarticular disorder, is suspected [37].

Inflammation of the elbow region most often involves the olecranon bursa and the medial and lateral epicondyles. "Tennis elbow" is generally lateral epicondylitis, and "pitcher's elbow" is medial epicondylitis. These conditions cause pain that radiates from the elbow down to the forearm. The patient may drop heavy objects because of a feeling of decreased strength, although there is no real loss of strength or range of motion. Palpation of the involved epicondyle causes pain. Activities involving lower arm movement, such as tennis or hammering, may precipitate an attack. Olecranon bursitis usually is caused by leaning or falling on the elbow. There may not be severe pain, but swelling is often extensive [37].

Tenosynovitis involves inflammation of the tendon and tendon sheath and is also known as de Quervain tenosynovitis of the wrist [38]. When the tendons at the base of the thumb become irritated or inflamed this causes the tunnel around the tendon to swell and results in pain and difficulty grasping and holding objects. Overuse is the most common cause [38]. New repetitive activity, hormonal fluctuations associated with pregnancy and breastfeeding, and wrist fractures also are possible causes of de Quervain tenosynovitis [39].

Stenosing tenosynovitis, also referred to as "trigger finger," occurs when the pulley/tendon relationship between the hand and fingers is restricted by thickening or swelling at the base of the fingers. This creates pain and a distinctive catching, popping, or locking action in the finger or thumb. A cycle of triggering, inflammation, and swelling is common. Like carpal tunnel syndrome, stenosing tenosynovitis has been associated with other health conditions, such as gout, diabetes, and rheumatoid arthritis. In many cases, the actual cause is not clear [40].

The most common inflammatory problem of the hip is trochanteric bursitis. Pain, which is distributed over the lateral aspect of the hip and thigh, may inhibit ambulation. An increase in pain is seen with abduction and internal rotation against resistance. The patient feels tenderness with palpation over the greater trochanter. Patients who have leg length discrepancy may develop this inflammation in the hip of the longer leg [37].

Four bursa in the knee can cause significant discomfort for the patient when inflamed [37]:

- Prepatellar bursa

- Superficial infrapatellar bursa

- Deep infrapatellar bursa

- Pes anserine bursa

Prepatellar bursitis ("housemaid's knee") results from the combined action of excessive kneeling and leaning forward, as when gardening. Superficial infrapatellar bursitis ("clergymen's knee") can result from excessive kneeling. Deep infrapatellar bursitis and pes anserine bursitis are secondary to excessive weight bearing or unusually strenuous exercise [37].

Achilles tendinitis is a painful inflammation of the tendon of the ankle with or without swelling. This injury often results from a single episode of overuse. It can also occur in runners who wear shoes with rigid soles. Recurrent episodes of Achilles tendinitis, when a patient resumes activity before complete healing has occurred, can result in progressive scar formation, which may require surgical repair [37].

Therapeutic Measures

The measures employed for relief of bursitis and tendinitis vary according to the patient's age and the location, cause, and severity of the injuries. Recommendations usually include [37]:

- Short-term immobilization, particularly during differential diagnosis

- Ice packs applied to the affected area

- Physical therapy and structured exercise after the initial period of rest

- Anti-inflammatory medication

Occasionally, local corticosteroid injections are administered to the inflamed bursa or tendon area. While this approach is relatively widespread, it is not supported by well-designed systematic reviews [41].

Physical therapy and increasing return to activities is the best practice for these patients. Physical therapy consists of a four-step approach [42]:

1. Pain reduction and load management (isometric loading and avoiding positions of compression)

2. Isotonic loading (heavy-slow resistance through concentric-eccentric phases)

3. Energy-storage loading (plyometric loading)

4. Return to activity/sport

Exercise is crucial in the rehabilitation process, and active movement is started early. For example, in bursitis of any bursa of the knee, quadriceps-setting exercise is begun as soon as pain allows. When pain and tenderness have completely subsided, range of motion and full quadriceps activity are initiated. Physical therapists are often involved in designing and implementing exercises for patients, according to their individual needs. Occupational therapists may also participate if the nature of the problem involves a modification or change in job [15].

In some cases, fluid may be aspirated from the bursal space to relieve the symptoms. Any fluid obtained should be cultured and inspected. X-rays of joints are usually normal, but in some instances, calcium deposits can be identified as the precipitating factor. Arthrography is indicated in specific types of shoulder trauma to rule out any disruption of the joint capsule. Surgery is rarely used for bursitis or tendinitis unless rupture of the tendon occurs [37].

Specific Nursing Measures

Goals of nursing care are to relieve the patient's pain, maintain maximum mobility, and prevent joint contracture. Assessment of pain and range of motion is important both initially and after treatment to measure improvements. Reassurance and support can contribute to the relief of pain, so it is helpful to assure the patient that the pain of bursitis or tendinitis/tendinosis is usually of short duration [35].

Instrumental to the success of treatment is comprehensive patient education. Patients should receive instruction on physical therapy exercises (including frequency), pain management techniques, and return to activities; written instruction should also be provided. If pain is relieved with pharmacotherapy, the patient may be tempted to use the affected area too soon. It is important to caution patients to refrain from early resumption of activity to avoid reinjury and/or the creation of scar tissue [35].

Polymyalgia Rheumatica

Polymyalgia rheumatica is an immune-mediated inflammatory disorder characterized by muscle stiffness, pain, and weakness around the neck, shoulders, and hip. While this is an inflammatory disorder, the cause of trigger is unclear; genetic, infectious (e.g., Epstein-Barr virus, parvovirus), and gut health-related etiologies have all been suggested, with varying levels of evidence [43]. The incidence increases with age, with the greatest incidence in White patients older than 50 years of age; the average age at diagnosis is 70 years.

Clinical Manifestations

As noted, the characteristic symptoms of polymyalgia rheumatica are pain and stiffness in the shoulders, neck, upper arms, and hip area. The pain and stiffness are usually worse upon waking in the morning or after resting, and usually last an hour or more. Patient may experience difficulty performing normal activities, including rising from bed or a chair, dressing, and brushing hair. Many patients will have difficulty raising their arms above the shoulders [44]. Less common signs and symptoms include flu-like symptoms (e.g., low-grade fever, weakness, loss of appetite, weight loss) and swelling of the wrists or joints in the hands. Onset of symptoms is typically over the duration of a few days but may be as short as overnight.

Diagnosis is typically based on the presence of elevated inflammatory markers, particularly ESR and immunoglobulin G (IgG). In addition, these patients will display a decreased number of circulating B cells compared with healthy adults [43].

A significant portion of patients with polymyalgia rheumatica are also diagnosed with giant cell arteritis, and research indicates the co-occurrence of these conditions is common even without the presence of symptoms [43].

Therapeutic Measures

The EULAR and the ACR have issued a joint guideline for the management of polymyalgia rheumatica [45]. The cornerstone of treatment is at least 12 months of glucocorticoid therapy. This typically consists of 12.5–25 mg prednisone, although a lower dose may be preferred in patients at risk for glucocorticoid-related adverse events (e.g., those with osteoporosis, glaucoma, diabetes). Drug therapy should be tapered up to effective dose and tapered down when discontinued.

Care of patients with polymyalgia rheumatica includes monitoring for and preventing (when possible) the adverse effects of long-term steroid therapy. This can include vitamin D and calcium supplementation as well as bisphosphonate prophylaxis for those at increased risk for fracture [43]. Because close monitoring is necessary, patient education should include the necessity for keeping all follow-up appointments.

IMMUNOLOGIC DISORDERS

The disorders in this section are believed to have an autoimmune etiology. As with many autoimmune disorders, there are a variety of potential initiating factors, including viral infections, genetic predisposition, and exposure to toxins [46].

Autoimmune disorders may be generally classified as organ-specific or generalized. Autoimmune connective tissue diseases are generalized, usually involving a progressive degradation of collagen in connective tissue throughout the body. Rheumatoid arthritis is among autoimmune disorders but will be discussed later in this course, because joint involvement is the major problem [46]. Some autoimmune disorders result in musculoskeletal manifestations but have an etiology in another body system. For example, fibromyalgia is characterized by widespread musculoskeletal pain and fatigue, but it is believed to be the result of nervous system dysfunction.

Autoimmune connective tissue disorders can be associated with significant morbidity mortality. However, early diagnosis and treatment have improved prognosis, though they remain chronic (incurable) conditions. Successful therapy for patients with autoimmune disease requires an interprofessional team approach in order to ensure the best outcomes for patients [46].

Familiarity with each disorder will prepare the nurse to be alert for manifestations, exacerbations, and patient education needs. Because patients are often prescribed several medications to help manage the disorder, nursing management often includes medication management. Comfort measures are another important aspect of nursing care during acute phases or exacerbations. Proper positioning, use of splints, and small comfort measures (e.g., backrubs, smoothing wrinkled sheets, creating a calm environment) all contribute to the patient's well-being [46].

The nurse will explain to patients how they can try to prevent exacerbations of specific manifestations of their disease and how to cope with them when they do occur. Prevention measures may include avoiding stress, cold, sun, or certain drugs [46].

Systemic Lupus Erythematosus

Four different forms of lupus have been identified: cutaneous lupus erythematosus, drug-induced lupus, neonatal lupus, and systemic lupus erythematosus (SLE) [47]. Cutaneous lupus mainly affects the skin. It is associated with chronic skin eruptions that, if left untreated, can lead to scarring and permanent disfigurement. Drug-induced lupus is associated with ingestion of various drugs that result in lupus-like symptoms. Neonatal lupus is a rare, non-systemic condition affecting infants of women with lupus. SLE, which affects multiple organ systems as well as the skin, is considered the most common of the four forms.

SLE, often referred to simply as lupus, is a chronic inflammatory autoimmune disorder of the connective tissue, primarily affecting the skin, joints, blood, and kidneys [47,48,49]. In this autoimmune disorder, antibodies are formed within the body that target healthy body systems, causing inflammation and structural changes. The word lupus means "wolf" in Latin, while erythematosus means "redness." The disease is named for the characteristic red rash that appears on the face and is thought to resemble a wolf's face [47,49]. The term "lupus erythematosus" was coined in 1851 by Pierre Cazenave, a French dermatologist, but writings describing lupus date to ancient Greece [49,50].

Lupus has been characterized as a multidimensional, unique, complex, challenging, unpredictable, and often elusive disease [47]. It is a non-organ-specific systemic disease with a varying prognosis that can be mild, serious, life-threatening, or even fatal. The disease is characterized by recurring remissions and exacerbations, often called flares, that occur most commonly in the spring and summer [48,51]. Periods of remission vary considerably among those diagnosed with lupus [47].

The number of reported cases of lupus varies based on different sources; it is believed that there are at least 1.5 million affected individuals in the United States [52,53]. More than 90% of SLE cases occur in women, with most women developing symptoms in their childbearing years (15 to 45 years of age) [54]. New diagnoses of lupus in women older than 45 years of age are uncommon [49]. SLE is most common among African Americans, with African American women having three times the incidence of White American women [54]. The incidence of lupus is also greater in Hispanic, Asian, and Native American women when compared to White women [55]. Statistics show that Black and Hispanic women tend to develop the disease at a younger age, are more likely to develop more serious complications (particularly cardiovascular complications and kidney disease), and tend to have a higher mortality rate from the disease as compared to White women [54].

The exact cause of lupus remains a mystery, but researchers believe that it results from multiple factors [49,56]. Possible causes may be interrelated and include immunologic dysfunction, genetic factors, hormones, and environmental influences [50,51].

Immune dysregulation, in the form of autoimmunity, is thought to be the prime cause of lupus. In patients with lupus, the body produces an accelerated inflammatory response, resulting in the production of autoantibodies, causing immune complexes (antigens combined with antibodies) [49,56]. These autoantibodies and complexes assault the body's own healthy cells and tissues [47,49,50,51]. Symptoms of SLE are the result of the damage to the body's tissues secondary to the immunologic response. One of the hallmark indicators of lupus is the formation of autoantibodies, and the presence of autoantibodies in the blood is a key factor to the diagnosis of lupus [47,49,51].

The strong hereditary component of lupus is supported by the fact that first- and second-degree relatives of patients with lupus are at a greater risk for developing lupus [57]. Estimates indicate that 5% to 13% of relatives will develop lupus, but only 5% of children whose mothers had lupus will develop the disease [57]. For those with a genetic predisposition, environmental factors may trigger lupus [47]. Environmental factors that may precipitate or exacerbate lupus include physical or emotional stress, streptococcal or viral infections, exposure to sunlight, immunizations (live vaccines), surgery, smoking, chemical agents (drugs, metals, or toxins), certain foods or supplements, and other environmental irritants [47,50,58]. Further, female sex hormones are believed to have a potential role, as women in their reproductive years are most susceptible to lupus.

Diagnosis

The diagnosis of lupus may be a challenge for the healthcare provider as well as the patient. In 2019, the EULAR and the ACR published updated classification criteria for lupus (Table 1) [59]. The EULAR/ACR criteria classifies a person as having lupus if they meet entry criterion of an ANA titer of >1:80, followed by additive weighted criteria (seven clinical and three immunologic) in which the patient must meet one clinical criterion and ≥10 points between the clinical criteria and immunologic criteria [59].

Table 1: CLASSIFICATION CRITERIA FOR THE DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Domain

Criteria

Weight

Entry Criterion

Positive antinuclear antibody (ANA) titer

ANA titer of >1.80 on Hep-2 cells or an equivalent positive test (ever)

Must be positive to continue to additive criteria

Additive Criteria, Clinical

Constitutional

Fever

2

Hematologic

Leukopenia

Thrombocytopenia

Autoimmune hemolysis

3

4

4

Neuropsychiatric

Delirium

Psychosis

Seizure

2

3

5

Mucocuteanous

Non-scarring alopecia

Oral ulcers

Subacute cutaneous OR discoid lupus

Acute cutaneous lupus

2

2

4

6

Serosal

Pleural or pericardial effusion

Acute pericarditis

5

6

Musculoskeletal

Joint involvement

6

Renal

Proteinuria>0.5 g/24h

Renal biopsy Class II or V lupus nephritis

Renal biopsy Class III or IV lupus nephritis

4

8

10

Additive Criteria, Immunology

Antiphospholipid antibodies

Anti-cardiolipin antibodies

OR

Anti-ß2GP1 antibodies

OR

Lupus anticoagulant

2

Complement proteins

Low C3 OR low C4

Low C3 AND low C4

3

4

SLE-specific antibodies

Anti-dsDNA antibody

OR

Anti-Smith antibody

6

Source: [59]

Clinical Manifestations

No two people with lupus will experience identical symptoms. The onset of lupus may be acute or insidious, vague, or even nonspecific. On average, individuals with lupus have symptoms of the disease for two to three years before a diagnosis is made [49]. Symptoms are the result of the inflammatory and immune response of the individual's body to the disease process [49]. Repetitive cycles of exacerbations and remissions of symptoms are a hallmark of the lupus disease process.

