MD17 • Physicians and Physician Assistants 2017

Table of Contents

MD17 • Physicians and Physician Assistants 2017

How to Receive Credit

NetCE 10 Hour Course #98771 • Parkinson Disease

98771 • Parkinson Disease

1. INTRODUCTION

2. BACKGROUND

3. EPIDEMIOLOGY

4. RISK FACTORS AND ETIOLOGY

5. PATHOPHYSIOLOGY

6. DIAGNOSTIC WORKUP

7. TREATMENT OF PARKINSON DISEASE

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 15 Hour Course #94101 • Low Back Pain

94101 • Low Back Pain

1. INTRODUCTION

2. EPIDEMIOLOGY

3. RISK AND PROGNOSTIC FACTORS

4. CLINICAL COURSE

5. PATHOPHYSIOLOGY

6. ASSESSMENT AND DIAGNOSIS

7. TREATMENT OPTIONS

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 5 Hour Course #41030 • Burnout in Physicians

41030 • Burnout in Physicians

1. INTRODUCTION

2. HISTORY AND DEFINITION OF BURNOUT

3. DEVELOPMENT OF BURNOUT

4. IDENTIFICATION AND MEASUREMENT OF BURNOUT

5. BURNOUT AMONG PHYSICIANS

6. FACTORS ASSOCIATED WITH BURNOUT

7. STRATEGIES TO PREVENT AND COPE WITH STRESS AND BURNOUT

8. CONCLUSION

Works Cited

MD17 • Physicians and Physician Assistants 2017

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

MD17 • Physicians and Physician Assistants 2017

Expiration Date: 09/30/2019

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.

98771 • Parkinson Disease

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.

Table of Contents

98771 • Parkinson Disease

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. BACKGROUND

DEFINITIONS

3. EPIDEMIOLOGY

PREVALENCE AND INCIDENCE

DEMOGRAPHICS

MORTALITY RATES

4. RISK FACTORS AND ETIOLOGY

RESEARCH

ENVIRONMENTAL RISK FACTORS

GENETIC RISK FACTORS

RISK FACTOR INTERACTIONS

5. PATHOPHYSIOLOGY

DOPAMINERGIC PATHOPHYSIOLOGY AND LOSS OF MOTOR FUNCTION

CORE PATHOLOGIC FEATURES

DEVELOPMENT AND PROGRESSION OF PATHOPHYSIOLOGY

NATURAL HISTORY OF DISEASE PROGRESSION

NON-MOTOR SYMPTOM APPEARANCE AND DISEASE STAGE

PRE-MOTOR SYMPTOMS

ASSESSMENT AND DIAGNOSIS OF PARKINSON DISEASE

CLINICAL FEATURES

6. DIAGNOSTIC WORKUP

DIAGNOSTIC CRITERIA

PATIENT HISTORY

NEUROLOGIC EXAMINATION

DIAGNOSTIC CONFIRMATION

SCREENING TESTS

DIFFERENTIAL DIAGNOSIS

7. TREATMENT OF PARKINSON DISEASE

OVERVIEW OF TREATMENT APPROACHES THROUGH DISEASE PROGRESSION

MEDICATION NON-ADHERENCE

PHARMACOTHERAPIES

MANAGEMENT OF EARLY PARKINSON DISEASE

MANAGEMENT OF LATER PARKINSON DISEASE

MANAGEMENT OF ADVANCED PARKINSON DISEASE

MANAGEMENT OF NON-MOTOR SYMPTOMS

END-STAGE PARKINSON DISEASE

ADJUNCTIVE TREATMENT MODALITIES

PRACTICE CONSIDERATIONS

8. CONCLUSION

9. RESOURCES

Works Cited

Evidence-Based Practice Recommendations Citations

98771 • Parkinson Disease

Education Category. Infection Control / Internal Medicine

Release Date. 05/01/2019

Expiration Date. 04/30/2022

Course Overview

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options. As a chronic condition, patients with PD have ongoing contact with their primary care provider for PD and non-PD related concerns. Additional aspects related to PD are likely to be encountered, including issues with medications prescribed to control PD symptoms, comorbid conditions, and polypharmacy. This course will review all of the relevant aspects of PD diagnosis and treatment necessary for the optimal care of patients with the disease.

Audience

This course is designed for all healthcare providers in the primary care setting who may encounter patients with Parkinson disease.

Course Objective

The purpose of this course is to provide physicians, nurses, and other members of the interprofessional healthcare team a review of current concepts of pathogenesis, disease progression, diagnosis, and management of Parkinson disease, in order to improve patient care and quality of life.

Learning Objectives

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

1. Outline the history, epidemiology, and clinical signs/symptoms of Parkinson disease (PD) and scientific developments related to recognition of the disease.

2. Describe the assessment and management of PD.

3. Assess motor and non-motor symptoms and signs in relation to pathophysiology of PD.

4. Anticipate the time course of symptom development in patients with PD, and use this to assess clinical probability and to inform follow-up of a patient in whom the diagnosis is unclear.

5. Refine history and clinical examination skills in order to detect the early motor and non-motor signs and symptoms of PD.

6. Develop a strategy for the initial workup of patients with suspected PD that conforms with diagnostic and clinical staging criteria.

7. Compare and contrast syndromes that may mimic PD and their differential diagnosis.

8. Devise a treatment strategy and select an appropriate drug regimen for the management of PD.

9. Create an approach to the management of PD based on stage of the disease, severity of symptoms, and rate of progression.

10. Discuss the role of non-motor symptoms of PD and devise a strategy for treatment.

11. Outline a long-term plan for monitoring the course of illness, including patient and family education and safety precautions.

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

John V. Jurica, MD, MPH

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

Alice Yick Flanagan, PhD, MSW

Abimbola Farinde, PharmD, PhD

James Trent, PhD

Division Planners Disclosure

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Parkinson disease (PD) is a neurodegenerative disorder that affects approximately 1% of those older than 60 years of age [1,2]. Improved recognition of both non-motor and motor symptoms can promote early diagnosis and treatment of PD. Importantly, early intervention leads to better quality of life for the patient, and this may be facilitated by improved understanding of PD pathophysiology, signs and symptoms, differential diagnosis, and therapeutic options [3,4]. As a chronic progressive illness, patients with PD require regular follow-up with their primary care provider working in concert with a neurology consultant and other members of the interprofessional care team. Important aspects of care likely to be encountered include the need to adjust dosage or alter drug treatment, attention to medication side effects/toxicity, management of comorbid conditions, and risk of polypharmacy. This course will review the relevant pathophysiology and clinical aspects of PD, including principles of diagnosis and treatment options in relation to stage of disease and other considerations important to the optimal care of patients.

2. BACKGROUND

The clinical syndrome now known as parkinsonism was first described in 1817 by the English physician James Parkinson as "the shaking palsy" [5]. This disorder is characterized by the motor symptoms of resting tremor, muscle rigidity, and bradykinesia. Over time the non-motor features of PD have been increasingly identified, including sensory, autonomic, and neuropsychiatric symptoms, some of which appear before motor dysfunction is evident. The precise cause of PD is unclear, but disease manifestations are known to result from the disruption of dopaminergic neurotransmission within the central, peripheral, and autonomic nervous systems. The defining pathologic feature of PD is the loss of dopamine-producing cells and the local deposition of aggregates of the protein alpha-synuclein (Lewy bodies) in the substantia nigra region of the brain [8].

The onset of PD is insidious, the course progressive, and neurologic signs are often asymmetrical. The four primary motor symptoms and signs are [8]:

- Tremors of the hands, arms, legs, and jaw

- Stiffness and rigidity of the limbs and trunk

- Bradykinesia (slowness of movement)

- Postural instability caused by impaired balance and coordination

In time, symptoms become more pronounced and the simple tasks of daily living, such as walking, talking, and swallowing, become increasingly difficult. Other, non-specific symptoms of PD include sleep behavior disorder, constipation, labile emotional state, and depression. While the symptoms are amenable to treatment, the disease is slowly progressive and eventually disabling for most patients.

There is no blood test or other laboratory procedure proven to be specific for the diagnosis of PD [8]. The diagnosis rests on clinical findings and pattern of progression, often requiring multiple examinations over time. Laboratory testing and neuroimaging is useful to exclude other diagnostic possibilities. Drug treatment of PD is directed toward replenishing local tissue dopamine levels in an effort to facilitate neurotransmission and improve motor function. Effective long-term management is rendered best by an interprofessional team care approach.