Common symptoms of lupus include fever, weight loss, malaise, fatigue, skin rashes, polyarthralgia, vasculitis, Raynaud syndrome (discussed in detail later in this course), patchy alopecia (hair loss), and painless ulcers of the mucous membranes [51]. Fatigue is probably the most universal symptom, described as a persistent complaint of a paralyzing fatigue that normal rest may not relieve [47]. Vague symptoms of lupus include aching, fatigue, low-grade or spiking fever, chills, and malaise. Episodic fever is reported by more than 80% of all patients with lupus, with a low-grade fever most often noted [47]. Infection is certainly a major concern and is a potential symptom for patients with lupus. Those with lupus are more susceptible to opportunistic infections due to alterations in their hematologic system, especially in white blood cells. Women with lupus may also experience irregular periods or amenorrhea due to the disease process [47,49].

Skin rashes are very common among patients with lupus; approximately 80% of patients report skin involvement [47]. A red, raised rash over the nose and cheeks characterizes the classic "butterfly rash" of lupus. The butterfly rash is reported by 55% to 85% of all patients with lupus at some point during their disease process [47]. Discoid lupus lesions may also be seen. Ultraviolet light often aggravates skin eruptions, and approximately one-third of all patients with lupus are found to be photosensitive [47,60]. Oral, nasal, and vaginal ulcers may occur. Conditions such as alopecia, pruritus, alteration in wound healing, and bruising are other common dermatologic symptoms.

Polyarthralgia (pain in multiple joints) occurs in more than 90% of lupus cases [47]. The joint pain associated with lupus is similar to that experienced by rheumatoid arthritis patients and is often called lupus arthritis. Most patients complain of morning joint stiffness and pain. The pain is typically symmetrical, and joints may become tender, warm to the touch, and swollen. The dominant extremities are usually more inflamed. Joints commonly affected include the toes, ankles, fingers, wrists, elbows, and knees [61]. Joint pain is often one of the first and most common complaints of those with lupus and is often what initially brings them to a healthcare provider [50]. Additional musculoskeletal symptoms that may occur include subcutaneous nodules, tendonitis, tendon rupture, and carpal tunnel syndrome [47].

Anemia and cardiopulmonary abnormalities are relatively common among patients with SLE, affecting 50% of patients [47,49,62]. The most common cardiac complication of lupus is pericarditis, while pleurisy is the most common respiratory complication [47,49].

Nervous system involvement secondary to lupus is common and can range from mild to severe. Central nervous system involvement may result in cognitive disorders, including confusion, fatigue, memory impairment, and difficulty in articulating thoughts [49]. Cognitive dysfunction is estimated to occur in up to 90% of patients with lupus and is not associated with lupus disease activity [63].

Renal damage is one of the most serious complications of lupus, often causing such symptoms as hematuria, proteinuria, urine sediment, cellular casts, urinary tract infections, and fluid/electrolyte imbalance. Renal involvement has the potential to cause renal failure, affecting up to 50% of patients [47]. Renal disease is a leading cause of death in patients with lupus [47].

Ophthalmic disease affects approximately 20% of patients with lupus [47]. Ophthalmic symptoms associated with lupus may include a lupus rash on the eyelids, conjunctivitis, dry eyes, glaucoma, and cataracts [47]. In severe cases, retinal exudates or blindness may occur.

Therapeutic Measures

There is currently no cure for lupus, and long-term disease management is required. Due to the variability of lupus symptoms, treatment protocols differ for each individual. The range of treatments, however, are increasing in number and becoming more effective; thus, the disease can be controlled reasonably well in most people. The ultimate goal of treatment is to suppress immune system abnormalities, prevent disease flares, and reduce inflammation and other complications secondary to lupus [51].

Treatment is based on such factors as symptoms and severity, overall general health, activity level, school and/or family schedule, age, family and social situations, other medical conditions, and financial and insurance considerations [50].

Although there is no cure for lupus, there are several types of drugs available to aid in the treatment and management of secondary symptoms. Among these drug classes are nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antimalarials, biologics, and immunosuppressives. In cases of severe lupus kidney disease not helped by pharmacologic intervention, dialysis or kidney transplant may be necessary.

Specific Nursing Measures

Nurses may see patients with SLE in both inpatient and ambulatory care settings. Discovering early symptoms and signs of exacerbations and complications is important in prolonging the life of patients with SLE. Carefully monitor all diagnostic study reports to remain well informed about the patient's progress [46].

Individuals diagnosed with lupus are encouraged to do all of the following [47,49,50,51]:

- Get plenty of physical and emotional rest.

- Maintain a healthy diet.

- Establish an exercise regimen.

- Avoid sunlight.

- Seek prompt treatment of infection.

- Limit stress.

- Set realistic goals and priorities.

- Maintain effective communication with their healthcare providers.

- Develop a support system, including family, friends, healthcare professionals, community organizations, and organized support groups.

- Avoid triggering or aggravating factors.

- Seek regular health care.

Eight to 10 hours of sleep per night along with naps are recommended for patients with lupus. In addition, individuals with lupus should minimize stress to reduce emotional distress, as well as avoid direct prolonged sunlight, especially during the hours between 10 a.m. and 4 p.m. The use of a sunscreen with a sun protective factor (SPF) of 15 or greater that protects against both ultraviolet A and B rays is recommended along with protective clothing such as long sleeves and a hat [47]. Routine exercise is important to reduce fatigue and maintain joint mobility.

Social support can have a positive impact on individuals diagnosed with lupus. However, seeking and gaining social support can be difficult when one is experiencing a chronic illness such as lupus, because tremendous energy is necessary to maintain social networks [64]. Lupus symptoms, as well as treatment side effects, can present a challenge for individuals in maintenance of their pre-illness social relationships and activities. Furthermore, to gain necessary support, individuals with lupus should understand and then communicate to others what they need to assist them in managing their disease.

Keller noted similar findings in her research on social support and psychologic distress in women with lupus. She concluded that "younger women with lupus were more psychologically distressed than older women with lupus and that women with shorter duration since diagnosis were more distressed" [65]. Keller also found that the perception of having social support and being satisfied with the social support were more important than the number of social supports [65]. Thus, perception of and satisfaction with social support has been found to reduce psychologic distress.

One important potential source of assistance can be support groups. It has been noted that "participating in a support group can provide emotional assistance, boost self-esteem and morale, and help to develop or improve coping skills" [51]. Successful support groups can assist patients to gain insights into how to live with their lupus [66]. Darner found that women with lupus who had been diagnosed for longer periods of time had a healthier psychosocial adjustment [67]. Therefore, those newly diagnosed with lupus may require more support and interventions to aid in psychosocial adjustment.

Systemic Scleroderma

Systemic scleroderma, also called sclerosis, is an autoimmune connective tissue disorder that causes fibrous changes in the skin, synovium, and small arteries of the digits, as well as in various internal organs, most notably the esophagus, intestines, heart, lungs, kidneys, and thyroid. The disease occurs in various forms, ranging from a primarily skin condition (localized scleroderma) to the CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, which is thought to be more benign, to involvement of visceral organs (systemic scleroderma). Some patients with mild-to-moderate types of scleroderma can progress to the visceral and more extensive cutaneous lesions associated with systemic scleroderma [46].

In all forms of the disease, there is vascular injury at the level of small arteries and capillaries, and the resulting decrease in circulation is the cause of the tissue changes. The precipitating factor for the onset of systemic scleroderma is not clear, although there is some evidence that genetic and environmental factors play a role. Silica and certain organic solvents are recognized as risk factors of occurrence of systemic scleroderma. In addition, the prevalence of the disease is 13 times higher in first-degree relatives of patients than in the general population [68]. The result is an activation of the immune system, causing blood vessel damage and injury to tissues that result in scar tissue formation and the accumulation of excess collagen.

There are no definitive tests to diagnose systemic scleroderma, and diagnosis is primarily based on clinical evaluation. Autoantibodies occur in this disorder, and the ESR may be elevated. As part of the diagnostic workup, the following tests may be performed [68]:

- Nailfold capillaroscopy

- Screening for antinuclear antibodies (mainly anti-centromere and anti-scl70/anti-topoisomerase antibodies)

- Transthoracic echocardiography

- High-resolution computed tomography (CT) of the chest

- Diffusing capacity of the lung for carbon monoxide and spirometry

- Hand x-ray

- Esophageal manometry

Clinical Manifestations

The most frequent presentation in systemic scleroderma is the clinical triad of skin changes, Raynaud phenomenon, and esophageal hypomotility. However, manifestations are often present in other organ systems, requiring continual monitoring [46].

The most typical changes in all types of scleroderma occur in the skin. Typically, skin changes begin with swelling of the hands and gradual thickening, tightening, and hardening of the skin of the fingers (sclerodactyly). The fingers become tapered and in severe cases claw-like, with impaired mobility. Ulcers may develop on fingertips and over knuckles as the skin becomes taught. Skin changes can progress proximally at a slow rate, eventually affecting the face. In these cases, the skin of the face becomes tight and shiny, with a loss of normal wrinkles and skin folds. The nose may become beaked, and sometimes radial furrowing is seen around the mouth. Patients may experience an impaired ability to fully open their mouths. In extreme cases, the face becomes expressionless [46].

Most patients with systemic scleroderma have Raynaud syndrome, and this is often the first symptom to appear. With Raynaud syndrome, there is diminished blood flow to the digits secondary to vasoconstriction of the digital arteries, typically triggered by cold, vasoconstriction drugs, or emotional states. The initial sign is digital pallor, which progresses to cyanosis, then to erythema on rewarming [46].

The patient may have pain and stiffness in both small and large peripheral joints. Occasionally, patients develop arthritis and synovial effusion. Contracture and atrophy of the fingers may eventually occur [46].

Hypomotility of the esophagus occurs in most patients with systemic scleroderma. This typically presents as gastroesophageal reflux, with resulting heartburn and stricture, and potentially difficulty swallowing. In some cases, patients require esophageal dilation. Gastrointestinal involvement can progress to the intestine and colon, with development of hypomotility of the small intestine and wide-mouth diverticula [46]. In patients with gastrointestinal involvement, impaired nutrition is common.

Systemic scleroderma can also cause cardiopulmonary problems. Dyspnea may develop as a result of pulmonary hypertension and interstitial fibrosis. The examiner may hear fine dry rales or crackles at the bases of the lungs, and spirometry is often abnormal. Manifestations involving the heart are primarily the result of lung complications, but dysrhythmias, conduction disturbances, pericarditis, and pericardial effusions uncommonly occur [46].

In some patients, the kidneys can be seriously affected, with malignant hypertension rapidly producing renal failure, the leading cause of death for these patients. High renin levels and proteinuria are signs of kidney involvement [46].

Hematologic problems, in addition to a mild normochromic, normocytic anemia, include vitamin B12/folic acid deficiency anemia, which may occur secondary to bacterial overgrowth in an atonic small intestine. There is also a risk for gastrointestinal bleeding and resultant iron-deficiency anemia [46]. Other manifestations include thyroid disease, biliary cirrhosis, trigeminal sensory neuropathy, and Sjögren syndrome [46].

Therapeutic Measures

Treatment of systemic scleroderma is symptomatic and driven by the stage and organ involvement of the disease. In its 2017 guideline for the treatment of systemic scleroderma, the EULAR has established guidelines for the management of manifestations, organized by affected body system [69]. For patients with systemic scleroderma-associated Raynaud phenomenon, evidence supports nifedipine to reduce the frequency and severity of attacks. As such, oral nifedipine should be considered as first-line therapy. Phosphodiesterase-5 (PDE-5) inhibitors should also be considered [69]. For patients with severe disease who do not improve on oral therapy, intravenous iloprost is the recommended approach.

Intravenous iloprost is also recommended for patients with systemic scleroderma who experience digital ulcers [69]. PDE-5 inhibitors have been proven to expedite healing and prevent the development of digital ulcers and should be considered for these patients. Patients who do not respond to calcium channel blockers, PDE-5 inhibitors, or iloprost therapy, may be prescribed bosentan, which has been shown to reduce the number of new digital ulcers in patients with systemic scleroderma. Physical therapy for the hands is important to prevent contractures. For patients with Raynaud phenomenon, biofeedback is sometimes useful for controlling temperature in the hands and feet [46].

For patients whose systemic scleroderma is characterized by pulmonary arterial hypertension, EULAR recommends treatment with endothelin receptor antagonists (e.g., ambrisentan, bosentan, macitentan), PDE-5 inhibitors (e.g., sildenafil, tadalafil), or riociguat [69]. In cases of severe disease, intravenous epoprostenol is the first-line option. In cases of malabsorption by the small intestine, absorption often improves with the use of tetracycline, which destroys the bacterial overgrowth that occurs with hypomotility [46].

Hypertension is treated aggressively with angiotensin-converting enzyme (ACE) inhibitors to prevent irreversible renal damage [46]. The risk for scleroderma renal crisis in increased in patients taking glucocorticoids, and these patients should be closely monitored [69].

Arthritis responds to NSAIDs, and the dry eyes (sicca syndrome) of Sjögren syndrome are helped by artificial tears. A patient with dry mouth (xerostomia) should have frequent dental exams, because this condition predisposes patients to severe dental caries [46].

Specific Nursing Measures

Patients with known or suspected systemic scleroderma should be thoroughly assessed, including the skin, joints, and cardiovascular, pulmonary, and gastrointestinal status. The eyes and mouth should be evaluated for adequate lacrimal and salivary gland secretions. It is important to closely monitor blood pressure and review laboratory results. Venipuncture in the antecubital area may be difficult because of skin changes; further, finger sticks should be avoided. If only a small amount of blood must be drawn, the earlobe may be the best site [35].

Patient education should include a clear explanation of the nature and course of systemic scleroderma, including signs of more serious involvement. For some patients, demonstration of range-of-motion exercises to prevent joint contracture may be warranted. Patients should be encouraged to use moisturizing lotions to decrease dryness [35].

Patients with Raynaud phenomenon are advised to avoid cold, ergotamine, and amphetamines. They should be cautioned to take precautions against cold weather, including the use of warm gloves and socks. The use of nicotine should be avoided, as it is associated with pronounced peripheral vasoconstriction, which markedly aggravates Raynaud syndrome [35].

Patients with esophageal dysmotility should be advised to eat small, frequent meals and to chew their food thoroughly; meals should be followed with water. Proton pump inhibitors (PPIs) and antacids after meals and at bedtime can help to help to relieve gastroesophageal reflux disease. Resting and sleeping with the head of the bed elevated may also help to relieve symptoms [35].

The face and hands often undergo considerable changes in scleroderma, which alters the patient's appearance and manual dexterity. The facial skin becomes taut, the nose may become beaked, and telangiectasias may appear on the face. Tapering of the fingers, with tightness of the overlying skin, occurs as flexion contractures may be present [35]. These physical changes may cause varying levels of disability, but they can also have a negative effect on the patient's self-esteem and self-worth. Referral to mental health care and participation in support groups can be helpful.

TRAUMATIC DISORDERS

Sprains and Strains

Traumatic injuries to the soft tissues surrounding joints—muscles, ligaments, and tendons—are called sprains and strains; chronic injury is joint instability. The acute injury may arise from blunt trauma to the muscle or joint; excessive exercise; or twisting, stretching, or forcible extension of a joint (e.g., "twisting" the ankle). Surgery is seldom needed unless complete rupture occurs, but the pain of such an injury can be severely limiting [70].

A sprain is an injury to a ligament caused by forcing a joint beyond its normal range of motion. The ligament may be stretched or actually torn. Sprains usually occur following a blunt blow during sports activities or falls. A strain is an injury to a muscle and/or tendon at any location from origin to insertion.

Strains are associated with excessive stretching of a muscle or muscle unit; they usually do not occur because of a blow or direct trauma. Poor conditioning, improper warm-up before activity, muscle fatigue or weakness, and strength imbalance can all contribute to muscle or tendon strain. Both strains and sprains have a high incidence of recurrence [70].

Clinical Manifestations

A sprain causes pain, swelling, local hemorrhage, spasm of the muscle that moves that joint, and disability. Pain occurs with passive movement of the joint, and there is intense pain over the involved ligament itself. Sprains are graded according to damage to the ligaments and the resultant joint instability [70]. A Grade I sprain is characterized by slight stretching and microscopic tearing of the ligament fiber, mild tenderness, and swelling around the joint. A Grade II sprain is identified by partial tearing of the ligament, moderate tenderness and swelling, and an abnormal looseness in the joint. The most severe is a Grade III sprain, which consists of a complete tear of the ligament, significant swelling and tenderness, and substantial instability.

The most common sprains affect the ankle and occur when inversion of the foot tears a ligament, usually the anterior talofibular ligament. Knee sprains cause swelling, hemarthrosis, significant decrease in range of motion, and joint laxity. Often the person hears a "pop" when the injury occurs and later describes the knee as feeling as it is going to "give way." The medial collateral ligament is most commonly involved [70]. Following the acute injury, patients are usually able to bear weight.

Strains cause pain, swelling, muscle spasm, and hemorrhage into the muscle. Discoloration and weakness may also be present. Pain increases with active flexion or passive stretching, which helps in differentiating strains from sprains. Strains are graded according to loss of muscle strength [70,71]:

- Grade 1: A mild injury with no appreciable tissue tearing and no substantial (less than 5%) loss of function or strength

- Grade 2: A moderate injury with nearly half of muscle fibers torn, reduced strength, and some residual function

- Grade 3: A severe injury resulting from the complete rupture of the muscle, severe swelling and pain, and complete loss of function

Therapeutic and Specific Nursing Measures

Approaches to the treatment of strains and sprains are similar. Before initiating treatment, a thorough assessment and history to determine the nature and cause of the injury as well as any significant health problems that may influence the treatment. When a suspected strain or sprain occurs, the first-line treatment consists of five components known by the acronym PRICE:

- Protection: The affected joint or muscle should be covered to minimize the risk of additional traumatization.

- Rest: The patient should take steps to avoid use of the joint, tendon, or muscle to allow time for repair and healing.

- Ice: The application of cold will reduce pain and swelling (by causing vasoconstriction), and patients should be instructed to apply cold compresses up to several times per day, but to limit duration to 20 minutes or less.

- Compression: In order to reduce diapedesis and promote lymphatic drainage, the area may be bandaged. Patients should be instructed that wrappings should not be so tight as to restrict circulation.

- Elevation: The affected limb should be elevated to the level of the heart (or as close as possible) to promote venous return and reduce inflammation.

The PRICE regimen is usually continued for one week after injury, though there is some controversy about whether cold or heat is used after the first 24 hours. Cold is usually recommended for five to seven days because of its anti-inflammatory and analgesic effect. Then, wet heat may be used to aid in muscle relaxation and promote blood flow to the area [35].

With a second- or third-degree sprain, an x-ray should be taken to rule out fracture. Patients with sprains are usually immobilized for one week. When all pain on motion has ceased, patients can begin active range-of-motion and muscle-strengthening exercises. NSAIDs are the treatment of choice [35].

The PRICE regimen and NSAIDs are also appropriate for management of a strain. Emphasis is placed on prevention of recurrence through the use of muscle-strengthening and stretching exercises. Patients should be advised to engage in warm-up exercises before engaging in strenuous activity. For example, for patients with chronic ankle sprain/instability, slow stretching of the Achilles tendon daily can effectively reduce the incidence of recurrent sprain. Surgical intervention is recommended only in cases of complete muscle rupture [35].

Rhabdomyolysis

Rhabdomyolysis is a condition that develops as a result of the rapid dissolution of damaged or injured skeletal muscle [72]. Though not strictly a traumatic disorder, the most common cause of rhabdomyolysis is direct trauma to the skeletal muscle. However, any trigger of muscle destruction can theoretically result in rhabdomyolysis, and additional causes include infection, drugs/toxins, electrolyte disorders, endocrine disorders, extremes of body temperature, and excessive exertion [73].

As discussed, the function of skeletal muscle relies on ATP metabolism, electrolyte exchange, and intact myocytes. When these factors break down, the intracellular components of the muscle (e.g., electrolytes, creatine kinase, lactate dehydrogenase, myoglobin) are released into the body and enter the bloodstream. In more severe cases, this can lead to acute kidney injury, electrolyte imbalances, renal failure, and even death.

Clinical Presentation

The presentation of rhabdomyolysis is typically believed to consist of muscle pain, weakness, and discolored (reddish-brown) urine. Though this is considered the "classic" triad of symptoms, less than 10% of patients will present with all of these symptoms [73]. More than half of patients present only with myoglobinuria.

Diagnosis of rhabdomyolysis depends on detection of plasma creatine kinase. A diagnostic level has not been definitively identified, but most experts use a concentration five times the upper limit of the normal reference range (1,000 IU/L) [72].

Therapeutic Measures

Treatment of rhabdomyolysis focuses mainly on prevention of kidney damage and acute renal failure. Therefore, fluid therapy to increase urine output (and dilute urine) is the standard of care. The American Society of Nephrology has identified an ideal fluid regimen for these patients consisting of half isotonic saline (0.45%, or 77 mmol/L sodium), to which 75 mmol/L sodium bicarbonate is added [74]. At least 3–6 L should be administered per 24 hours; however, up to 10 L (or more) may be given if continuous supervision is possible. If necessary, 10 mL/hour of mannitol 15% may be added to further increase urine output. In cases that have already progressed to overt renal failure, extracorporeal blood purification is warranted [74].

In addition, supportive treatment of resultant hypovolemia and electrolyte imbalances (e.g., hyperkalemia, hypocalcemia) is necessary. Measures to help stabilize temperature are often necessary. Patients' input and output should be monitored and documented. Pain management is often necessary, and patients should be assessed for severity and quality of ongoing pain.

8. SPECIFIC DISORDERS OF THE JOINTS

Because of their location and constant use, joints are particularly susceptible to stress, injury, and inflammation. In addition, many autoimmune disorders manifest in the joints.

DISORDERS OF MULTIFACTORIAL ORIGIN

A wide variety of joint conditions are multifactorial in origin, including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, gout and pseudogout, low back pain, scoliosis, Charcot arthropathy, and carpal tunnel syndrome [37,75].

Joint disorders of multifactorial origin can disrupt normal life activities, and families and job security can be negatively affected unless patients seek proper medical attention and counseling. Among the disorders discussed in this section, only gout can be cured, but the other disorders can be controlled to varying degrees so that in most instances the patient can maintain a fairly normal lifestyle [37,75].

Psoriatic Arthritis

Psoriasis is often associated with inflammatory arthritis and a negative rheumatoid factor. Psoriatic skin lesions usually precede the development of arthritis, and in most cases, there is correlation between joint flares and skin flares. However, some patients with psoriatic arthritis have very mild or no psoriatic skin lesions. Heredity is the most specific risk factor, but environmental factors also play a role; the exact etiology is unknown [76].

Clinical Manifestations

The manifestations of psoriatic arthritis vary from patient to patient. Some have distal joint involvement, while others have widespread deformity, ankyloses, and joint destruction. The disease can be symmetrical or asymmetrical, and some patients have spondylitis, sacroiliitis, eye problems, or a combination. Nodules are not present with psoriatic arthritis [76].

In patients with psoriasis, silver-white scaly patches develop on the elbows, legs, scalp, and back. Nails are often pitted (20 pits or more per nail), and arthritis is more common with nail changes than with skin lesions. Onycholysis is common [76].

Joint symptoms usually begin with the acute onset of pain and swelling of distal interphalangeal (DIP) joints. A gout-like symptom in the great toe often gives a "sausage" appearance to the joint, but the disability is usually not as great as with rheumatoid arthritis. Spondylitis is often found in families with a strong background of psoriatic arthritis. Upon x-ray examination, some people show marked articular destruction with resorption of bone. A shortening of the middle phalanx of the DIP joints of fingers and toes has a characteristic cuplike appearance, and in some cases, an entire phalanx is destroyed. Extra-articular symptoms include conjunctivitis, episcleritis, or uveitis [76].

Laboratory studies of patients with psoriatic arthritis reveal mild anemia, an elevated ESR, negative rheumatoid factor, positive ANA, and an elevated uric acid level. Clinical diagnosis is made by considering nails, peripheral arthritis, and spinal involvement. Nail and skin changes in psoriatic arthritis may be hard to differentiate from those in reactive arthritis [76].

Therapeutic Measures

Therapeutic measures for psoriatic arthritis are aimed at both the arthritis and the psoriasis [76]. Nonpharmacologic approaches include physical and occupational therapy, exercise, smoking cessation, weight loss, and massage therapy. Symptoms may be controlled with NSAIDs and/or glucocorticoids (oral or injection). In treatment-naive patients with active psoriatic arthritis, a tumor necrosis factor (TNF) inhibitor is recommended over oral, small-molecule drugs (OSMs) as a first-line option. However, OSMs may be used instead of a TNF inhibitor in patients without severe disease, particularly if they prefer an oral treatment option [77].

Gout

Gout is a metabolic disorder associated with elevated urate levels in the body and is the most common cause of inflammatory arthritis in the United States. Gouty arthritis is characterized by recurring episodes of acute, usually monoarticular, arthritis that tend to remit over several days to weeks; however, undiagnosed, untreated patients are at risk for developing a chronic deforming arthritis. An estimated 9.2 million adults in the United States are affected [78]. Gout is rarely encountered in persons younger than 30 years of age, with the predominant age range being 30 to 60 years. However, onset may occur in men in their early 20s who have a genetic predisposition and lifestyle risk factors. The peak age of onset in women is the sixth to eighth decade of life [78]. The estimated prevalence of gout is 5.9% in men and 2.0% in women [78]. The prevalence and incidence of gout has increased over the past several decades [78,79].

Evidence Based Practice Recommendation

The American College of Rheumatology conditionally recommends that patients with gout limit their consumption of purine-rich foods (e.g., meat and seafood), alcohol, and high-fructose corn syrup (particularly in sweetened soft drinks and energy drinks).

https://www.rheumatology.org/Portals/0/Files/Gout-Guideline-Final-2020.pdf

Last Accessed: September 26, 2022

Certainty of Evidence: Low or very low

Gout develops in persons with hereditary or acquired chronic hyperuricemia or in those with marked perturbations in serum urate associated with such factors as alcohol consumption, drug use, eating foods high in purines, overweight/obesity, and myeloproliferative disorders [78,80]. The normal serum urate is generally considered to be ≤6.8 mg/dL. The majority of patients at the time of an acute flare have demonstrable hyperuricemia (in excess of 7 mg/dL); however, about 20% do not. The presence of hyperuricemia in the absence of symptoms is not diagnostic of gout [78]. In all cases, the hyperuricemia is caused by some dysregulation in the balance between production and excretion of urate. An estimated 80% to 90% of gout cases are due to urate underexcretion and not overproduction [78]. Hyperuricemia can occur without precipitating gout, and in the absence of symptoms, it may not warrant intervention [78,81].

Uric acid is a final metabolic product of purine nucleotides found in many foods and in human tissue. Intermediary processes of purine metabolism include the initial breakdown of purines to inosine and then to hypoxanthine. Hypoxanthine is metabolized to xanthine, and xanthine to uric acid, with both stages catalyzed by the enzyme xanthine oxidase (the primary site for pharmacologic intervention by allopurinol) [82].

The human body is limited in its capacity to excrete a heavy urate load. In the setting of persistent hyperuricemia, often combined with stress to weight-bearing joints such as the great toe, monosodium urate crystals precipitate within joint synovial fluid, producing an intense inflammatory reaction. With chronicity, adjacent tissues may become saturated with urate, leading to deposits within articular, periarticular, bursal, bone, auricular, and cutaneous sites. These deposits, termed tophi, are detectable on physical exam or by radiographs and are a cardinal pathognomonic feature of gout. The presence of crystals, within joint fluid or in tissue, activates monocytes and macrophages to clear the crystals through phagocytosis. The release of proinflammatory cytokines and chemokines into the immediate area triggers an acute inflammatory reaction and influx of neutrophils into the joint space [83,84,85].

Clinical Manifestations

The clinical presentation of gout is typically one of arthritis and intense pain, and patients may exhibit inflammation and edema in the afflicted joint. Although the great toe is the most common site, other joints and their surrounding tissue can be affected, including the insteps, ankles, heels, knees, wrists, fingers, and elbows [78]. Gout may be confused with other causes of arthritis as all forms share the cardinal signs of inflammation: pain, redness, warmth, tenderness, and swelling [80,86]. While gout initially manifests in severe, discrete episodes of pain, the condition may progress to more frequent attacks with shorter asymptomatic periods between attacks [78,86]. Synovial fluid analysis is the gold standard for diagnosing gout, confirmed by the presence of monosodium urate.