DEFINITIONS

Parkinsonism: A motor disorder syndrome and core clinical feature of PD that includes bradykinesia plus tremor, rigidity, and/or postural instability. Parkinsonism is non-specific, as corticobasal degeneration, multisystem atrophy, and other neurodegenerative disorders may show features of parkinsonism. All patients with PD have parkinsonism, but not all patients with parkinsonism have PD [1,6,7].

Idiopathic Parkinson disease: Synonymous with PD, the most common cause of parkinsonism. Idiopathic means unknown cause, and idiopathic PD refers to parkinsonism not attributed to corticobasal degeneration, multisystem atrophy, or other neurologic disorder and not the direct result of gene mutation [1,6,7].

Sporadic Parkinson disease: PD without direct familial/genetic cause. Synonymous with idiopathic PD.

Bradykinesia: An abnormal degree of slowness when initiating voluntary movement and progressive reduction in speed and amplitude with repetitive movement. The core motor symptom of PD.

Dementia: The progressive decline in cognitive function due to neurologic damage or disease, with decline greater than expected from normal aging.

Dyskinesia: Involuntary movements with a rotatory, writhing appearance that can affect the limbs, trunk, or face. Dyskinesias are typically associated with dopaminergic therapy in later PD.

"On" and "off" states: With long-term levodopa use in later PD, many patients develop fluctuating drug response, termed "on" and "off" motor states. "On" describes optimal motor response to medication (typically levodopa); "on with dyskinesias" describes involuntary writhing movements during medication efficacy. "Off" describes resurgent motor symptoms and impairment, sometimes accompanied by non-motor symptoms such as low mood or fatigue. "Off" episodes commonly occur during loss of medication effect before the next dose [1,6,7].

3. EPIDEMIOLOGY

PREVALENCE AND INCIDENCE

Sporadic (idiopathic) PD is the second most frequent neurodegenerative disorder after Alzheimer disease [8]. The prevalence of diagnosed PD in the United States is estimated to be 500,000, but the actual number is thought to be twice that, as many persons with the condition are as yet undiagnosed or misdiagnosed [8]. Roughly 60,000 new cases are diagnosed each year, the majority of which are persons older than 60 years of age. The population prevalence is 1% in persons 60 years of age or older and up to 4% in those 80 years of age or older. About 10% of patients with PD had onset of illness before 50 years of age. Women develop PD at lower rates and with later onset than men; the delayed onset has been attributed to the neuroprotective effects of estrogen on the nigrostriatal dopaminergic system [1,2]. The variable prevalence of PD throughout the world suggests that environmental and genetic factors interact with ethnic differences in disease pathogenesis [2].

The cost of treating PD in the United States is estimated to be $14 billion annually, and the indirect costs add another $6.3 billion [8]. Because of the aging population, the number of persons with PD is expected to double by 2040.

DEMOGRAPHICS

The incidence of PD varies by age, race, and ethnicity. The ratio of men to women is roughly 2:1 [9]. As noted, the incidence is markedly higher in each decade after 60 years of age, peaking after 80 years of age. The rate is highest among Hispanic individuals, followed by non-Hispanic whites, Asians, and black persons [9]. However, there is some variation in the incidence in each racial/ethnic group when divided by sex, with black men and Asian women at greater risk than their other-sex counterparts.

MORTALITY RATES

The United States has the fourth highest annual death rate from PD in the world. In 2011, 23,111 people died from PD, the 14th most common cause of death in the United States. From 1999 to 2011, there was a 30% increase in the annual death rate from PD (from 5.2 to 7.4 per 100,000 persons) [10]. Between 2000 and 2013, age-adjusted death rates from PD per 100,000 increased for men (8.8 to 11.0) and women (3.9 to 4.8) [11].

4. RISK FACTORS AND ETIOLOGY

Idiopathic PD, like other neurodegenerative diseases, has a complex pathogenesis involving the interaction of several genetic contributions, each with minor impact, with environmental factors [12]. Risk factors associated with the development of PD include other medical conditions, abnormal physiologic processes, and exposure to specific substances and environmental toxins. Genetic associations are less robust, but several gene mutations confer greater risk of PD (Table 1).

Table 1: RISK AND GENETIC FACTORS ASSOCIATED WITH PARKINSON DISEASE

Category

Risk Factors

Medical conditions and lifestyle factors

Post-infection states

Head trauma

Elevated cholesterol

High caloric intake

Substance use

Methcathinone (manganese content)

Methamphetamine and amphetamines

Environmental toxins

Herbicides
and pesticides

Methanol and organic solvents

Carbon disulfide

Cyanide

Inflammatory, immune, and oxidative processes

Inflammation with microglia activation

Mitochondrial dysfunction

Nitric oxide toxicity

Oxidative stress

Signal-mediated apoptosis

Gene mutations

Alpha-synuclein gene (SNCA)

Eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1)

Glucocerebrosidase gene (GBA)

Leucine-rich repeat kinase 2 (LRRK2) gene loci

PTEN-induced putative kinase 1 (PINK1) gene loci

Superoxide dismutase 2 gene (SOD2)

Vacuolar protein sorting 35 homolog gene (VPS35)

Source: [1]

RESEARCH

Current understanding of how environmental factors increase or mitigate risk of developing PD was accelerated by a series of studies from two distinct lines of investigation. These investigations identified specific protective and risk factors, greatly contributing to the knowledge of pathogenesis and pathophysiology in PD.

Identification of Factors Protective Against PD

The first line of investigation began in the early 1960s, with an unexpected finding that linked cigarette smoking with protection against PD. This association between smoking and neuroprotection from PD has been replicated in numerous epidemiologic, pre-clinical, and case-control studies. These studies also identified coffee drinking (and caffeine) as a factor that reduced risk of developing PD [13].

In these studies, risk of developing PD is shown as odds ratio (OR), where the odds of developing PD in cigarette or coffee users was compared to non-user reference groups. An OR of 1.00 signifies no difference from the reference group, while a number greater than 1 means increased odds of developing PD and a number less than 1 indicates decreased odds of PD.

In one study, smoking, other lifestyle behaviors, family history of PD, and their interaction were examined for possible association with risk of PD diagnosis by comparing 1,808 patients in Denmark with PD diagnosis with 1,876 matched population controls [14]. Strong inverse associations were found between cigarette smoking and risk of PD, even in smokers who quit 10 years before PD diagnosis. Compared with never-smokers without PD family history, the OR was 2.81 in never smokers with family history, versus 1.60 in smokers with family history. Duration had the greatest effect in modulating the smoking-PD relationship. Current smokers who smoked 40 years or more had ORs as low as 0.30. Unlike the correlation between longer smoking and lower PD odds, smoking more than 10 cigarettes per day did not further reduce odds.

Moderate coffee intake (3.1 to 5 cups per day) (vs. no coffee intake) showed an OR of 0.45. Moderate alcohol intake (3.1 to 7 units per week) (vs. no alcohol use) was associated with an OR of 0.60; higher daily alcohol did not further reduce the odds of developing PD. Stronger negative OR for PD was found in smokers with medium-high coffee or moderate alcohol intake than with each alone. Coffee intake association with lower PD odds was found in men and women; only men showed lower risk estimates with caffeine and alcohol, largely attributed to beer consumption [14].

These findings were consistent with numerous prior studies, including publications from the prospective NIH-AARP Diet and Health Study [7,15]. In this study, 306,895 participants (58.8% male, 50 to 71 years of age) were evaluated in 1995–1996 and again in 2000–2006 for development of PD.

One NIH-AARP study examined caffeine intake, risk of PD, and whether smoking affected this relationship [15]. Higher caffeine use in 1995–1996 was associated with lower risk of PD diagnosis in 2000–2006 for men (OR=0.75) and women (OR=0.60). The linear trend for lower odds with higher caffeine was significant for both sexes [15].

The authors also performed a meta-analysis, which confirmed the inverse association between caffeine intake and risk for PD in men and women. Together with the study findings, this data led the researchers to conclude that gender differences do not influence caffeine risk reduction of PD. Smoking and caffeine may act independently to reduce PD risk [15].

Another NIH-AARP study examined cigarette smoking and risk of PD by comparing those who developed PD to those who did not. Odds for developing PD were 0.78 in past smokers and 0.56 in current smokers, with 0.47 in men and 0.74 in women. For few current smokers at baseline who developed PD, other comparisons were not relevant [16]. The greatest reductions in odds for PD were found with current smoking and higher daily amount/duration of past smoking [16].