Therapeutic and Nursing Measures

Gout is perhaps the most easily treated, and preventable, form of arthritis. This is due to widespread understanding of its underlying mechanisms and the availability of effective treatment [80]. It is managed by controlling the current acute attack and preventing future attacks. Medications addressing the underlying pathophysiology include the xanthine oxidase inhibitors (XOIs) allopurinol and febuxostat and the uricosuric agents probenecid, fenofibrate, and losartan [80,87]. (Note: The use of fenofibrate and losartan for the treatment of gout is off label.)

The initial steps include patient education, testing to rule out other causes of hyperuricemia, and evaluation of the disease burden to determine appropriate treatment. All patients with hyperuricemia and established gout should be advised to begin dietary modification. This involves avoiding organ meat high in purine content, high-fructose corn syrup, and excessive alcohol use. Portions of high purine-content seafood, sugar, and salt should be limited. The ideal diet will include low- or non-fat dairy products and vegetables. Other lifestyle modifications can also assist in managing gout, including weight loss in overweight patients, regular exercise, smoking cessation, and adequate hydration [83,87,88].

The acute pain of gout may be treated with NSAIDs, a cyclooxygenase-2 (COX-2) inhibitor, systemic corticosteroids, or oral colchicine monotherapy in mild-to-moderate disease (≤6 on a 10-point pain scale). Combination therapy (i.e., colchicine and NSAIDs, oral corticosteroids and colchicine, or intra-articular steroids with each of the other options) may be used in cases of severe disease with intense pain and polyarticular presentation. Intramuscular triamcinolone acetonide is recommended in patients unable to take oral medication or likely to be poorly adherent to the multidose oral regimen [87].

An inadequate response to therapy after escalation (<20% pain reduction within 24 hours or <50% pain reduction after ≥24 hours) should prompt reconsideration of the diagnosis. If gout is confirmed, switching to another form of monotherapy or adding a second agent may prove effective [83,87].

Urate-lowering therapy should be initiated in all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flares [88]. Therapy should be started within 24 to 36 hours of the onset of an acute gout attack unless otherwise contraindicated. Urate-lowering therapy is not recommended for patients experiencing their first flare, or for patients with asymptomatic hyperuricemia (serum urate >6.8 mg/dL) with no prior gout flares or subcutaneous tophi [88]. Allopurinol (≤100 mg/day) is the preferred first-line agent. Febuxostat (≤40 mg/day) is an acceptable alternative [88]. Probenecid may be used as an alternative to allopurinol or febuxostat if there is contraindication or intolerance to these preferred agents. However, probenecid should be avoided in patients with a history of urolithiasis [83,87,88].

Clinicians may also consider screening for the HLA-B*5801 allele, which is associated with high risk of severe allopurinol hypersensitivity reaction. High-risk persons include Koreans with an estimated glomerular filtration rate <60 mL/min/1.73 m2 or those with Han Chinese or Thai ancestry [89].

Anti-inflammatory prophylaxis (against precipitating an acute flare) is recommended when initiating urate-lowering therapy in asymptomatic patients [88]. Colchicine was once the treatment of choice but is now less commonly used than NSAIDs because of its narrow therapeutic window and risk of toxicity [90]. To be effective, colchicine therapy is ideally initiated within 36 hours of onset of the acute attack [78]. In the case of colchicine intolerance or contraindication, prednisolone may be used [88]. Prophylaxis should continue after achieving target serum urate level for three months in patients without tophi, for six months in patients with resolved tophi, and with any remaining signs of gout activity in all patients [88].

Patients with intermittent symptoms or chronic synovitis with tophi (chronic tophaceous gouty arthritis) should be treated with a single-agent XOI, such as allopurinol, at a dose to achieve and maintain the serum urate level within normal range [83,87]. If the serum urate target is not achieved or disease activity persists, a uricosuric agent may be added to the XOI. Pegloticase therapy should be considered if the serum uric target is not achieved, disease activity persists, more than seven attacks occur per year and no tophi, two or more attacks per year and tophi, or chronic tophaceous gouty arthritis is present [88,89].

Pseudogout

Calcium pyrophosphate deposition disease, or "pseudogout," is a similar crystalline arthritis that occurs in patients with underlying osteoarthritis and is identified by the presence in synovial fluid of calcium pyrophosphate dehydrate crystals [78,80,85]. X-ray findings of articular cartilage calcification usually accompany it. Many patients with pseudogout have other disorders, such as diabetes, hypothyroidism, and gout [37].

Clinical Manifestations

In pseudogout, arthritis occurs in a large joint, which is erythematous, swollen, warm, and painful. Like gout, pseudogout is usually monoarticular, but involvement of other joints can follow in succession. Attacks are often precipitated by trauma, surgery, or medical illness. Onset of symptoms is rapid, with a peak in 12 to 36 hours. Episodes are intermittent, usually involve the same joint, and typically last about one to two weeks. Joints are normal between attacks [37].

Therapeutic and Nursing Measures

The deposition of calcium pyrophosphate dihydrate crystals cannot be reversed. Acute attacks of pseudogout are treated with NSAIDs, colchicine, and/or oral corticosteroids; in more severe cases, drainage of the affected joint may be helpful [37].

Nursing measures for pseudogout include careful joint assessment, thermo- or cryotherapy, and monitoring for symptoms and signs of systemic illness and side effects of medications [18]. Patient education for home care includes instruction in the safe application of heat or ice, range of motion exercises, and the nature and side effects of prescribed medications. A weight-reduction diet can be helpful promote the long-term health of weight-bearing joints [18].

Low Back Pain

When it occurs, back pain is most often localized to the lower back, and chronic back pain is almost always chronic low back pain. Although acute-onset low back pain 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 low back pain continues beyond 12 weeks, the prospect for subsequent remission is poor and progression to chronic low back pain is likely. Chronic low back pain imposes a great burden: for patients, pain and disability; for society and the healthcare system, an enormous expense in direct and indirect costs.

Risk factors for developing low back pain 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 low back pain episodes are single-event or repetitive exposures to mechanical stress and age-related degenerative spinal changes. With chronic low back pain, mechanical and biophysiologic factors play a minimal secondary role to the primary contribution from psychosocial factors [91].

Clinical Manifestations

The onset of low back pain is described as discomfort in the vicinity of the low back ranging from a dull ache to a sudden, sharp, shooting or stabbing pain and may include limited flexibility and/or range of motion or inability to stand straight [92]. Although the symptoms of back pain can originate anywhere from the thoracic spine to the sacrum and coccyx, most cases originate in the lumbar spine, as this is the site of support for upper body weight [92].

With low back pain, the clinical presentation varies according to etiology. In general, radicular pain suggests nerve root involvement, while axial pain suggests disk degeneration, facet arthropathy, sacroiliac (SI) joint arthropathy, or myofascial pathology of the spine.

Nonspecific Low Back Pain. Up to 85% of low back pain in patients presenting to the primary care setting is nonspecific, meaning that it lacks a clear origin and is not caused by specific local or systemic disease or spinal abnormality [93]. Nonspecific low back pain is a diagnosis of exclusion made after ruling out serious causes of the back pain. Although pain can originate from ligaments, facet joints, muscle, fascia, nerve roots, the vertebral periosteum, or outer portions of the disk, the effective management of nonspecific low back pain does not require a precise anatomic diagnosis [94]. The pain is usually unilateral and may radiate to the buttocks or posterior thigh but not past the knee. This can lead to incorrect diagnosis of radiculopathy or disk herniation. However, true radicular symptoms radiate below the knee in a dermatomal distribution and can involve sensory loss, weakness, or reflex changes. Painful spasm may be present, and pain may be worsened by movement, while lying flat decreases the pain. Complaints of numbness, weakness, or bowel or bladder dysfunction are absent [95]. Degenerative changes revealed by lumbar imaging should usually be considered nonspecific, because they poorly correlate with symptom severity [96].

Lumbosacral Radiculopathy. Lumbosacral radiculopathy is a clinical diagnosis of nerve root irritation and compression, resulting in a symptom distribution of the affected lumbar or sacral nerve root such as numbness, weakness, or paresthesia. Sciatica is the most common symptom of lumbar radiculopathy and refers to pain that radiates down the leg below the knee in the distribution of the sciatic nerve to indicate nerve root compromise from mechanical pressure or inflammation [96].

Causes of lumbar radiculopathy include disk herniation, arthritic degeneration, cord compression, spinal stenosis, tumor, and infection. With herniated disk, the pain is described as a deep, aching, axial midline pain concurrent with radicular pain. Discogenic pain results from a tear in the outer disk layer (annulus fibrosis) that causes the inner gelatinous material (nucleus pulposus) to prolapse, inflame, and compress a nerve root [95]. The resulting pain from pressure and nerve irritation improves with the resolution of local inflammation, and the disk protrusion may spontaneously remit with time. Although disk herniation and radiculopathy are often viewed as causally linked, herniation is often asymptomatic and only occasionally the cause of sciatica [95].

Lumbar Spinal Stenosis. Lumbar spinal stenosis refers to the frequently age-related narrowing of the spinal canal that may result in bony constriction of the cauda equina and the emerging nerve roots [96]. Spinal stenosis can produce pain in the low back that radiates down the back of both legs, often worsened with standing or walking. To make the pain more bearable, patients often walk a short distance with a hunched back, and then sit down for relief. The pain will then dissipate after several minutes. Congenital lumbar canal stenosis is a predisposing factor. Patients show less tenderness over the lumbar spine than those with acute lumbar disk herniation, and the straight leg-raising test may be normal [97].

Most persons 60 years of age and older exhibit varying degrees of spinal stenosis from disk herniation, osteophytes, or degenerative spondylolisthesis. Fortunately, clinical pain manifests in less than 30% and, just as with degenerative disk disease, there is poor correlation between symptom severity and extent of spinal canal stenosis revealed by MRI [95].

Myofascial Pain. Myofascial pain of the low back or neck is common, especially following trauma or repetitive motion injury. This is thought to result from strain or sprain to the muscles and ligaments. Myofascial pain is described as a deep, aching, poorly localized discomfort made worse by activity. It can be limited to discomfort in the paraspinal muscles or may extend to the buttocks and upper thigh areas [98].

Epidural Compression Syndrome. Epidural compression syndrome is an umbrella term that encompasses spinal cord compression, cauda equina syndrome, and conus medullaris syndrome. While these conditions differ in the level of neurologic deficit at presentation, they are otherwise similar in symptoms, evaluation, and management. Massive herniation of a midline disk, typically at the L4 to L5 disk level, is the most common cause of epidural compression syndrome. Tumor, epidural abscess, spinal canal hematoma, or lumbar spine spondylosis represent other causes [95].

In these patients, neurologic status at diagnosis is the greatest predictor of ultimate neurologic outcome and underscores the importance of early accurate diagnosis. The dominant symptom is back pain with accelerating pain severity. Pain from epidural spinal cord compression is made worse with recumbent positioning, and unilateral or bilateral radiculopathy may develop over time. For many patients, leg pain or neurologic symptoms are more dominant than back pain. Also common at diagnosis is symmetrical lower extremity weakness that may have progressed to gait disturbance or paralysis. Decreased lower extremity reflexes are associated with cauda equina syndrome [95].

Lumbar Facet Joint Syndrome. Lumbar facet joint syndrome is seen in as many as 35% of patients with low back pain and is frequently associated with arthritis or lumbar facet joint injury [97]. Dominant symptoms include unilateral low back pain that may radiate down the back or front of the thigh and morning stiffness with isolated facet arthropathy [99]. Tenderness is usually found over the lumbar paraspinal muscles and facet joints. Back pain is worsened with back extension and lateral rotation to the side of the pain, and the leg-raising test is negative. MRI and CT findings of facet joint arthropathy do not correlate with clinical findings [97].

Sacroiliac Joint Syndrome. SI joint syndrome typically manifests as localized pain in the lower back or upper buttock area that overlies the SI joint. Pain is intensified by attempts to walk up stairs, and while pain may be referred to the posterior thigh, extension below the knee is unusual [100]. Tenderness over the SI joint is often found in physical examination, and pain is aggravated by the Patrick test or single-leg standing [97]. The onset of SI joint pain is usually gradual (over months to years), and although etiology is often elusive, trauma, infection, and tumor represent infrequent yet known causes of SI joint pain [100].

Assessment and Diagnosis

Most patients with acute low back pain have ligamentous or muscle strain syndrome, follow a benign course, and show significant improvement within two to three weeks. The challenge for clinicians is to recognize early the possibility of serious disease, such as spinal metastatic cancer or vertebral and epidural space infection, and then to identify those with herniated disk, radiculopathy, or spinal stenosis.

The proper assessment of the patient with back pain requires vigilance and careful attention for factors and warning signs suggestive of serious or life-threatening disorders. A thorough history and physical examination should be performed on all patients, during which the patient is assessed for the presence of warning signs or ''red flags." Red flags represent alarm symptoms or signs that warrant prompt, specific diagnostic testing, urgent treatment, or referral to a specialist. Among these are weight loss, prior history of cancer, nocturnal or rest pain, age older than 50 years, recent trauma, fever and chills, history of injection drug use, chronic corticosteroid therapy, difficulty urinating, bowel or bladder incontinence, and neurologic deficits such as saddle anesthesia, perianal or perineal sensory loss, or motor weakness in the extremities [93,95,101]. As an example, there is a common association between spontaneous vertebral fracture and any combination of age older than 70 years, female gender, recent trauma, and prolonged corticosteroid use. There is also a moderate to highly significant predictive value for age older than 50 years, history of prior cancer, unexplained weight loss, and failure of conservative therapy in identifying spinal malignancy [101].

Patients should also be assessed for "yellow flags," or risk factors for poor prognosis and chronicity [94,101]. Areas to explore include maladaptive beliefs, attitudes, and behaviors regarding the back pain and recovery, such as passivity or reluctance to self-manage, dependency on the provider to "cure," fear avoidance beliefs, and beliefs that harm will come from activity and discomfort. Other areas include depression, anxiety, maladaptive coping response to stress, social withdrawal or isolation, and lack of social support. Adverse economic and work environment circumstances, such as job dissatisfaction, excessive and inflexible physical workplace demands, high levels of work-related stress, poor workplace social support, and adversarial or dysfunctional workplace relationships should also be noted [94]. Early detection and intervention (if indicated) for problematic motivational, emotional, or social dysfunction are important because these factors influence the selection and effectiveness of therapeutic interventions.

In the absence of red flags, use of imaging and diagnostic tests for acute low back pain is discouraged, as imaging findings rarely change clinical management. Overuse of lumbar imaging in low back pain correlates with, and likely contributes to, the two- to threefold increase in surgical rates for low back pain over the last 10 years [93]. Assigning significance to imaging anomalies requires skill at the specialist level to integrate historical, clinical, and imaging findings. Imaging abnormalities are essentially normative by 40 years of age; for instance, 80% of persons 60 years of age and older exhibit a protruding disk, which is symptomatic for only a fraction of patients. Incorrect communication of imaging findings to the patient may lead to patient fixation, contribute to fear-avoidance behaviors, and increase the risk of iatrogenic aggravation of chronic low back pain. Guidelines suggest that physicians without advanced training defer imaging tests to qualified specialists [93,102].

However, imaging and other testing should be performed in patients with new-onset or progressive neurologic deficits and those with suspicion of serious underlying conditions. In patients with persistent pain and symptoms consistent with radiculopathy or spinal stenosis, MRI should be performed only when such patients are candidates for surgery or epidural steroid injection. CT scanning is an alternative option to first-line MRI [93].

Therapeutic Measures

Although acute low back pain improves in most patients within three to six weeks using conservative therapy, up to 33% of patients with low back pain report pain of moderate or greater severity at one-year follow-up and 20% report ongoing pain severe enough to limit activity [96]. With chronicity, low back pain may become disabling and impose a severe emotional and functional burden. The management goals for chronic low back pain are to minimize pain and disability, improve functional status, and facilitate restoration of normal activity, while limiting the use of marginally effective or inappropriate medication [93].

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/guideline/low-back-pain

Last Accessed: September 26, 2022

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

Many pharmacologic therapies and minimally invasive or invasive procedures have been utilized in a strategy designed simply to relieve pain—with variable results. However, there is little evidence these focused pain approaches are comparable or superior to interventions that focus primarily on restoration of function instead of pain relief. This contradicts the biomedical model in medicine that emphasizes escalation of costly and invasive therapies to achieve "pain cure" in patients lacking response to lower-intensity approaches [102,103]. It is now recognized that treatment for conditions such as chronic low back pain persisting in the absence of a unique underlying pathologic lesion must address potential contributory factors such as affective disorders, maladaptive beliefs and coping skills, and interpersonal and occupational dysfunction. Dysregulated cortical, pre-frontal, and higher neural level mechanisms associated with chronic low back pain are being identified and may represent therapeutic targets in functional restoration-based approaches. As with other chronic pain syndromes, greater understanding of pain pathway alterations will better inform therapy selection.

Virtually universal among practice guidelines for chronic low back pain is the emphasis on a multidisciplinary, multi-modal approach that includes exercise and activity, cognitive restructuring of maladaptive attitudes and coping skills, a behavioral component addressing fear avoidance, physiotherapy and manual therapy, and analgesics as indicated [93,96,102,104,105,106,107]. This is often best accomplished by consultation or referral to an established pain treatment center. Multidisciplinary functional restoration programs, which are intensive (more than 100 hours) biopsychosocial interventions whereby physical rehabilitation is combined with cognitive-behavioral therapy and delivered by an interdisciplinary team, embody this recommendation. Moderate-to-strong evidence supports their efficacy in chronic low back pain. They have been found effective in reducing pain and improving physical function, work readiness, and return to work. Weaker outcomes are found in programs that are less intensive or lacking a behavioral component. Patients who do not improve with less intensive therapy options and have high levels of pain, distress, and disability should be considered for multidisciplinary functional restoration programs [94].

Scoliosis

Scoliosis is a lateral curvature of the spine, most commonly in the thoracic area with convexity to the right and compensatory convex curve to the left in the cervical and lumbar areas. Scoliosis can be functional (a result of poor posture or leg-length discrepancy) or structural (a result of deformity of the vertebral bodies, paralysis, congenital malformations, or idiopathic causes). Idiopathic causes are the most common and appear with increased growth during adolescence. It disproportionately affects girls, who are 10 times more likely to be diagnosed than boys at 10 years of age or older [108].

Clinical Manifestations

Symptoms of backache, fatigue, and dyspnea occur only after scoliosis is well established. Untreated scoliosis can result in pulmonary insufficiency from decreased lung capacity, back pain, degenerative arthritis of the spine, intervertebral disease, and sciatica [108]. While screening for idiopathic scoliosis has typically occurred between 10 and 18 years of age, the current evidence is insufficient to assess the balance of benefits and harms [109].

Older patients may exhibit kyphosis, a postural curvature of the spine that is due to aging, disc degeneration, atrophy of spinal muscles, osteoporosis, or vertebral collapse. Adults with kyphosis have a rounded back and possible weakness and generalized fatigue. Kyphosis rarely produces local tenderness except in severe osteoporosis with compression fractures [108].

Therapeutic Measures

Early treatment of scoliosis consists of a combination of physical therapy, bracing, and/or surgery. If the condition is untreated in adolescence, problems that develop can only be treated symptomatically. Any upper respiratory tract infections are treated aggressively to prevent pneumonia and atelectasis [108].

Specific Nursing Measures

Patients with scoliosis often have body image issues and difficulty finding clothes that fit properly. When patients with scoliosis are hospitalized for any problem, careful attention to positioning is essential; improper positioning is not only extremely uncomfortable for the patient, but it can precipitate a vertebral fracture, especially in those with osteoporosis [108].

Carpal Tunnel Syndrome

Carpal tunnel syndrome is generally associated with such umbrella terms as repetitive stress injuries, work-related upper extremity disorders, musculoskeletal disorders, entrapment neuropathies, and cumulative trauma disorders [110,111]. Specifically, carpal tunnel syndrome is a painful disorder of the wrist and hand that occurs when the median nerve (which runs from the hand to the forearm) becomes compressed [112,113].

The carpal tunnel is a narrow passageway on the palm side of the wrist. Surrounded by bones and ligaments, the carpal tunnel houses and protects the tendons of the hand and the median nerve, which controls sensations to the thumb and fingers. When the median nerve becomes pinched or compressed (due to swelling or irritation in adjacent tissues or tendons), the result can be pain, numbness, hand weakness, and in extreme cases, loss of hand function. Cases of bilateral carpal tunnel syndrome have been reported, but typically only one hand is affected [112,114,115]. Carpal tunnel syndrome is rare in children; it usually occurs only in adults [116].

Clinical Manifestations

The symptoms of carpal tunnel syndrome typically appear gradually and may include [114,116]:

- Numbness, burning, or tingling in the fingers and palm of the hand

- Pain in the wrist, palm, or forearm, especially during use

- Decreased grip strength

- Weakness in the thumb

- Sensation of swollen fingers, whether or not swelling is apparent

- Difficulty distinguishing between hot and cold

Symptoms may cause waking during the night with the urge to "shake out" the hand or wrist. Symptoms may occur with activities that require prolonged grasping and/or flexing of the wrist (e.g., driving, holding a book). Left untreated, carpal tunnel syndrome can progress to persistent numbness and permanent loss of hand function. In severe and chronic cases, irreversible muscle damage or atrophy may occur [112,116,117]. Complete sensory loss in the hand has also been reported.

Assessment and Diagnosis

Early diagnosis of carpal tunnel syndrome is important to prevent muscle atrophy or damage to the median nerve that cannot be reversed by treatment [112,116]. Early diagnosis, including a physical examination, medical history, routine laboratory tests, and imaging, can also help to identify or rule out other health conditions that may present with similar signs and symptoms and require specialized treatment [118,119]. The physical examination should include specific testing, such as Phalen's maneuver or Tinel's sign, that can produce the symptoms of carpal tunnel syndrome [114,116]. In elderly patients, particular attention should be given to the objective evidence of carpal tunnel syndrome rather than subjective complaints [120].

Therapeutic and Nursing Measures

Surgery, corticosteroids, NSAIDs, diuretics, wrist splints, exercise, ultrasound therapy, laser therapy, and yoga are among the methods that have been recommended for the treatment of carpal tunnel syndrome [121,122,123,124,125]. Although no single treatment method has been universally accepted, there is agreement that the treatment of carpal tunnel syndrome should begin as early as possible and should include attention to underlying causes, such as diabetes or rheumatoid arthritis. There is also agreement that successful treatment depends on patient compliance with the treatment program [116,126].

Evidence Based Practice Recommendation

According to the American Academy of Orthopaedic Surgeons, strong evidence supports that the use of steroid (methylprednisolone) injection should improve patient-reported outcomes in those with carpal tunnel syndrome.

https://www.aaos.org/globalassets/quality-and-practice-resources/carpal-tunnel/cts_cpg_4-25-19.pdf

Last Accessed: September 26, 2022.

Strength of Recommendation: Strong (Evidence from two or more “high” strength studies with consistent findings for recommending for or against the intervention)

Corticosteroid injection has been found to improve patient satisfaction, symptoms, and function when measured at intervals of 2, 4, 8, and 12 weeks. As noted, it demonstrates a more significant overall improvement in the symptoms of carpal tunnel syndrome than oral corticosteroids but does not appear to provide a better long-term outcome (greater than six months) than splinting or NSAIDs. Two treatment injections do not appear to provide any added benefit when compared to one treatment injection [124,127].

Splinting has been found to improve patient satisfaction, symptoms, and function when measured at intervals of 2, 4, and 12 weeks. The American Academy of Orthopaedic Surgeons suggests that splinting be considered before surgery. This may be particularly helpful when weighing the risks of surgery versus the benefits. Splinting is not recommended for use after routine carpal tunnel release surgery. The benefit of splinting for postoperative rehabilitation is undetermined [126,127,128].

NSAIDs are used to treat a variety of acute and chronic pain conditions, including carpal tunnel syndrome, but opinion varies as to their effectiveness and safety for long-term use [129,130,131]. Specifically, NSAIDs have been associated with gastrointestinal and cardiovascular risks and toxicity with long-term use [132].

Diuretics and vitamin B6 (pyridoxine) may also help with temporary relief of symptomatic carpal tunnel syndrome, but their long-term benefits are unproven [127,131,133]. Acupuncture, yoga, exercise, laser therapy, activity modification, and ergonomic workplace modifications also have been mentioned as non-surgical treatment alternatives, but most experts agree that further research is needed to determine the viability and efficacy of these methods [116,124,126,127,131,134,135].

Carpal tunnel release is the preferred treatment for patients with chronic or severe carpal tunnel syndrome. It is achieved by either an open or endoscopic procedure [116,122,126,128]. Both types of surgery are generally performed on an outpatient basis under local anesthesia. Open release surgery involves making an incision of up to 2 inches at the base of the palm of the hand and cutting the transverse carpal ligament, which releases pressure on the median nerve [116,136]. Endoscopic surgery involves making a small, one-half inch incision at the wrist and introducing an arthroscope beneath the transverse carpal ligament. Using the scope as a guide, the ligament is cut, relieving pressure on the median nerve [116,134,136].

DEGENERATIVE DISORDERS

Osteoarthritis

Osteoarthritis is the most common form of arthritis and is characterized by degeneration of cartilage and its underlying bone within a joint, with resultant bony overgrowth. This process of tissue breakdown eventually leads to pain and joint stiffness [137]. Osteoarthritis develops most frequently in the knee, hip, and hand. Although pain in the lower back and the neck are the most frequently occurring musculoskeletal conditions and are the leading cause of functional limitation and work absences, the etiology of back and neck pain is often unclear, with many cases involving muscles and ligaments rather than osteoarthritic changes [138,139,140].

Osteoarthritis is classified as primary or secondary. The cause of primary osteoarthritis is idiopathic; no abnormality is the cause of changes in the joint [141]. Secondary osteoarthritis is the result of a known cause, most often trauma/injury or systemic diseases. Secondary osteoarthritis is most often found in the shoulder, elbow, and ankle and is more likely to become clinically apparent at a younger age than primary osteoarthritis [141,142,143,144]. A population-based study showed that secondary osteoarthritis related to trauma accounts for approximately 12% of the overall prevalence of symptomatic osteoarthritis of the knee, hip, or ankle [145]. Injuries sustained in sports activities comprise a large portion of post-traumatic osteoarthritis [146]. A wide variety of systemic diseases have been identified as frequent causes of secondary osteoarthritis; these conditions include metabolic diseases, endocrine disorders, bone dysplasias, and crystal deposition diseases [141,147].

Clinical Manifestations

The diagnosis of osteoarthritis at most joints is made primarily on the basis of clinical findings, with imaging studies and laboratory tests more useful for ruling out other diagnoses rather than for confirming the diagnosis of osteoarthritis [148,149,150]. Although radiographic findings are considered to be diagnostic criteria for osteoarthritis, radiographs are not usually part of the initial diagnostic evaluation for several reasons. The primary reasons are the lack of evidence of early osteoarthritic changes on radiographs and the poor correlation between symptoms and radiographic evidence of osteoarthritis [148,151,152,153]. Thus, the absence of radiographic evidence of osteoarthritis in the presence of joint-related symptoms should not exclude the diagnosis of osteoarthritis.

When obtaining a history, questions should focus on the nature of joint-related symptoms, patients' self-reports of limitations in function or activities, and information related to established risk factors for osteoarthritis. The following questions can help elicit important information needed for a diagnosis:

- Do you have any joints that hurt? If so, how long have they been bothering you?

- When does the pain occur? After certain physical activities? At rest?

- Do you have relief of pain if you rest?

- Does the pain bother you at night? Does pain wake you up at night?

- Are your joints stiff when you wake up in the morning? If so, how long does the stiffness last?

- Do the joints that hurt ever lock up or give out on you?

- Do you have a family history of osteoarthritis or rheumatoid arthritis?

- What types of recreational activities or sports do you participate in? If you play sports, do you do so for leisure or competitively?

- What is your occupation? Are there tasks or activities that are part of your job that bother any joints?

- Have you ever had an injury to a joint?

- Are there daily activities or other tasks that you cannot do because of pain or other symptoms in any joint?

The primary symptom of osteoarthritis of the knee is pain, especially with weight-bearing exercise or activity, that improves with rest. Stiffness in the joint occurs in the morning, lasting 30 minutes or less, and may occur after periods of inactivity [154]. The clinical presentation of hip osteoarthritis is similar to that of knee osteoarthritis, with pain being the most common symptom driving individuals to seek medical care [155]. Pain related to hip osteoarthritis is an ache—most often diffuse—that is usually felt during use of the joint and relieved by rest. Pain is typically gradual, variable, or intermittent; the joint may feel stiff after a period of inactivity [155]. The loss of function or mobility is usually related to the degree of pain.

Osteoarthritis of the hand is characterized by pain with use, which affects one or a few joints at any one time, and mild stiffness in the morning and/or after a period of inactivity [158]. The severity of osteoarthritis-related pain varies, and the pain may be intermittent. The joints most often affected are the distal and proximal interphalangeal joints and the base of the thumb [156,157,158]. Individuals who have evidence of osteoarthritis at several joints in the hand are at increased risk for generalized osteoarthritis, and clinicians should evaluate such patients as appropriate [158].