In the NIH-AARP study, amount and type of alcohol use was studied for risk of PD. Compared to non-drinkers, the odds ratio for developing PD was 0.73 with 1 to 1.99 drinks of beer per day, 1.22 with liquor, and 0.74 with wine. Beer and liquor consumption showed opposite effects [17].

Higher circulating levels of uric acid have also been associated with decreased incidence of PD and with slower rate of decline in patients with PD. This suggests a link to the neuroprotective effects of caffeine and the purinergic system [7,18].

Identification of Environmental Risk Factors

A second line of investigation began when the first environmental risk factor was identified. In the early 1980s, a parkinsonism syndrome developed in persons who used a tainted street drug. An illicit lab produced a meperidine (Demerol) analog that contained 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic impurity. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B. MPP+ is a neurotoxin that, following dopamine neuron uptake via the dopamine transporter, destroys striatal dopamine neurons by inhibiting mitochondrial complex I activity. Ten persons who ingested this batch developed a severe, irreversible parkinsonism syndrome [19,20]. Extensive evaluation of these patients at onset and over time led to many breakthroughs in the understanding of PD and related conditions. Also identified were several persons with MPP+ exposure who developed mild-to-moderate, but not severe, parkinsonism. For the first time, an environmental factor was linked to PD pathogenesis, initiating environmental risk factor research. The variable consequences from exposure also helped prompt research into protective factors [19,21,22,23].

ENVIRONMENTAL RISK FACTORS

Pesticides (i.e., herbicides, insecticides, fungicides, and rodenticides) that increase the risk for developing PD include paraquat and rotenone. Neurotoxic mechanisms have been proposed based on findings that substances such as MPTP cause selective damage to dopaminergic neurons in the nigrostriatal pathway through mitochondrial complex I toxicity [7].

Paraquat exposure induces reactive oxygen species formation, and while not shown to stimulate Lewy body formation, it accelerates alpha-synuclein misfolding, disrupts membrane conductance, and accelerates protein aggregation [24,25]. Rotenone inhibits mitochondrial complex I, enhances alpha-synuclein fibril formation, and increases alpha-synuclein aggregation, modification, misfolding, and toxicity [26,27]. The data suggest environmental factors that increase oxidative stress or inhibit mitochondrial function can lead to alpha-synuclein misfolding and nigrostriatal damage, processes that underlie PD [7].

A retrospective study of methamphetamine or amphetamine use as a risk factor for PD/parkinsonism/essential tremor was performed by examining statewide medical records in Utah (1996 through 2011) for all persons 30 years of age and older. A methamphetamine/amphetamine cohort and cocaine cohort were compared to a population control cohort unexposed to drugs or alcohol. Methamphetamine/amphetamine users showed increased risk compared to population controls; cocaine users did not exhibit elevated risk of PD compared to controls. The nearly three-fold increased risk of PD in methamphetamine/amphetamine users confirmed prior observations and suggests PD risk in users may be higher than previous estimates. A suggestion that female and male users may differ in PD susceptibility warrants further study [28].

Pre-clinical research identified nicotine exposure as a possible protective factor against methamphetamine-induced dopaminergic deficits [29]. Using oral nicotine, researchers found that nicotine exposure from adolescence through mid-adulthood attenuated methamphetamine-induced striatal dopaminergic deficits associated with drug use in early adulthood. High-dose nicotine attenuated the negative effects of methamphetamine in late adolescence, but the protective effects did not persist. High-dose nicotine from post-adolescence to early adulthood did not protect against methamphetamine in very early adulthood, but high-dose nicotine from post-adolescence to full adulthood did protect against methamphetamine in mid-adulthood.

Nicotine neuroprotection is not due to nicotine alteration of methamphetamine pharmacology but from nicotine effects on nicotinic acetylcholine receptors (nAChRs). Imaging analysis found that nicotine increased striatal α4β2 nAChR expression, while methamphetamine and nicotine decreased striatal α6β2 nAChR expression. This suggests that nicotine protects against methamphetamine-induced striatal dopaminergic deficits by affecting α4β2 and/or α6β2 expression, with additional influence from nicotine exposure duration and the age of onset [29].

A meta-analysis of data from this study concluded that higher body mass index (BMI) in overweight (BMI 25–29.9) or obese (BMI ≥30) persons had no impact on the risk of developing PD [30].

GENETIC RISK FACTORS

Inherited genetic mutations are responsible for a small proportion of PD, with the most common genetic form of PD, PARK8, accounting for 2% of PD cases in the United States [31]. Penetrance is incomplete in this inherited parkinsonism, and PD manifestation in carriers is determined by environmental exposure or other genetic factors [31].

Idiopathic PD is a sporadic disorder, and twin studies have not shown a strong genetic basis in patients older than 50 years of age. However, genetic mutations have been increasingly mapped, and rare autosomal dominant and recessive familial forms have been identified in small numbers of patients. These include the SNCA, Parkin, PINK-1, DJ-1, GBA, and LRRK2 genes that code various proteins, with some carrying the same name as the mutation and components of the ubiquitin-protease system. In addition, mutations in the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, confer a greater risk of PD [32,33].

The protein alpha-synuclein is a key element in Lewy pathology and contributes to familial and sporadic PD. Duplications and triplications of wild-type SNCA, the gene encoding alpha-synuclein, have been identified in typical and early-onset PD, suggesting SNCA overexpression is related to PD pathogenesis [7].

RISK FACTOR INTERACTIONS

Gene-environment interactions in PD were examined by studying smoking and caffeine use interaction with 10 single nucleotide polymorphisms at or near four PD susceptibility genes in 584 patients with PD and 1,571 controls. Combining smoking and caffeine exposure showed significant interaction with one single nucleotide polymorphism at SLC2A13, near LRRK2. Each A allele was associated with a 35% increase in PD risk in never-smokers with low caffeine intake and a 32% lower risk in smokers with high caffeine intake. This study suggests a potential gene-environment interaction for PD [34].

History of traumatic brain injury also increases PD risk [35]. The SNCA Rep1 variation may mediate the association between brain injury and PD risk. Pooled results from two case-control studies found head injury unrelated to risk of later PD, but relative to subjects with medium-length Rep1 alleles, head injury was strongly associated with PD in those with long Rep1 alleles. Those with both head injury and long Rep1 were diagnosed with PD an average of five years before those with neither risk factor. High levels of alpha-synuclein (as with Rep1 expansion) may initiate and/or accelerate neurodegeneration following head injury [36].

5. PATHOPHYSIOLOGY

Unless otherwise stated, the following discussion pertains to sporadic (idiopathic) PD (i.e., cases lacking heritable/gene mutation cause).

DOPAMINERGIC PATHOPHYSIOLOGY AND LOSS OF MOTOR FUNCTION

PD is the most common neurodegenerative cause of parkinsonism, a syndrome characterized by progressive deterioration in motor abilities resulting from dopaminergic neuron loss in the substantia nigra pars compacta and ventral tegmental area. Dopamine neuron loss is most prominent in the ventral lateral substantia nigra; 60% to 80% of these neurons are lost when motor symptoms emerge and PD is diagnosed [8,12].

Substantia nigra pars compacta dopamine neuron loss and striatal dopaminergic deficits, including nicotinic receptor-mediated dopaminergic signaling, underlie motor symptom development in PD. The results of numerous studies linking cigarette smoking with protection against PD are explained by the actions of nicotine. Acetylcholine influences striatal dopamine release predominantly through action at nAChRs, and nicotine protects against nigrostriatal damage by stimulating nAChRs. Modulation of the nicotinic cholinergic system is an active area of PD research, also fueled by evidence that nAChR drugs may reduce PD progression and levodopa-induced dyskinesias [13,37].

Structural and Functional Pathophysiology

The origin of motor dysregulation in PD is neuronal degeneration in the substantia nigra pars compacta and loss of dopaminergic regulation of the striatum. The striatum is an entry point for cortical projections into the basal ganglia, and the basal ganglia-thalamocortical motor circuit modulates the cortical output required for normal movement. Cortical signaling enters the striatum and is processed through the basal motor circuit; motor circuit output is relayed through the internal globus pallidus and the substantia nigra pars reticulata. The basal ganglia circuit involves two dopaminergic pathways:

- The direct pathway of striatal neurons with dopamine D1 receptors, projecting to the globus pallidus and substantia nigra reticulata

- The indirect pathway of striatal neurons with D2 receptors, projecting to the striatum/external globus pallidus connection and the external globus pallidus/subthalamic nucleus connection

In PD, striatal dopamine depletion deactivates the excitatory D1 direct pathway and hyperactivates the inhibitory D2 indirect pathway. Alterations in these two pathways inhibit voluntary movement [7,8,12].

Pathogenic Mechanisms

There is a consistent line of evidence linking PD to a neurodegenerative process involving oxidative stress, mitochondrial dysfunction, and neuroinflammation. Environmental and genetic factors induce mitochondrial dysfunction, resulting in abnormal accumulation of miscoded proteins (mostly alpha-synuclein) and generation of oxidative stress in enteric, peripheral, and central nervous systems. In turn, oxidative stress, excitotoxicity, and mitochondrial dysfunction promote the destruction of dopamine neurons and dopaminergic function in midbrain systems [12,38,39,40].

CORE PATHOLOGIC FEATURES

Along with substantia nigra dopamine neuron loss, postmortem confirmation of PD diagnosis requires the presence of Lewy body pathology—intraneuronal aggregates of misfolded (pathogenic) forms of the protein alpha-synuclein. In addition to other pathologic effects, alpha-synuclein aggregates are associated with axonal and neuronal dysfunction, sequestration of vital neurotransmitter enzymes, and reduction or loss of cytoplasmic tyrosine hydroxylase and choline acetyltransferase. These effects compromise cellular integrity and fuel degeneration and contribute to neuronal death [41].

A third pathologic feature of PD is increased gliosis. Gliosis refers to an increased number and activation state of astrocytes and microglia, glial cell types that respond to injury or damage with altered morphology and production of inflammatory molecules. Increased gliosis is found in areas of neurodegeneration, which is not limited to the nigrostriatal pathway but evident throughout the brain to suggest a generalized neuroinflammation. Misfolded alpha-synuclein aggregates directly activate microglia, further linking alpha-synuclein and neuroinflammation to PD. These findings support a role of the innate immune system in the neurodegenerative process of PD [7].

DEVELOPMENT AND PROGRESSION OF PATHOPHYSIOLOGY

Neuroscience findings have transformed the concept of PD, now recognized as a disease with pathology distributed throughout the enteric, peripheral, and central nervous systems. Nigrostriatal motor pathology is one pathophysiologic phase on a continuum of processes that begin long before motor symptoms emerge [7,12,42].

An essential initiating event for PD is induction of alpha-synuclein misfolding. This is followed by aggregation of misfolded alpha-synuclein and initial formation of alpha-synuclein aggregates in neurons. Very few neuron types are vulnerable to alpha-synuclein inclusions; the most vulnerable are projection neurons with long, thin, sparsely myelinated axons. Glutamatergic, gamma aminobutyric acid-ergic, dopaminergic, noradrenergic, serotonergic, histaminergic, and cholinergic projection cells can become involved, but within neurotransmitter types, some subgroups are selectively vulnerable (dopaminergic substantia nigra pars compacta neurons) while others are not (dopaminergic hypothalamic neurons) [43].

Neurons with the greatest exposure to potentially hostile environmental factors are selectively vulnerable to alpha-synuclein inclusions. Aggregates form in these enteric, peripheral, and central neurons and propagate trans-synaptically from neuron to neuron. A regional distribution pattern of aggregated alpha-synuclein emerges through specific involvement of susceptible and axonally interconnected projection neurons within the nervous system [41].

Evidence indicates that PD originates in structures outside the brain, including the enteric nervous system of the gastrointestinal tract and salivary glands. The olfactory bulb has very early involvement. A primary route of disease progression is through enteric nervous system neuronal connections to the vagal nerve motor nucleus in the lower brainstem. The pathology then spreads through visceromotor and somatomotor brainstem centers to the locus coeruleus, basal forebrain, striatum, basal ganglia-thalamocortical motor circuit, central amygdala, and cortical structures. Other routes are through spinal cord centers via descending projections from lower brainstem nuclei and from autonomic projections connecting the enteric nervous system with spinal cord peripheral ganglia and preganglionic nuclei [7,8,41].

A classification method was developed to identify the extent of postmortem pathology resulting from PD. This system uses six stages to roughly demarcate the sequence of anatomic involvement and symptom emergence throughout the disease course (Table 2). The stages occur in two phases: the pre-clinical phase (stages 1 through 3) and the clinical, or motor, phase (stages 4 through 6). Each stage includes newly affected regions along with those involved in previous stages [8,41,42,44,45].

Table 2: STAGES OF PARKINSON DISEASE

Stage

Description

Preclinical phase

1

Lesions (Lewy body pathology/alpha-synuclein aggregates) develop in olfactory structures, salivary glands, enteric and peripheral autonomic nervous system, parasympathetic and sympathetic ganglion projection neurons, and lamina I of the spinal cord.

2

The pathologic process enters the lower brainstem, including vagal nerve projection neurons that connect the enteric nervous system with the central nervous system, the lower raphe nuclei, and the locus coeruleus.

3

Lesions spread in the midbrain tegmentum, the basal forebrain, and into the substantia nigra

Clinical (motor) phase

4

The pathology is entrenched in the substantia nigra pars compacta and infiltrates the amygdala, the intralaminar thalamic nuclei, and the hippocampal CA2 sector.

5

Lesions spread in the cingulate
and temporal cortex.

6

Lesions infiltrate the frontal and parietal cortex.

Source: [8,41,42,44,45]

PD is clinically diagnosed by the presence of cardinal motor features, broadly defined as bradykinesia, rest tremor, rigidity, and postural/gait impairment. The inclusion of postural/gait dysfunction in clinical criteria has been challenged, because it typically appears later in the disease course (instead of during the onset of motor symptoms) and is influenced by non-dopaminergic pathology primarily involving cortical cholinergic neurodegeneration [46].

NATURAL HISTORY OF DISEASE PROGRESSION

The progression of disease and disability in PD varies and is partially influenced by patient factors such as age. In general, from the mean age at diagnosis of 61 years, the mean time to death is 14 years overall. Survival time is a mean 24 years for patients diagnosed in their 40s and 9.7 years for patients diagnosed in their 70s [4]. With the onset of subclinical non-motor symptoms decades before diagnosis, pathologic processes that underlie PD are probably active over a 40-year period in many patients [45].

Throughout the disease course, all patients experience deterioration in motor function associated with increased impairment and disability and declining quality of life. The later stages of the disease are characterized by reduced efficacy of oral medication, increased medication-related side effects, dysphagia, cognitive dysfunction with conversion of mild cognitive impairment to dementia, reduced mobility with increased tendency to fall, and in many, dependence on others for activities of daily living. The mode of death often involves respiratory compromise from bronchopneumonia or aspiration [4].

Mild cognitive impairment later progressing to dementia is very prevalent in patients with PD, and roughly 80% of patients develop dementia within 20 years of diagnosis. Cerebrospinal fluid levels of alpha-synuclein predict the progression of cognitive decline in PD [47]. Dementia in PD and Alzheimer disease is associated with central nervous system (CNS) accumulation of protein aggregates such as b-amyloid peptide. B-amyloid peptide deposition in the striatum strongly correlates with dementia, suggesting this accumulation is a contributing factor to the development of cognitive impairment and neurodegeneration in PD [48]. Subjects with PD and dementia show degeneration of several subcortical nuclei, including the cholinergic nucleus basalis of Meynert, the medial substancia nigra, and the noradrenergic locus coeruleus. Presence of secondary neuropathologies may further increase oxidative stress, decrease brain energy, and enhance brain degenerative processes in patients with PD [12].

NON-MOTOR SYMPTOM APPEARANCE AND DISEASE STAGE

PD is typically diagnosed following the onset of motor features (stage 4) that prompts the patient to seek medical attention. Pre-motor prodromal disease can manifest in non-motor features, such as depression, fatigue, rapid eye movement (REM) sleep behavior disorder, anosmia, and constipation, that reflect disease involvement in autonomic, enteric, or somatomotor systems. Visuospatial and cognitive dysfunction, especially mild cognitive impairment with dominant executive dysfunction manifested in diminished multitasking, planning, retrieval, concentration, and attention performance, are increasingly recognized as prevalent in earlier stages [4]. As mentioned, physical appearance, severity, and progression of pre-motor and motor features corresponds to the nervous system and brain areas afflicted by pathologic infiltration [44,49,50,51].