Pain related to osteoarthritis of the shoulder is typically progressive, related to activity, deep in the joint, and often localized posteriorly [142]. Pain is usually present at rest and interferes with sleep, with nocturnal pain becoming more common as the disease progresses. More advanced disease is also associated with stiffness that limits function.

Individuals with osteoarthritis of the elbow typically have pain, stiffness, and weakness in the joint [143]. Later stage disease is associated with pain when carrying a heavy object at the side of the body with the elbow in extension. The history is important when evaluating symptoms related to the elbow because of the strong relationship between trauma or occupation with osteoarthritis, especially in individuals who are younger than 40 years of age [159].

A history of ankle fracture or ligamentous injury is a hallmark feature of osteoarthritis of the ankle [144]. Diagnostic evaluation includes radiographs of the ankles made with the patient standing. MRI is also recommended, as it can provide evidence of osteonecrosis as well as indicate the amount of involvement, the extent of bone loss, and the size of subchondral cysts [144].

Therapeutic Measures

There is currently no curative therapy for osteoarthritis, and treatments to alter or arrest the disease process are few and mostly ineffective [151]. As clinicians on the frontline of care, primary care providers and nurses are typically the first to see individuals with symptoms indicative of osteoarthritis. Primary care providers can coordinate the management of osteoarthritis, and a multidisciplinary approach is best. The ACR and the Association of Rheumatology Health Professionals (a division of the ACR) support such an approach, noting that the healthcare team may include a rheumatologist, primary physician, nurse, nurse practitioner, physician assistant, physical therapist, occupational therapist, physiatrist, psychiatrist, psychologist, orthopedic surgeon, social worker, registered dietician, vocational counselor, and others [160].

Evidence Based Practice Recommendation

According to the American Academy of Orthopaedic Surgeons, oral acetaminophen is recommended to improve pain and function in the treatment of knee osteoarthritis when not contraindicated.

https://www.aaos.org/globalassets/quality-and-practice-resources/osteoarthritis-of-the-knee/oak3cpg.pdf

Last Accessed: September 26, 2022

Strength of Recommendation: Strong (Evidence from two or more "high" quality studies with consistent findings for recommending for or against the intervention.)

The optimal management of osteoarthritis encompasses both nonpharmacologic and pharmacologic measures, beginning with basic modalities and following a so-called pyramid approach as the disease progresses or symptoms do not respond [161]. Several factors should be considered when selecting treatment modalities, including risk factors (e.g., age, comorbidity, overweight/obesity), the level of pain and functional limitations, signs of inflammation, and degree of structural damage [162].

Many treatment options are associated with benefits and risks, and the clinician should discuss the benefits and risks with patients and support their participation in the decision-making process [163,164]. Patient preferences are an important consideration when choosing treatment options and establishing treatment goals, and the ACR advocates care that addresses treatment goals that are meaningful to the individual patient [160]. Decision aids can help enhance patients' knowledge of treatment options, improve patients' participation in their care, and produce realistic expectations of outcomes [164]. Decision aids for osteoarthritis have been developed in a variety of media (e.g., print, online, video) and are available online (https://decisionaid.ohri.ca) [164].

The pain and disability associated with osteoarthritis often has a substantial psychologic and social effect. It is important to discuss these aspects with patients and to address psychologic issues, especially depression, in order for treatment measures to be effective [165].

Specific Nursing Measures

Education and self-management, through lifestyle modifications are universally recognized as the core of treatment in clinical guidelines [166]. This recommendation is based on research showing that education helps patients become more involved in their care, leading to improved outcomes [163]. The Agency for Healthcare Research and Quality notes that an effective partnership is the key to the effective management of osteoarthritis; the healthcare professional's role in this partnership is to [163]:

- Encourage patients to change their behavior to improve symptoms or slow disease progression

- Promote the proper use of medications

- Instruct patients on how to interpret and report symptoms accurately

- Support patients' efforts to maintain normal activities

- Help patients adjust to new social and economic circumstances and cope with emotional consequences

Nurses should emphasize to patients that adhering to the management program will alleviate their symptoms, improve their function, and enhance their quality of life. Education should be tailored to address individual needs. For example, patients who participate in sports should be advised to avoid sports with direct contact and high impact and to wear protective equipment to prevent injury [167]. Similarly, for patients in occupations with high risk for osteoarthritis, clinicians should discuss the importance of avoiding high-risk tasks. It is also essential to encourage patients with osteoarthritis of the glenohumeral joint or the elbow to modify activities that led to the development of the disease [143,159]. Periodic contact during follow-up can help promote self-management [166].

IMMUNOLOGIC DISORDERS

Rheumatoid Arthritis

Rheumatoid arthritis is defined as a chronic inflammatory disease characterized by uncontrolled proliferation of synovial tissue and a wide array of multisystem comorbidities [24]. In its most common presentation, rheumatoid arthritis affects the joints, causing inflammation of the synovium and cartilage and bone loss. The precise etiology of rheumatoid arthritis is presently unknown [26]. Most likely it has an autoimmune origin (whereby an individual's immune system confuses healthy synovial tissue for foreign substances, thereby attacking the synovial joint surfaces) given that autoantibodies (e.g., rheumatoid factor, ACPA) are present and often precede the clinical manifestation of rheumatoid arthritis by many years [22,25,168].

The course and severity of the illness can vary considerably, and infection, genetic factors, and hormones may contribute to the disease. Rheumatoid arthritis appears to require the complex interaction of genetic and environmental factors with the immune system and ultimately in the synovial tissues throughout the body. Triggers for rheumatoid arthritis have long been the target of active research. Purported triggers have included bacteria (Mycobacterium, Streptococcus, Mycoplasma, Escherichia coli, Helicobacter pylori), viruses (rubella, Epstein-Barr virus, parvovirus), and superantigens [25,26,27].

Although rheumatoid arthritis has a clear genetic component, only about 1 in 25 White individuals with the so-called shared epitope develop rheumatoid arthritis [27]. Even if one monozygotic twin has rheumatoid arthritis, there is only approximately a one in six chance that the other twin will develop the same disease. Thus, other factors in addition to genetics are active as precipitators or triggers of rheumatoid arthritis [27].

Clinical Manifestations

Findings on general physical examination are normal except for an occasional low-grade fever (38°C) and a slightly elevated pulse rate. The characteristic patient with rheumatoid arthritis initially presents with complaints of pain and stiffness in multiple joints. There is prominent and prolonged morning stiffness (lasting more than one hour) that usually begins gradually with fatigue, loss of appetite, widespread muscle aches, and weakness [23,25,27].

After this initial presentation, joint pain appears. When the joint is not used for some time, it can become warm, tender, and stiff. After inflammation of the joint, increased synovial fluid is produced and the joint becomes swollen. There is accompanying soft tissue swelling, and joint pain is often felt bilaterally, affecting the fingers, wrists, elbows, shoulders, hips, knees, ankles, toes, and neck [25]. Though the joints are tender, the small joints of the hands and feet are not usually painful when the patient is at rest. Palmar erythema and prominent veins on the dorsum of the hand and wrist indicate increased blood flow. Distal interphalangeal joints are rarely involved. The temperature over the involved joints (except the hip) can be elevated, but there is usually no accompanying erythema. There are limitations in the range of motion, muscle strength, and function around inflamed joints.

In addition, soft, poorly delineated subcutaneous nodules (rheumatoid nodules) are often found in the extensor surface of the forearm. Soft, small lymph nodes are found occasionally in epitrochlear, axillary, and cervical areas [24]. Other symptoms that may present include anemia due to deficits in bone marrow production; eye burning, itching, and discharge; or lung inflammation (pleurisy) [23,24,25,27]. Joint destruction may occur within one to two years after the appearance of the disease.

Rheumatoid arthritis is not solely a disease of joint destruction; it can involve almost all organs. Approximately 18% to 41% of patients with rheumatoid arthritis develop extra-articular manifestations [169,170]. Rheumatoid arthritis may cause inflammation of the outer cardiac lining (pericarditis) and cardiac muscle (myocarditis), leading to congestive heart failure. In a population-based cohort study, patients with rheumatoid arthritis had a significantly higher risk of cardiovascular disease than those without rheumatoid arthritis [171]. More than half of the patients 50 to 59 years of age and all of those older than 60 years of age with a new diagnosis of rheumatoid arthritis had a more than 10% increased risk of cardiovascular disease within 10 years of rheumatoid arthritis onset.

Pulmonary manifestations are also seen in patients with rheumatoid arthritis, occurring in approximately 30% to 40% of patients. In approximately 10% to 20% of these patients, involvement of the respiratory system is the first manifestation of rheumatoid arthritis [170]. There are several types of potential pulmonary manifestations of rheumatoid arthritis: pleural disease, interstitial pneumonitis, and fibrosis. Pleural effusions and pulmonary rheumatoid nodules are the most common manifestations, along with high rheumatoid factor titers [172,173,174]. Pleuritis is more often found in autopsies of patients with rheumatoid arthritis than in living patients. In about 20% of patients, pleuritis develops concurrently with rheumatoid arthritis onset [174]. Although pleuritic pain is not usually a major complaint, the effusions may be large enough to cause dyspnea. Pulmonary fibrosis can either be slowly progressive or result from pulmonary inflammatory disease; on physical exam of the lungs, they present with fine, diffuse, dry rales.

Ocular involvement is another major manifestation of rheumatoid arthritis, usually manifesting as scleritis, development of anterior uveitis, and peripheral ulcerative keratitis (corneal melt) [175,176]. These disorders are associated with inflammatory cytokines produced by ocular mononuclear cell infiltrates [176,177].

Osteopenia and osteoporosis are very common extra-articular complications in patients with rheumatoid arthritis [178]. The development of osteopenia in patients with rheumatoid arthritis appears to occur independent of corticosteroid use and is directly linked to elevated levels of the RANK ligand expressed by T cells, which promotes osteoclastic bone resorption [178,179,180].

Diagnosis

Rheumatoid arthritis is a clinical diagnosis [181]. As discussed, several laboratory tests are recommended for the diagnosis of rheumatoid arthritis, including rheumatoid factor, ESR, CRP, and anti-CCP antibody [22]. While the results of these tests are relatively sensitive and specific, false positives are possible. In 2010, a multi-biomarker disease activity test, Vectra DA, was introduced. This test uses a unique algorithm to derive a composite score (1 to 100) based on the results of 12 blood protein biomarkers, including vascular cell adhesion molecule-1, epidermal growth factor, vascular endothelial growth factor A, interleukin-6 (IL-6), TNF receptor type 1, matrix metalloproteinase-1 or collagenase-1, matrix metalloproteinase-3 or stromelysin-1, YKL-40, leptin, resistin, serum amyloid, and CRP [182,183]. Vectra DA has been independently verified and found to correlate well to disease activity measured with rheumatoid arthritis assessment tools (e.g., Disease Activity Score in 28 joints using the CRP level). The test is validated for use in adults already diagnosed with rheumatoid arthritis but is not intended to diagnose rheumatoid arthritis [184].

There are several other laboratory tests used in the differential diagnosis of rheumatoid arthritis. Complete blood count may reveal mild normochromic and either normocytic or microcytic anemia (hemoglobin 10 g/dL); white blood cell count and differential may reveal thrombocytosis [24,29]. Although baseline evaluation of renal and hepatic function is not sensitive or specific for rheumatoid arthritis, it is recommended because the findings will guide medication choices.

Popular imaging tests for rheumatoid arthritis include joint ultrasound, MRI, and joint x-rays. Imaging studies may show normal findings or osteopenia and erosions near joint spaces in early disease; wrist and ankle films are useful as baselines for comparison with future studies [24,185]. Implementing the modern treatment strategy in rheumatoid arthritis (i.e., early initiation and optimal adjustments of aggressive therapies) requires methods for early diagnosis and sensitive monitoring of the disease process.

A number of different medical conditions may be considered in the differential diagnosis of rheumatoid arthritis [181,186,187,188]. These include:

- Connective tissue diseases (e.g., lupus, scleroderma, polymyositis)

- Fibromyalgia

- Hemochromatosis

- Infectious endocarditis

- Lyme arthritis

- Osteoarthritis

- Polyarticular sepsis

- Sarcoidosis

- Thyroid disease

- Viral arthritis

Therapeutic Measures

Rheumatoid arthritis has no known prevention or cure. Lifelong treatment is usually required, including medication, physical therapy, exercise, and possibly surgery. In order to provide the best outcomes, patients should be educated regarding the most appropriate treatment regimens for their disease manifestations, as earlier rheumatoid arthritis diagnosis can assist in aggressive early treatment for rheumatoid arthritis (when indicated), thereby delaying joint destruction. The 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis is now a well-established diagnostic and prognostic tool; as such, guidelines (e.g., the 2016 update of the EULAR Recommendations for the Management of Rheumatoid Arthritis with Synthetic and Biological Disease-Modifying Antirheumatic Drugs) recommend that patients start treatment with a disease-modifying antirheumatic drug (DMARD) immediately following a rheumatoid arthritis diagnosis [189]. Therapeutic goals include preservation of function and quality of life, minimization of pain and inflammation, joint protection, and control of systemic complications, with the ultimate aim being low disease activity or remission [23,24,27,189,190].

Today, the recommended standard of treatment is a tightly controlled, aggressive strategy tailored to each patient, with modifications to the individual medication regimen to achieve a particular target (remission, or alternatively, low disease activity) in a specific period of time (usually six months) [189,191]. The "treat-to-target" approach for a patient with early high disease activity and poor prognostic features typically involves initiation of methotrexate and/or another DMARD(s) immediately upon diagnosis [189,190,191]. Initial combination therapies with DMARDs, particularly those including a biologic anti-TNF agent, appear to provide earlier clinical improvement and less joint damage progression in patients with early moderate or highly active disease; they can be withdrawn successfully, and fewer treatment adjustments are needed than with initial monotherapies [189,191,192,193,194]. Patients with active disease are monitored closely (every one to three months), and it is recommended that treatment adjustments be made if there is no improvement at three months (or if the six-month target has not been reached) [189,191]. Patients with low-to-moderate disease activity or high disease activity without poor prognostic features are typically started on DMARD monotherapy. NSAIDs, glucocorticoids, or COX-2 inhibitors are often used concurrently to treat rheumatoid arthritis-associated joint pain and inflammation. However, they do not alter the disease course and should not be used as single therapy.