Motor symptoms can also appear long before diagnosis. A prospective study found motor symptom onset 10 years before formal PD diagnosis. In this study, primary care patients were assessed for prodromal PD symptoms at three time points over 10 years. Symptom frequency was compared in patients later diagnosed with PD with those remaining PD-free (controls). Some symptoms were not analyzed [49]. Ten years pre-diagnosis, tremor was 7.6 times more likely and constipation twice as likely in patients who developed PD than in controls. Five years pre-diagnosis, patients who developed PD were more likely to show tremor, balance impairments, constipation, hypotension, erectile dysfunction, urinary dysfunction, dizziness, fatigue, depression, and anxiety than controls.

The progression of non-motor symptoms in PD, and stage of pathophysiologic progression that underlies their emergence, is shown in Table 3 [7,42,52].

Table 3: PATHOLOGY AND NON-MOTOR SYMPTOMS IN VARIOUS STAGES OF PARKINSON DISEASE

Non-Motor Symptoms

Stage

Symptoms/Signs

Affected Nervous System Areas

Sensory

Olfaction

1

Decreased odor detection, identification (hyposmia)

Olfactory bulb

Anterior olfactory nucleus

Pain

2, 3

Vague discomfort

Burning pain or paresthesia

Serotonergic pathways

Dopaminergic pathways

Autonomic

Gastrointestinal

1

Nausea

Constipation

Decreased gastric emptying

Colonic dysmotility

Esophageal dysmotility

Dorsal motor nucleus of the vagus

Enteric ganglia

Genitourinary

2

Urinary frequency, urgency

Incontinence

Erectile dysfunction

Gain setting neurons

Pelvic autonomic ganglia

Cardiovascular

1

Orthostatic hypotension

Dorsal motor nucleus of the vagus

Sympathetic ganglia

Thermoregulatory

3, 4

Hyperhydrosis

Hypohydrosis/anhydrosis

Sympathetic ganglia

Hypothalamus

Neuropsychiatric

Sleep disorders

2, 3

Sleep cycle disruption

Excessive daytime sleeping

REM sleep behavior disorder

Locus ceruleus/subceruleus

Raphe nuclei

Pedunculopontine nucleus

Suprachiasmatic nucleus

Behavioral disorders

2, 3

Apathy

Depression

Anxiety

Locus ceruleus

Raphe nuclei

Ventral tegmental area

Dementia

4, 5, 6

Bradyphrenia

Executive dysfunction

Memory decline

Visuospatial impairment

Dopaminergic (substantia nigra, ventral tegmental area)

Cholinergic (nucleus basalis of Meynert)

Cortical/subcortical pathology

Source: [7,42,52]

It should be noted that PD is heterogeneous, and not all patients exhibit full-blown motor and non-motor syndromes. Some patients exhibit motor features that remain modest in severity for many years, or cognitive and behavioral functions that appear normal or minimally affected. Overall, the clinical features are most easily viewed as motor and non-motor components of the PD phenotype [7].

PRE-MOTOR SYMPTOMS

Several pre-motor symptoms have been studied for their relationship to disease process and PD diagnosis.

REM Sleep Behavior Disorder

REM sleep behavior disorder is characterized by dream enactment behavior during sleep, including yelling, laughing, or crying; complex voluntary movements; falling out of bed; and even violent behaviors with injury. REM sleep behavior disorder is an extremely powerful predictor, or prodromal marker, of developing synuclein-mediated neurodegenerative diseases, which eventually occurs in at least 80% and most frequently involves PD [53,54].

A 16-year follow-up study of men diagnosed with REM sleep behavior disorder found that 80.8% eventually developed parkinsonism/dementia and were diagnosed with PD (62%); dementia with Lewy bodies (14%); multisystem atrophy (9.5%); clinically diagnosed, autopsy-confirmed Alzheimer disease plus Lewy body pathology (9.5%); or profound unspecified dementia (5%) [55]. Of those who progressed to parkinsonism, the mean age of REM sleep behavior disorder onset was 57.7 years; the mean age of parkinsonism/dementia onset was 71.9 years. Overall, the mean interval from REM sleep behavior disorder onset to parkinsonism/dementia onset was 14.2 years (range: 5 to 29 years). In these patients, lower brainstem involvement, particularly the pons, appeared long before the onset of motor features [55].

The first published methodology with high accuracy in predicting PD development used data from patients with REM sleep behavior disorder. These patients were regularly evaluated throughout the 10-year period following their initial REM sleep behavior disorder diagnosis. Using this data, prodromal markers of PD were analyzed for predictive validity. Factors that highly predicted PD when combined were (in descending order of strength) subtle motor dysfunction, nonuse of antidepressants, abnormal color vision, olfactory loss, and advanced age. Factors found non-predictive when aggregated were mild cognitive impairment, depression, "Parkinson personality," treatment with clonazepam or melatonin (for REM sleep behavior disorder), autonomic markers, and male sex [53].

Olfactory Dysfunction

Studies of olfaction in PD have shown abnormalities in up to 100% of patients, making olfactory dysfunction the most robust predictor of developing PD. As noted, many patients complain of declining sense of smell long before parkinsonism onset. As it is not disabling and relatively nonspecific, anosmia has mostly failed to gain traction as a predictive and clinical feature of PD [56].

Constipation

Constipation is a notoriously bothersome and common symptom in PD that results from peripheral autonomic involvement in the early pathogenic process [56]. Compared with middle-aged men who reported more than two bowel movements per day, men who reported fewer than one bowel movement per day were prospectively identified as more than four times more likely to develop PD. This suggests lower bowel involvement is an early sign that, in some patients, predated PD by 15 years or more [57].

Excessive Daytime Sleepiness

Excessive daytime sleepiness has also been identified as a midlife risk factor for PD, suggesting early brainstem involvement and subsequent sleep disturbances as a pre-diagnostic feature [58].

ASSESSMENT AND DIAGNOSIS OF PARKINSON DISEASE

As noted, parkinsonism refers to the motor features of bradykinesia, tremor, rigidity, and postural instability resulting from nigrostriatal dopamine neuron loss in PD, as well as dementia with Lewy bodies, multisystem atrophy, progressive supranuclear palsy, and corticobasal degeneration. PD is the most common neurodegenerative cause of parkinsonism, comprising 80% of cases [59].

The centrality of the motor syndrome remains the core feature that defines clinical PD and by which PD is diagnosed. However, the pathologic process of PD is now established as beginning in non-dopaminergic structures of the brain or peripheral nervous system, during which non-motor features dominate. This is reflected in a new diagnostic classification, prodromal PD, now considered a true stage of PD, and in the 2015 International Parkinson and Movement Disorder Society (MDS) PD diagnostic criteria that incorporate non-motor manifestations of PD [60].

Non-motor symptoms of PD appear before motor symptoms and are usually present at diagnosis or develop and progress in severity through the disease course. Non-motor symptoms may appear as early as three decades before motor features, during the prodromal PD phase. They are present earlier in the neurodegenerative process than motor features, which require 60% to 80% loss of dopaminergic neurons to emerge [42]. Criteria for prodromal PD have been published, and while early detection of PD before the onset of motor features could be immensely valuable, the absence of neuroprotective or disease-modifying therapy against PD, ethical issues from disclosure of disease risk, and the frequently shifting understanding of PD discourage any attempts to clinically diagnose the motor symptom prodrome of PD [61]. Nonetheless, identification and treatment of non-motor symptoms are essential due to their potentially great negative impact on patient well-being [1,8].

CLINICAL FEATURES

Motor Symptoms of PD

In PD, the cardinal motor features of bradykinesia, resting tremor, rigidity, and postural/gait impairment reflect parkinsonism [62]. A mnemonic for the core motor features is TRAP [7]:

- Tremor at rest

- Rigidity

- Akinesia (i.e., bradykinesia and hypokinesia)

- Postural instability

It is important to note that postural instability, while a cardinal motor feature, is seldom a problem early in the course of PD and may not be evident at diagnosis, as it usually appears later in the disease course [60].

Bradykinesia

Bradykinesia, as typically defined, combines the definitions of bradykinesia (slowness) and hypokinesia (decreased movement amplitude) [60]. Bradykinesia is reduced speed in initiating and executing movement, and altered fine motor control and dexterity. It is not just slowness in movements, but slowness in initiating voluntary movement, with progressive fatiguing during repetitive movements that presents in reduced speed and amplitude during finger or foot tapping. Slowness of movements, progressive reduction in speed and amplitude of repeated movements, delay in initiating movements, and freezing gait eventually occur in 80% to 90% of patients with PD [63].

Bradykinesia is the defining feature of parkinsonism and the essential clinical sign because the slowed, disordered motor movements directly correlate with functional abnormality in basal ganglia-cortical neuronal circuits, where aberrant dopamine-mediated firing patterns within indirect and direct pathways inhibit activity in cortical motor system neurons [4,7]. The slowed, small-amplitude movements in bradykinesia interfere with limb control, dexterity in tying shoes or buttoning shirts, and swallowing (dysphagia). It may also present as decreased facial expression and eye blinking (hypomimia), weak voice (hypophonia), and progressively smaller handwriting (micrographia) [4,62,64].

Rigidity

Rigidity is increased muscle tone in flexor and extensor muscle groups at rest and resistance to passive stretch movement in flexor and extensor muscles with the limb relaxed. Rigidity is present in 80% to 90% of patients with PD, usually unilaterally at the onset of motor symptoms. It often, but not always, co-occurs with tremor. Rigidity results from altered firing rates in the basal ganglia, a fundamental feature of parkinsonism. The resultant motor system output reflects inappropriate activation of agonist and antagonist muscles that present in bradykinesia and rigidity [7]. In early-stage disease, rigidity may manifest as pain, such as frozen shoulder or low back pain, obscuring the diagnosis of a CNS disorder [4].

Rest Tremor

Rest tremor, an initial symptom in 70% to 90% of patients, refers to a 4–6 Hz tremor in the fully resting limb, suppressed during movement initiation. Rest tremor is a rhythmic, oscillatory involuntary movement and one of the most characteristic signs in clinical medicine. The most distinguishing rest tremor is the "pill-rolling" type, with rubbing movements of thumb and index fingers against each other. Rest tremor is thought to initiate with nigrostriatal degeneration and subthalamic nucleus or globus pallidus disinhibition, or disrupted thalamo-cortical-cerebellar circuits leading to abnormal thalamic pacemaker cell function [4,7].

Tremor in parkinsonism is distinct from other forms of tremor by its asymmetry, speed, dominance at rest, reduction or cessation during action, re-emergence when maintaining a posture, and increased amplitude during tasks requiring mental concentration [4].

Postural Instability

Postural instability is defined as difficulty adjusting to postural change, and together with gait impairment and postural abnormalities, it comprises the axial motor signs of PD [65]. Postural instability and other axial signs do not usually present in early PD, reflecting pathophysiology beyond dopamine motor neuron loss [7]. As such, the inclusion of axial signals in the cardinal motor features required for the parkinsonism diagnosis in PD has been challenged [60].

Postural and gait impairment result from loss of postural reflexes, which leads patients to adopt a stooped posture. The loss of postural reflexes is also a major contributor to falls [66]. In PD, the gait is slow, with short shuffling steps on a narrow base that appears as if the patient is chasing his or her own center of gravity. Patients show decreased arm swing; turning around is slow, with multiple small steps, and freezing gait can occur, especially in crowded or narrow places. Festination, a very fast succession of steps with the patient only able to stop when meeting an obstacle, may also be present. Walking and turning becomes difficult or impossible in patients with PD when additional cognitive load, such as dual tasking, is imposed [67,68].

Brainstem pathology is now recognized as a major contributor to the clinical features in PD. Postural control problems with imbalance, falls, and freezing gait tend to occur later in PD and reflect cholinergic neuron degeneration and dysfunction outside of the basal ganglia [7]. Persons with parkinsonism or other extrapyramidal neurodegenerative disorders frequently develop problems with balance and may experience frequent falls. The vestibular system controls balance and is synaptically linked to the extrapyramidal system, possibly contributing to posture and balance dysfunction [62].

Non-Motor Symptoms

The frequency and diversity of non-motor symptoms in PD is substantial, and includes autonomic, neuropsychiatric, olfactory, sensory, and sleep disorders that occur in 80% to 90% of patients (Table 4). Non-motor symptoms can manifest before, during, or after motor symptoms and may result in greater impairment of quality of life. The prevalence of cognitive, autonomic, and mood disorders is very high; progression can result in patients requiring care in a supervised environment [7].

Table 4: NON-MOTOR SYMPTOMS IN PARKINSON DISEASE

Category

Symptoms

Autonomic dysfunction

Constipation

Orthostatic hypotension

Sexual dysfunction

Sweating

Urinary retention and urgency

Sialorrhea (also from decreased swallowing movements)

Neuropsychiatric

Apathy

Anxiety, panic attacks

Cognitive deterioration, from mild impairment to dementia

Depression (dysphoria, suicidal ideation)

Impulse-control disorders (e.g., obsessions, hypersexuality, compulsive shopping, binge eating), usually associated with dopamine agonist use

Psychoses (hallucinations, delusions)

Sensory symptoms

Olfactory dysfunction (hyposmia)

Paresthesias (tingling, numbness), other abnormal sensations

Decreased visual contrast and color discrimination

Decreased visual motion perception

Sleep disturbance

Daytime somnolence

Insomnia

REM sleep behavior disorder

Restless legs syndrome

Sleep attacks

Sleep apnea

Other

Fatigue

Pain

Weight loss

Source: [1,4]

A 2010 survey found that up to 62% of patients with PD do not volunteer symptoms such as apathy, pain, sexual dysfunction, bowel incontinence, constipation, or sleep disorders either through embarrassment or unawareness of symptom relevance to PD. Clinicians may not understand that these symptoms require assessment. Their under-reporting has important therapeutic and societal implications, as most are treatable. Left unaddressed, non-motor symptoms detrimentally affect patient quality of life, frequently lead to hospitalization and institutionalization, and quadruple the cost of PD care [69].

6. DIAGNOSTIC WORKUP

Disease-specific screening tests or biomarkers for PD are not yet available, and definitive diagnosis is only possible at autopsy by confirmation of striatal dopamine neuron loss and Lewy body pathology [64]. Idiopathic PD is diagnosed through patient history and physical examination, often performed sequentially over time in order to identify signs of progression and the emergence of defining clinical features. History or physical findings inconsistent with features of idiopathic PD are explored further to rule out or confirm an alternate diagnosis. Clinicians with limited experience caring for patients with PD should consider referring a patient with suspected disease to a physician with expertise in movement disorders to confirm diagnosis [2].

DIAGNOSTIC CRITERIA

Evidence Based Practice Recommendation

According to the European Academy of Neurology and the Movement Disorders Society European Section, only the Brain Bank clinical diagnostic criteria for Parkinson disease have been validated and are therefore recommended as probably effective for clinical practice.

https://www.movementdisorders.org/MDS-Files1/MDS-ES/MDS-ES--EFNS/BerardellietalEFNSMDSESene12022.pdf

Last Accessed: April 11, 2019

Level of Evidence: B (At least one convincing prospective study or overwhelming evidence from retrospective studies)

The UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria have been the most widely used diagnostic criteria for PD, recommended for use in North America and Europe as a straightforward, objective, and accurate approach (Table 5) [4,63,71]. With these criteria, three major steps are required for PD diagnosis. The presence of parkinsonism must be established, but parkinsonism is non-specific to PD and additional steps are required for a PD diagnosis.

Table 5: UK BRAIN BANK CLINICAL DIAGNOSTIC CRITERIA FOR PARKINSON DISEASE

Step

Criteria

Step 1: Diagnosis of parkinsonian syndrome

Bradykinesia and one or more of the following:

- Muscular rigidity

- Resting tremor 4–6 Hz

- Postural instability (not due to primary visual, vestibular, cerebellar, or proprioceptive dysfunction)

Step 2: Exclusion criteria for Parkinson disease

History of repeated strokes with stepwise progression of parkinsonian features

History of repeated head injury

History of definite encephalitis

Oculogyric crises

Neuroleptic treatment at onset of symptoms

More than one affected relative

Sustained remission

Strictly unilateral features after three years

Supranuclear gaze palsy

Cerebellar signs

Early severe autonomic involvement

Early severe dementia with disturbances of memory, language, and praxis

Babinski sign

Cerebral tumor or communicating hydrocephalus on computed tomography scan

Negative response to large-dose levodopa

MPTP exposure

Step 3: Supportive positive criteria of Parkinson diseasea

Unilateral onset

Rest tremor present

Progressive disorder

Persistent asymmetry affecting side of onset most

Excellent levodopa response (70% to 100% symptom reduction)

Severe levodopa-induced chorea

Levodopa response ≥5 years

Clinical course ≥10 years

aThree or more required for diagnosis of definite PD.