Occasionally, surgery is needed to correct severely affected joints. Surgeries serve to relieve joint pain, correct deformities, and modestly improve joint function [23,24,27]. The most successful locations of surgery are those performed on the knees and hips [23,24,27]. The first surgical treatment performed is a synovectomy, which removes part or all of the joint lining (synovium). This procedure may only provide temporary relief, but it can be effective for patients for whom pharmacologic treatment has not resulted in improvements. Surgeries performed in later-onset disease include total joint replacement with a joint prosthesis. In extreme cases, total knee or hip replacement can have enhanced importance, making the difference between a dependent or independent lifestyle for a patient.

Range-of-motion exercises and individualized exercise programs prescribed by a physical therapist can also delay the loss of joint function. Joint protection techniques, heat and cold treatments, and splints or orthotic devices to support and align joints may be of assistance [23,24,27]. Some therapists will use specialized devices to apply deep heat or electrical stimulation to reduce pain and improve joint mobility [23,24,27]. Occupational therapists can construct splints for the hand and wrist and teach patients with rheumatoid arthritis how to protect and use their joints most effectively. In addition to physiotherapy, occupational therapists can also show patients with rheumatoid arthritis how to better cope with limitations that can affect their daily tasks at work and at home. For example, many clinicians have recommended frequent rest periods between activities and proper sleeping habits (e.g., 8 to 10 hours of sleep per night) [195].

In addition to the medical management of rheumatoid arthritis, several lifestyle changes may improve symptom severity and decrease the number of flare-ups. The National Institute of Arthritis and Musculoskeletal and Skin Disorders recommends advising patients regarding rest and exercise, use of orthotic devices, stress reduction, and healthful diet [23].

INFECTIOUS DISORDERS

Infectious Arthritis

Infectious arthritis (also known as septic arthritis) is the inflammation of a joint resulting from an invading organism that attacks the synovium and synovial fluid. Viral, bacterial, and fungal infections all predispose susceptible people to arthritis involvement. Pathogens present in the host circulate freely in the bloodstream and become trapped in the richly perfused synovial membrane, leading to inflammation and subsequent degenerative changes. Infectious arthritis is an opportunistic disease that primarily occurs in patients with immunocompromise or who already have joint destruction from another disorder (e.g., rheumatoid arthritis). Early diagnosis and treatment can prevent serious degenerative changes [76,196].

Patients with infectious arthritis undergo repeated arthrocentesis, which can be stressful. Additional treatment will depend on the underlying pathogen, with antibiotics, antiviral, or antifungals prescribed as appropriate [76,196].

The nurse should be available to both the patient and family for psychological support, physical care, health education, and monitoring the patient's response to therapy. The control of pain and protection of the involved joint or joints are priorities of nursing management [76,196].

Therapeutic and Nursing Measures

The patient history is key to diagnosis, and nurses should be careful to obtain a complete and accurate history. This should include any recent viral (e.g., parvovirus, alphavirus, hepatitis, Epstein-Barr virus) and bacterial (e.g., Streptococcus pneumoniae) infection. In young, sexually active patients, the most common causative pathogen is Neisseria gonorrhea. For patients who develop infectious arthritis following trauma, puncture wounds, or injection drug use, Pseudomonas aeruginosa is the most likely cause [18,197].

It is important that the pathogen responsible for the infectious arthritis be identified and treatment begun as quickly as possible to prevent joint destruction. Isolating the organism will guide in the selection of intravenous antimicrobial therapy and the level of aggressiveness needed to control the infection. Pathogens are identified through the aspiration of synovial fluid, synovial fluid cultures, and synovial biopsy. Empiric therapy is started after joint aspiration is complete and cultures are obtained [76]. Other therapeutic measures for infectious arthritis include surgical excision of the affected synovium in instances where destruction of the joint cartilage, tendons, or both appears imminent [76].

To protect the intra- and extra-articular structure from future damage and reduce the patient's discomfort, the involved joint should be immobilized during the acute stage. However, after two to three days, aggressive physical therapy is recommended to prevent long-term damage and disability [18].

The involved joint should be assessed frequently for drainage and any change in condition. Sterile technique should be maintained with any dressing changes [18]. For patients receiving parenteral fluids, intake and output should be measured and documented accurately. Laboratory test results will be monitored daily, especially the results of culture and sensitivity tests [18].

Patient education should include instruction about range-of-motion exercises to maintain joint mobility; dressing change techniques and wound care, if appropriate; and adherence to prescribed medications. The patient should be advised of symptoms and signs of repeated infection (e.g., increased pain, fever, swelling, redness, drainage) and to avoid any trauma to the joint [18].

NEOPLASTIC DISORDERS

In this section, the discussion of masses and tumors of the joints and surrounding structures will be limited to the benign and malignant lesions generally included in a differential diagnosis for arthritis.

Masses and Benign Tumors of the Joint

Patients with a benign lesion of the joint may experience years of intermittent minor problems with the involved joint, with a history of discomfort and joint instability. Because the symptoms of a benign tumor can remain innocuous for long periods, joint damage may result prior to diagnosis. No matter the extent of damage, joint surgery is required to resolve the issue and prevent further deterioration [37].

Lipoma

A lipoma of a joint is a lobulated fatty mass. Lipomas develop frequently in the elbow or knee joint of patients with osteoarthritis [37]. In many cases, patients seek medical attention when the involved joint begins locking or when pain, decreased motion, or an effusion occurs. Effusion aspirate is clear, and x-rays are non-diagnostic [37].

Hemangioma

Hemangiomas are rare vascular tumors often associated with arteriovenous malformations of skin vascular disease. They tend to affect younger individuals, often teenage girls who have been symptomatic since childhood. The knee is the most commonly involved joint [37].

In patients with joint hemangioma, there is a history of episodic, unilateral "doughy" joint swelling; pain; limitation of motion; and locking, buckling, or both. Aspiration of the joint repeatedly produces serosanguineous fluid in the absence of trauma. X-rays early in the course of the hemangioma may appear normal; ultrasound is often more helpful. With more advanced disease, enlarged epiphyses, joint narrowing, and enlargement of the intercondylar notch layer may be visualized [37].

Surgical removal yields good results in the treatment of a localized hemangioma. If accessible, therapeutic embolization of a major feeder vessel may be effective as well. Because of the vascular nature of this tumor, a diffuse form may involve the entire joint capsule and make resection impossible. For these patients, radiation therapy is the usual treatment [37].

Synovial Chondromatosis

Synovial chondromatosis is a condition of unknown etiology in which numerous cartilaginous nodules form. These nodules involve the joint, bursae, and in some cases the tendon sheaths of a knee, hip, elbow, shoulder, or ankle. It is a self-limiting disease that most frequently affects young and middle-aged men [37].

Synovial chondromatosis has an insidious onset, and many years often pass before the patient seeks evaluation for the problem. Presenting symptoms usually consist of swelling, pain, stiffness, limitation of motion, and joint locking. Particularly with synovial chondromatosis, the patient experiences joint crepitation or a grating sensation from the multiple intrasynovial nodules. X-ray findings may demonstrate calcified, free-floating bodies in the synovium [37].

Excision of the involved synovium and removal of all loose bodies is the treatment of choice. Surgical therapy has a good prognosis, although the condition may recur if removal is incomplete [37].

Pigmented Villonodular Synovitis

Pigmented villonodular synovitis is a condition in which the synovial lining cells have a marked proliferation that results in the appearance of numerous villi and folds. The formation of the finger-like projections can affect not only the synovial lining but also the tendon sheath, bursa, and bone. Unilateral involvement of the knee, hip, ankle, or elbow joint of young adults is most common [37].

There are two forms of pigmented villonodular synovitis: localized and diffuse. The diffuse type causes pain and mild, episodic joint swelling over a period of months to years. Occasionally, the patient may note an acutely painful, warm, swollen joint with limited motion. Repeated aspirations of joint fluid yield dark serosanguineous fluid in the absence of trauma [37].

The localized type of pigmented villonodular synovitis occurs in either the medial or lateral knee compartment as a solitary nodule. It, too, may begin with episodic pain and mild swelling and can be misdiagnosed as torn meniscus. Serosanguineous fluid is rarely aspirated with this type of lesion [37]. Imaging studies may show soft tissue density, but angiographies are more useful because the vascularity of these enable the condition to be diagnosed [37].

Surgical resection is the treatment for both types of pigmented villonodular synovitis. The localized form is usually cured with simple excision. With the diffuse type, lesions may recur if synovectomy is incomplete [37].

Specific Nursing Measures

During the diagnostic phase, the health history is important. The nurse should concentrate on any significant joint trauma and inquire regarding any past history of arthritis. The patient should be asked for a detailed description of swelling, pain, limitation of motion, and/or joint instability [7].

In cases of significant joint instability, a cane or crutches may be necessary. Patients should also receive education on appropriate pain management measures, including thermotherapy, over-the-counter medications, and biofeedback. In most cases, the patient will also require education to prepare for surgery and postoperative recovery [7].

Postoperative care includes monitoring for wound drainage or other signs of infection, dressing changes (as necessary), and splinting. Discharge planning includes instruction in the care of the surgical site, activity restrictions, and follow-up appointments [7].

Malignant Tumors of the Joint

Malignant tumors of the joint are rare. However, if a patient has a slow-growing monoarticular mass, malignancy should be suspected [198].

Synovial Sarcoma

Though it is the most common primary tumor of the joint, synovial sarcoma is rare. This malignancy can appear at any age, although it seems to predominate in young adults. The growth generally appears on a lower extremity, but synovial sarcomas can also develop in an upper extremity, the neck, or the chest [198].

Patients with synovial sarcoma often present with a slow-growing mass that may have been present for months to years, depending on how deeply seated it is in tissue. Pain may be present, or the patient may have a vague sensation of discomfort over the involved area. There may also be localized swelling. In cases involving the neck, tumor invasion may produce hoarseness, dysphagia, or dyspnea [198].

As with most cancer, survival time is dependent on the size of the tumor, site in the body, and age at diagnosis. The five-year survival rate is approximately 60%; this increases to 75% in patients 30 years of age or younger. If the tumor is in an extremity, five-year survival is about 65%; if the tumor is present in the trunk, the rate decreases to 40% [199].

The goals of treatment for synovial sarcoma are to eliminate the tumor, preserve a functional limb, and minimize mortality and morbidity. Preoperative chemotherapy and radiation therapy may be undertaken to decrease the size of the tumor [198]. Wide surgical resection is typically undertaken, followed by continued radiation therapy.

Clear Cell Sarcoma

Clear cell sarcoma is a rare tumor that involves tendons rather than joint spaces. It can occur in any age group and usually is found in an extremity, particularly the foot. However, it can develop in the trunk, head, genitals, stomach, and intestines. Because of this lesion's location and its predisposition to metastasis, it can be difficult to remove entirely, making treatment complicated and prognosis poor [198]. The average age at diagnosis is 25 years [200].

The primary treatment of clear cell sarcoma is radical resection of the tumor. In some cases, an extremity may be amputated. Preoperative and postoperative radiation therapy are employed. In some cases, chemotherapy may be used, but it is not particularly effective [200].

TRAUMATIC DISORDERS OF THE JOINT

Permanent structural changes may occur in a joint as a result of cartilage and capsular tears, detachment of menisci, hemorrhagic effusions, articular fractures, or repetitive trauma. Because of the realignment of involved bone, bursa, and tendons, a mechanical deterioration of articular cartilage results in osteoarthritis [201,202].

Traumatic arthritis may result from unexpected force (e.g., sports, motor vehicle accidents) or from repetitive trauma—a chronic injury resulting from repeated smaller stresses to a joint through vibrations, blows, abnormal strain, or position. Injury resulting from repetitive stress is often related to occupation and lifestyle, for example, the stress placed on the metatarsophalangeal joints of a ballet dancer or the knees of a jogger. Over time, repetitive trauma may realign the joint and lead to the same result as an acute injury [201,202].

The patient with traumatic arthritis must make lifestyle changes. In order to continue participating in chosen sports or occupations, patients may require braces, splints, or special equipment; in some cases, they may need to halt participation or seek accommodations in their workplace. Although these options are effective in halting the progression of traumatic arthritis, they are often undesired or impossible for patients. The responsibility of the nurse is to provide accurate information about the alternatives available [201,202].

Nurses also play an important role in the therapeutic and preventive care of traumatic disorders. If they are the first person on the scene of an accident, nurses may be able to prevent any residual damage by splinting, elevating the area, and not allowing weight on the area to protect the joint. It may be possible to identify tasks that expose employees to repetitive trauma; employees then can rotate through the jobs rather than be assigned permanently to potentially harmful tasks [201,202].

Joint Effusions

Joint effusions can occur as a result of simple trauma or secondary to fractures, internal derangements, or severe sprains. Within 24 hours after a blow to the joint, synovial fluid accumulates. If blood vessels in the synovium are broken, hemarthrosis also occurs. The knee is most commonly affected by this injury, although it can occur in other joints as well [75].

Clinical Manifestations

In simple cases of traumatic synovitis, joint swelling with mild pain occurs. Aspiration of the joint produces clear fluid with elevated protein content and decreased viscosity. Hemarthrosis, which usually develops within 15 minutes to 2 hours after the trauma, is usually more painful than clear effusion and is accompanied by low-grade fever. Diagnosis of traumatic synovitis is primarily by physical examination, but x-ray examination is done to rule out fracture [75].

Therapeutic Measures

Immediately following injury, patients should be advised to apply cryotherapy (e.g., ice) for 30 minutes; this can be repeated up to four times per day to reduce swelling and relieve pain. After the first 24 hours, patients should switch to moist heat to relax surrounding muscles and reduce pain. If fluid accumulates in the joint, repeated joint aspirations may be necessary. Compression dressings applied to the joint, along with limited weight bearing, may be used, depending on the severity of the injury [75].

Dislocation and Subluxation

Dislocation is the complete displacement of a joint's articulating surfaces following trauma. Partial displacement of the articulating surfaces results in subluxation. Both subluxations and dislocations can damage soft tissues, nerves, or blood vessels if not attended to promptly. The joints most often affected are shoulders, wrists, elbows, fingers, hips, knees, and toes [75].

Clinical Manifestations

After injury, the joint appears deformed; it is tender, and motion is limited. The involved extremity may be visibly shortened. Joint pain may be intense, especially if articular surface fractures are present. With immediate treatment, there is a good prognosis. However, bone necrosis can result if reduction of the subluxation or dislocation is delayed [75]. Diagnosis is made through physical examination and patient history, with x-rays taken to evaluate joint displacement and to determine whether fractures are present [75].