Source: [71]

However, the UK Brain Bank diagnostic criteria were established more than 20 years ago (in 1992) and solely address motor symptoms, leading many to consider them outdated. This led to the 2015 publication of new PD diagnostic criteria by the MDS Task Force, comprised of North American and European experts. These criteria better reflect current understanding of PD as a multi-system disorder affecting all parts of the nervous system, often with a genetic component and a very slow progression of neurodegenerative processes reflected in a long prodromal period. These aspects are incorporated in the new criteria [60].

The first essential criterion of the MDS Clinical Diagnostic Criteria for PD is parkinsonism, defined as bradykinesia with rest tremor and/or rigidity [60]. Examination of cardinal motor features should follow as described in the MDS-United Parkinson Disease Rating Scale (UPDRS) [72]. After parkinsonism is diagnosed, PD may be diagnosed as either clinically probable or established based on the presence or absence of absolute exclusion criteria, supportive criteria, and guideline-defined "red flags" (Table 6) [60]. Clinically probable PD diagnosis requires [60]:

- Absence of absolute exclusion criteria

- Presence of no more than two red flags counterbalanced by supportive criteria

- If one red flag is present, there must also be at least one supportive criterion

- If two red flags, at least two supportive criteria are needed

Table 6: MDS CLINICAL DIAGNOSTIC CRITERIA FOR PD

Absolute exclusion criteria

Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar oculomotor abnormalities (e.g., sustained gaze evoked nystagmus, macro square wave jerks, hypermetric saccades)

Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades

Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia within the first five years of disease

Parkinsonian features restricted to the lower limbs for more than three years

Treatment with a dopamine receptor blocker or dopamine-depleting agent in a dose and time-course consistent with drug-induced parkinsonism

Absence of observable response to high-dose levodopa despite at least moderate disease severity

Unequivocal cortical sensory loss (i.e., graphesthesia, stereognosis with intact primary sensory modalities), clear limb ideomotor apraxia, or progressive aphasia

Normal functional neuroimaging of the presynaptic dopaminergic systema

Documentation of an alternative condition known to produce parkinsonism and plausibly connected to the patient's symptoms, or the expert evaluating physician, based on the full diagnostic assessment, feels that an alternative syndrome is more likely than PD

Supportive criteria

Clear, dramatic benefit to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. In the absence of documented initial response, dramatic response can be classified as:

- Marked improvement with dose increases or marked worsening with dose decreases. Mild changes do not qualify. Document objectively (>30% change in MDS-UPDRS) or subjectively (clearly documented history of marked changes from a reliable patient or caregiver)

- Unequivocal and marked on/off fluctuations, which must have at some point included predictable end-of-dose wearing off

Presence of levodopa-induced dyskinesia

Rest tremor of a limb, documented on clinical exam (past or present)

Presence of olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy

"Red flags"

Rapid progression of gait impairment requiring regular use of wheelchair within five years of onset

Total absence of motor symptom/sign progression over five or more years, unless the stability is treatment-related

Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first five years

Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent inspiratory sighs

Severe autonomic failure in the first five years of disease, such as:

- Orthostatic hypotension (orthostatic decrease of blood pressure within three minutes of standing by ≥30 mm Hg systolic or ≥15 mm Hg diastolic) in the absence of dehydration, medication, or other diseases explaining autonomic dysfunction

- Severe urinary retention or incontinence (nonfunctional) in the first five years of disease (excluding long-standing or small-amount stress incontinence in women). In men, urinary retention is not from prostate disease and must be associated with erectile dysfunction

Recurrent (more than once per year) falls from impaired balance within three years of onset

Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 years

Absence of common non-motor PD features, despite five years disease duration. Includes sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, anxiety, hallucinations)

Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic hyper-reflexia (excluding mild reflex asymmetry and isolated extensor plantar response)

Bilateral symmetric parkinsonism: patient/caregiver report of bilateral symptom onset without side predominance confirmed by objective exam

Prominence of postural instability early in the course of the disease

aExclusion of this criterion does not imply dopaminergic functional imaging is required for diagnosis. If no imaging has been performed, this criterion does not apply.

MDS-UPDRS = Movement Disorder Society-Unified Parkinson Disease Rating Scale, MIBG = meta-iodobenzylguanidine, NG = nasogastric.

Source: [60]

A diagnosis of clinically established PD is made if the patient displays [60]:

- Absence of absolute exclusion criteria

- At least two supportive criteria

- No red flags

The MDS PD criteria note that the establishment of parkinsonism motor features remains the foundation of PD diagnosis, but several pre-motor features are woven into the overall criteria [60]. While postural instability is a feature of parkinsonism, it is not a criterion for parkinsonism in the MDS guideline. Dementia with Lewy bodies is not considered an alternative parkinsonian syndrome; these patients can be diagnosed as PD (dementia with Lewy bodies subtype).

PATIENT HISTORY

Idiopathic PD is diagnosed by history and physical examination. The first step in the diagnostic process is taking a careful history by thoroughly questioning the patient and/or family members regarding [1,4,62]:

- Symptoms that emerged, their sequence, and perceived anatomical involvement, including symptoms that suggest bradykinesia, rigidity, resting tremor, and/or postural instability

- The presence and onset of pre-motor symptoms:

- Neuropsychiatric symptoms

- Autonomic dysfunction

- Sleep disorders

- Sensory symptoms

- Fatigue

- Past and present medical disorders

- Family history, including neurologic disorders and ethnic ancestry, as monogenic forms of PD are more frequent in some ethnic groups (e.g., LRRK2 in Ashkenazi Jews and North African Arabs)

- Exposure to illicit drugs associated with parkinsonism (e.g., methamphetamine, amphetamine)

- Environmental toxin exposure (e.g., manganese in welders)

It is also important to explore the possibility of prescription drug-induced parkinsonism. This is one of few reversible causes of the disorder, and identification by a complete medication evaluation will help avoid inappropriate treatment. The most frequent causes of drug-induced parkinsonism are typical antipsychotics (e.g., haloperidol, chlorpromazine), most atypical antipsychotics (e.g., risperidone, olanzapine), and the gastrointestinal agents prochlorperazine, promethazine, and metoclopramide. Infrequent causes are tetrabenazine, reserpine, methyldopa, flunarizine, cinnarizine, verapamil, valproic acid, and lithium. In one study of 155 cases of drug-induced parkinsonism between 1995 and 2009, 70% of patients developed symptoms within three months of beginning the prescribed medication; the remaining patients all developed symptoms within one year on the offending drug [150]. Recovery from drug-induced parkinsonism can be expected following discontinuation of the medication, though many weeks to months may be required for full resolution of symptoms.

The propensity for antipsychotic drugs to produce parkinsonian side effects has implications for managing patients with PD who experience psychosis as a complication of the disease. For such patients, some have recommended using clozapine, with quetiapine as a second-line option [1].

NEUROLOGIC EXAMINATION

A neurologic examination is performed to provide objective evidence of motor symptoms in the absence of other abnormalities. Simple observation will often reveal a generalized slowness and lack of spontaneous movement. Findings of parkinsonism motor features supported by patient history, confirm a diagnosis of idiopathic PD. Idiopathic PD will demonstrate any combination of the following, and motor symptom findings are usually asymmetrical [63].

Bradykinesia

To assess bradykinesia, ask the patient to perform repetitive movements as quickly and widely as possible, such as opening and closing the hand, tapping thumb and index fingers, or tapping the foot on the ground. Progressive slowness and/or loss of amplitude should emerge and may bring the movement to full arrest (freezing). To globally assess bradykinesia, observe spontaneous movements while the patient is sitting, standing up from a chair, or walking [62,64]. To avoid misdiagnosis, distinguish clinical bradykinesia from simple slowness in patients with decreased muscle power, spasticity, or reduced motivation in depression or in normal elderly populations that reflect non-specific slowness [62,64].