Therapeutic Measures

The longer the delay in correcting a joint displacement, the more difficult the procedure becomes because of edema and muscle spasms. Two types of procedures can correct this injury. Closed reduction is manual traction done under local or general anesthesia. The pain associated with this procedure can be intense, and pain management techniques (including strong analgesics) are necessary. If muscle spasms are an issue, tranquilizers and/or muscle relaxants may be administered. Open reduction is done when wire fixations of the joint or repair of torn ligaments is also necessary [75].

If present at the site of injury, the joint should be splinted—even if crooked—to prevent further damage. Cold compresses can be applied to decrease pain and swelling [35]. The area distal to the injury should be observed for evidence of vascular damage (e.g., pallor, absent pulse, abnormal coolness) and nerve damage (e.g., paresthesia, paralysis) [35].

If analgesics, muscle relaxants, or tranquilizers are administered, it is important to monitor the patient's respiratory status. Any dressings or casts should be checked for pressure that may impair blood flow. Patients should receive education on gradual mobilization and return to activities [7].

9. CASE STUDIES

SYSTEMIC LUPUS ERYTHEMATOSUS

Patient A is a woman, 29 years of age, with two small children. She presents to her primary care provider with complaints of rashes developing on her arms and legs whenever she spends time in the sun. She also reports several small patches of hair loss on her head that she attributes to the stress of new motherhood and to a recent trip and her fear of flying. She reports a lack of energy, being easily fatigued, and always needing to nap during the day. Patient A also reports mild pain in her fingers and elbows but attributes the joint discomfort to caring for the children. She states that these problems have been ongoing for approximately four months.

Medical History

Patient A has no known allergies and takes no prescription or over-the-counter medication aside from occasional naproxen for joint pain and antacid for heartburn. She neither smokes nor drinks alcohol. Her youngest child is 2 years of age, and she reports unremarkable childbirths and postpartum periods. Aside from the current complaints, the patient's medical history is unremarkable.

She has four brothers and three sisters. The family history indicates an older sister with rheumatoid arthritis, an aunt with pernicious anemia, and mother with hyperthyroidism.

Assessment and Diagnosis

The primary care provider conducts a full physical assessment (Table 2). Several laboratory tests are ordered, with the following results:

- Hematocrit (HCT): 23%

- Red blood cell (RBC) count: 3.5 million cells/mcL

- White blood cell (WBC) count: 5,500 cells/mcL

- Platelets: 350,000 cells/mcL

- ESR: 25 mm/hour

- Urinalysis: Normal

- ANA: 1:640

- Anti-DNA antibody test: Elevated

- Complement assay: Decreased C3 level at 43 mg/dL and decreased C4 level at 14 mg/dL

Table 2: PATIENT A'S FIRST PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

Significantly underweight, with a decrease in weight of 23 pounds since last exam one year prior

Height: 5 feet 5 inches (165.5 cm)

Weight: 108 pounds (49 kg)

Skin and nails

Multiple rash-like lesions on sun-exposed areas of the body, primarily on the arms and legs

Slightly jaundiced

Head and nose

Nares clear

Oropharynx benign and without obvious lesions

Mucous membranes moist

Eyes

Some yellowing within the sclera

Pupils equal, round, reactive to light and accommodation

Conjunctiva normal

No retinal exudates

Ears

Tympanic membranes intact

Neck

Supple

No signs of lymphadenopathy, jugular vein distension, or thyromegaly

Chest

Clear to auscultation throughout

Equal air entry bilaterally

No wheezing or crackles

Chest resonant on percussion

Abdomen

Soft and nontender

Active bowel sounds

No masses or organ enlargement

Extremities

No cyanosis, clubbing, or edema

Rash-like lesions present

Genitourinary system

Normal female

Neurologic status

Alert and oriented

Deep tendon reflexes 2+ with symmetrical flexor plantar responses

No focal deficits noted

Cardiovascular system

Regular rate and rhythm

Prominent S1and S2

Vital Signs

Blood pressure

110/70 mm Hg

Temperature

99.8° F

Heart rate

70 beats per minute with regular rhythm

Respiratory rate

15 breaths per minute

Source: Author

Further, a tissue biopsy of one of the lesions is taken and reveals vasculitis (i.e., white blood cells within the walls of blood vessels).

Based on the results of the assessment and laboratory studies, Patient A is diagnosed with SLE.

Management

A one-month course of prednisone with tapered doses is prescribed. Nabumetone, an anti-inflammatory, is added to the regimen prior to the prednisone being weaned off. After one month of treatment, all signs and symptoms of lupus have resolved.

However, 13 years later, Patient A again presents to her primary care provider, this time with complaints of a productive cough and transient stiffness and pain in her hands and feet (migratory polyarthritis). She is afraid that she is developing rheumatoid arthritis like her sister. The provider conducts a physical examination (Table 3) and is concerned that the patient may be showing signs of pneumonia. A chest x-ray revealed mild pulmonary edema but no white blood cell infiltrates in the terminal airways. Laboratory tests reveal:

- HCT: 43%

- Platelet: 330,000 cells/mcL

- WBC count: 1,200 cells/mcL

- Urinalysis: Within normal limits

Table 3: PATIENT A'S SECOND PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

Healthy and calm White woman

Height: 5 feet 5 inches (165.5 cm)

Weight: 131 pounds (59.5 kg)

Skin and nails

No lesions or abnormalities noted

Head and nose

Nares clear

Oropharynx irritated but without obvious lesions

Mucous membranes moist

Eyes

Pupils equal, round, reactive to light and accommodation

Conjunctiva normal

Ears

Tympanic membranes intact

Neck

Supple

Lymph nodes slightly enlarged

Chest

Auscultation reveals abnormal lung sounds (bronchitis)

No wheezing, but some crackles

Abdomen

Soft and nontender

Active bowel sounds

No masses or organ enlargement

Extremities

No cyanosis, clubbing, or edema

Axillary lymph nodes swollen

Genitourinary system

Normal female

Inguinal lymph nodes slightly enlarged

Neurologic status

Alert and oriented

Deep tendon reflexes 2+ with symmetrical flexor plantar responses

No focal deficits noted

Cardiovascular system

Regular rate and rhythm

Prominent S1and S2

Vital Signs

Blood pressure

140/90 mm Hg

Temperature

100.0° F

Heart rate

105 beats per minute with regular rhythm

Respiratory rate

15 breaths per minute

Source: Author

Patient A is diagnosed as experiencing a lupus flare and is prescribed a one-month course of prednisone along with a 10-day course of antibiotics to prevent pneumonia. Within three months, all signs and symptoms have resolved.

Five years later, Patient A returns to her primary care provider complaining of fatigue, anorexia, weight loss (25 pounds in the last four months), and significant swelling in her abdomen, face, and ankles. The nurse practitioner notes a "butterfly-shaped" rash present across the bridge of the patient's nose and cheeks. Blood tests reveal an HCT of 24% and a WBC count of 2,400 cells/mcL. A dipstick examination of the urine reveals an abnormal protein concentration, and microscopy indicates the presence of significant numbers of red and white blood cells. A 24-hour urine protein collection reveals excretion of 2.5 g protein in 24 hours.

Study Questions

1. What is the significance of the patient's family history?

2. Is this patient underweight, normal weight, overweight, or obese?

3. What underlying pathologic process is responsible for Patient A's hair loss? What is the relevance of the abnormal ESR?

4. Vasculitis in lupus results from the trapping of antigen antibody complexes in blood vessel walls followed by an intense inflammatory response to the immune complexes. Why is prednisone effective in relieving vasculitis?

5. What is the most likely cause of jaundice in this patent?

6. What pathophysiology underlies lymph node enlargement in this patient?

7. The patient's WBC differential was: 75% neutrophils, 15% lymphocytes, 5% monocytes/macrophages, 4% eosinophils, and 1% basophils. Which one of these white blood cell types has been specifically targeted by the patient's immune system?

8. Why was Patient A experiencing swelling throughout her body?

LOW BACK PAIN

Patient B is a woman, 35 years of age, who has worked as a housekeeper for the past 10 years. She is 5 foot 3 inches in height with a weight of 178 pounds. She presents to her primary care provider with complaints of low back pain. She reports having had this pain intermittently for several years; however, for the past two days, it has been worse than ever. The recent exacerbation started after vacuuming a rug (i.e., pulling and twisting at the waist). Patient B reports that the pain is primarily on the right lower side and radiates down her posterior right thigh to her knee; it is not associated with any numbness or tingling. The pain can be relieved by lying flat on her back with her legs slightly elevated and is lessened somewhat when she takes ibuprofen 400 mg. Except for moderate obesity and difficulty maneuvering onto the examination table because of pain, the patient's examination is fairly normal. The only abnormalities noted are a positive straight leg raise test, with raising the right leg eliciting more pain than the left. Her strength, sensation, and deep tendon reflexes in all extremities are normal.

Study Questions

1. What is the patient's likely diagnosis?

2. How will the patient be treated?

RHEUMATOID ARTHRITIS

Patient C is a woman, 50 years of age, who presents to her primary care provider for her annual exam. She reports having been very tired for the past month and also experiencing stiffness, pain, and swelling in multiple joints. She states, "I ache all over, and I have pain in different places all the time. One day it is in my right shoulder, the next day in my right wrist, and the following day my left wrist. I'm stiff everywhere when I get up in the morning or if I sit for any length of time. And I feel so tired, like I have a case of the flu that won't go away."

The patient has been diagnosed with hypothyroidism in the past, for which she is taking levothyroxine. She is also prescribed venlafaxine to treat major depressive disorder, and she indicates that her mood has been good, despite the fatigue. She is also taking an over-the-counter multivitamin and calcium supplement. Patient C reports rarely using alcohol and never smoking. There is no family history of autoimmune disorders.

Assessment and Diagnosis

The primary care provider does a complete physical exam (Table 4) and orders laboratory tests. The laboratory blood test results are:

- Sodium: 140 meq/L

- ANA: Negative

- HCT: 43%

- Uric acid: 2.9 mg/dL

- Potassium: 3.7 meq/L

- ESR: 38 mm/hour

- WBC count: 15,100 cells/mcL

- Cholesterol: 189 mg/dL

- Chloride: 104 meq/L

- Creatinine: 1.0 mg/dL

- Platelets: 270,000 cells/mcL

- Albumin: 4.0 g/dL

- Bicarbonate: 23 meq/L

- Blood glucose: 94 mg/dL

- RBC count: 4.7 million cells/mcL

- Thyroid stimulating hormone (TSH): 1.7 mcU/mL

- Blood urea nitrogen: 18 meq/L

- Hemoglobin: 14.9 g/dL

- Calcium: 8.8 mg/dL

- Rheumatoid factor: Positive

Table 4: PATIENT C'S PHYSICAL EXAM RESULTS

Parameter

Findings

General appearance

Pleasant and alert, but appears very tired and is in moderate acute distress from joint pain

Height: 5 feet 4 inches (162.5 cm)

Weight: 140 pounds (63.5 kg)

Skin and nails

Intact, warm, pink, and dry

No rashes

Normal turgor

Head and nose

Head atraumatic

Eyes

Pupils equal, round, reactive to light and accommodation

Normal funduscopic examination

Ears

Tympanic membranes intact

Neck

Supple with no jugular vein distention or thyromegaly

No bruits

Mild lymphadenopathy bilaterally

Chest

Clear to auscultation and percussion

No lumps, dimpling, discharge, or discoloration noted in breast exam

Abdomen

Soft, non-tender, and non-distended

Positive bowel sounds throughout

No superficial veins or organomegaly

Extremities

No clubbing or ankle edema

Hands: Swelling of the 3rd, 4th, and 5th proximal interphalangeal joints bilaterally. Pain in the 4th and 5th metacarpophalangeal joints bilaterally. Poor grip strength bilaterally.

Wrists: Good range of motion. Fixed nodule at pressure point on left side.

Elbows: Good range of motion. Fixed nodule at pressure point in right side.

Shoulders: Pain and decreased range of motion bilaterally.

Hips: Good range of motion.

Knees: Pain, significant edema, and decreased range of motion bilaterally.

Feet: No edema. Full plantar flexion and dorsiflexion and full pedal pulse bilaterally.

Genitourinary system

Last menstrual period 16 months ago

Normal pelvic exam

Neurologic status

Alert and oriented

Cranial nerves II–XII intact

Muscle strength 5/5 in upper extremities and 4/5 lower extremities

Deep tendon reflexes 2+ in biceps, triceps, and patella

Cardiovascular system

Regular rate and rhythm

Normal S1, S2, no S3or S4

No murmurs, rubs, or gallops

Vital Signs

Blood pressure

125/80 mm Hg

Temperature

100.0° F

Heart rate

80 beats per minute with regular rhythm

Respiratory rate

15 breaths per minute

Source: Author

A urinalysis is performed and is normal, with no RBCs, WBCs, or protein. A chest x-ray finds no fluid, masses, infection, or cardiomegaly. An x-ray of the hand shows soft tissue swelling and bone demineralization but no erosions. Synovial fluid removed from the left knee (7.4 mL) is cloudy and pale yellow in appearance; analysis indicates 14,000 white blood cells/mcL (primarily neutrophils) and a glucose level of 60 mg/dL.

Based on these findings, Patient C is diagnosed with rheumatoid arthritis and referred to a rheumatologist for follow-up.

Study Questions

1. Which of Patient C's vital signs is consistent with a diagnosis of rheumatoid arthritis and why?

2. Are there any other abnormal findings from the patient's physical exam that are consistent with a diagnosis of rheumatoid arthritis?

3. What is the association between the fixed nodules at pressure points on the left wrist/right elbow and a diagnosis of rheumatoid arthritis?

4. Why is it reasonable that this patient has no stiffness, pain, or swelling in the DIP joints of the fingers?

5. Which of these patient's laboratory test results are consistent with a diagnosis of rheumatoid arthritis?

6. In terms of the progression of the disease, what do the results of the hand x-ray suggest?

7. Which findings in the examination of the synovial fluid are consistent with a diagnosis of rheumatoid arthritis?

8. What causes limitation of joint motion that occurs early in the clinical course of rheumatoid arthritis? What causes limitation of joint motion that occurs late in the clinical course of rheumatoid arthritis?

10. CONCLUSION

With knowledge of the structures and function of the muscles, joints, and connective tissue and the dynamic pathology that intrudes and impedes normal function, nurses can readily provide quality and often life-saving actions. An awareness of why symptoms appear leads to quicker reporting to physicians of changes in the patient's condition. Nurses can also perform immediate interventions based on standing orders and recognition of what needs to be done in order to provide safe quality care. This knowledge changes what could be only technical care to professional care through the use of decision-making skills built upon the knowledge of pathophysiology.

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Evidence-Based Practice Recommendations Citations

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