Rigidity

Rigidity refers to "leadpipe" resistance, whereby velocity-independent resistance to passive movement is not influenced by an inability to relax (i.e., distinct from spasticity). This resistance is felt throughout the full range of movement, and unlike spasticity, it does not increase with higher mobilization speed. When resting tremor co-occurs with rigidity, "cog-wheel rigidity" can be felt during passive limb mobilization, especially in the wrist. When assessing rigidity, interruption of passive movement by a "cog-wheel" movement reflects the underlying 4–6 Hz tremor oscillation. In contrast, pyramidal tone (spasticity) is dependent on the velocity of passive movement and is described as ''clasp knife'' in quality because of the higher resistance during early acceleration of the passive movement followed by giving way, such as is seen when opening lock-blade knives [62]. Rigidity is assessed by passive movement of a joint and reinforced by asking the patient to move the opposite limb in a circular motion or open/close a fist.

Tremor

Resting tremor is often observed in patients with PD, and postural tremor and re-emergent resting tremor may be seen with arms outstretched. Resting tremor is best observed in the hands during patient focus on a mental task (e.g., eyes-closed countdown from 100) that facilitates muscle relaxation; in the legs with the patient seated on the edge of an exam table, with legs hanging and feet unsupported; and in the jaw when the patient is engaging another part of the body in activity [4,62].

Gait

Gait may be stooped or shuffling, with reduced arm swing. Patients often turn en bloc, requiring numerous steps to complete a 180° turn. The pull test (briskly pulling the patient backwards while standing) may be used to assess postural reflexes. Loss of postural reflexes generally occurs in later-stage disease.

DIAGNOSTIC CONFIRMATION

Unless signs or symptoms are observed that are inconsistent with idiopathic PD (i.e., MDS absolute exclusion criteria or red flags), no further testing is needed with history and exam findings consistent with idiopathic PD. Imaging tests are used only to confirm absolute exclusion criteria findings or to rule out or confirm red flag findings [60].

Evidence Based Practice Recommendation

The American College of Radiology recommends non-contrast magnetic resonance imaging (MRI) of the head in patients with Parkinson disease with typical clinical features and responsive to levodopa only for problem-solving purposes.

https://acsearch.acr.org/docs/69360/Narrative

Last Accessed: April 11, 2019

Strength of Recommendation: 7 (Usually appropriate)

However, there are a variety of special procedures available that help to confirm diagnosis, obtain additional information on disease type or severity, and differentiate PD from disease mimics (Table 7). Dopaminergic challenge tests that elicit objective improvement in motor function and alleviation of symptoms provide positive evidence for the diagnosis, although support is not universal [63,73]. Olfactory testing can help substantiate a PD diagnosis, is inexpensive, is extensively validated, and contributes to the early diagnosis and differential diagnosis of PD. Although it can help identify patients with pre-motor symptoms of PD, use alone is not diagnostic [1,63,74].

Table 7: EFNS/MDS-ES RECOMMENDATIONS FOR DIAGNOSTIC INSTRUMENT USE IN PARKINSON DISEASE

Diagnostic Modality

Level of Evidence

Indications for Use

Genetic testing

SNCA gene point mutations and multiplication

B

PD families suggestive of dominant inheritance

LRRK2 and known pathogenic variants

B

Typical PD with family history suggestive of dominant inheritance

Sporadic PD from specific populations with known founder effect mutations

GBA mutations

B

Founder effect mutations in PD cases in specific populations (e.g., Ashkenazi Jewish) with or without positive family history

Parkin, PINK1, DJ-1 mutations

B

PD with onset before 50 years with family history suggestive of recessive inheritance

Sporadic PD with onset before 40 years

ATP13A2, PLA2G6, FBX07

B

Very early onset PD cases

Olfactory tests

University of Pennsylvania Smell Identification Test (with other diagnostic tests)

A

PD versus atypical and secondary parkinsonism

A

Idiopathic PD versus recessive PD forms

A

Pre-motor PD

Neuropsychologic testing

Collateral history from a carer, cognitive assessment, and screening of REM sleep behavior disorder, psychosis, severe depression

A

During initial evaluation to exclude other causes of parkinsonism in patients with suspected PD

Transcranial sonography

Use with other diagnostic tests

A

Differential diagnosis of PD from atypical and secondary parkinsonism

A

Early diagnosis of PD

A

Detection of subjects at risk for PD

Magnetic resonance imaging (MRI)
in differential diagnosis

Conventional 1.5-Tesla MRI

A

Differential diagnosis of multisystem atrophy from PD

B

Differential diagnosis of progressive supranuclear palsy from PD (detection of midbrain atrophy and/or SCP atrophy)

C

1.5-Tesla diffusion-weighted MRI

A

Differential diagnosis of multisystem atrophy from PD (identification of putaminal diffusivity changes)

B

Differential diagnosis of progressive supranuclear palsy from PD (identification of SCP diffusivity changes)

Single photon emission tomography (SPECT) in differential diagnosis

123Ioflupane SPECT

A

Differential diagnosis of essential tremor from PD and atypical parkinsonism

123I-MIBG SPECT

A

Differential diagnosis of PD from multisystem atrophy

EFNS/MDS-ES = European Federation of Neurological Associations/Movement Disorders Society–European Section, MIBG = meta-iodobenzylguanidine, SCP = superior cerebellar peduncle.

Levels of evidence: A = effective, B = probably effective, C = possibly effective.

Source: [63]

Recommendations for genetic testing in diagnosing PD are inconsistent. Some view this testing as questionable in benefit due to lack of clarity on which populations to test, the consequences of test results, and cost issues [1]. Others highly recommend use of genetic testing to identify parkinsonism and PD genotypes that differ in clinical course, prognosis, and treatment response from idiopathic PD [63,74].

Some have suggested assessing all patients younger than 40 years of age with suspected PD for Wilson disease. Wilson disease is confirmed by low serum ceruloplasmin, elevated 24-hour urine copper, or the presence of Kayser-Fleischer rings on slit-lamp examination [73].

SCREENING TESTS

Screening tests are used to help identify common comorbidities, including depression and dementia in patients with PD. The American Academy of Neurology (AAN) recommends the following assessment tools when screening for comorbid conditions [75,76]:

- Depression: Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), Geriatric Depression Scale (GDS)

- Dementia: Cambridge Cognitive Examination (CAMCog), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA)

The MDS-UPDRS is widely used in research and in clinical practice to standardize the neurologic exam and present the findings as a pre-determined Likert scale. The UPDRS can be used to assess the clinical status of patients with PD during follow-up. This instrument assesses motor features, psychologic features, activities of daily living, and treatment complications. Increases of 2.5 and 4.3 points in UPDRS motor and total scores, respectively, indicate clinically relevant change [77,78].

If cognitive impairment is noted on mental status examination, magnetic resonance imaging (MRI) and neuropsychologic testing should be used to distinguish PD with dementia from other neurodegenerative disorders [1].

DIFFERENTIAL DIAGNOSIS

The diagnostic assessment of a patient suspected of having PD should include consideration of other, possibly reversible, disorders that may present with motor signs of parkinsonism. These are often referred to as "atypical" PD or "mimics" of PD and include [62,64]:

- Essential tremor

- Neurodegenerative syndromes

- Multisystem atrophy

- Progressive supranuclear palsy

- Corticobasal degeneration

- Dementia with Lewy bodies

- Symptomatic syndromes of non-neurodegenerative underlying cause:

- Drug-induced parkinsonism

- Vascular parkinsonism (i.e., ischemia/infarcts in the basal ganglia)

- Infectious disease (e.g., acquired immunodeficiency syndrome, subacute sclerosing panencephalitis, postencephalitic parkinsonism, prion disease)

- Neurotoxin exposure (e.g., carbon monoxide, manganese, MPTP)

- Structural disorder (e.g., tumor, hydrocephalus, subdural hematoma, trauma)

- Metabolic disease (e.g., Wilson disease, hypothyroidism)

- Other secondary causes

Assessment

Clues from the medical history and atypical exam findings should prompt a careful work-up to rule out or confirm an alternate diagnosis. The most common syndromes mimicking PD are essential tremor, vascular parkinsonism, Lewy body dementia, progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and drug-induced parkinsonism (Table 8). Neurologic consultation and neuroimaging studies are often needed to adequately assess many of these possibilities [1,2,63,79,80].

Table 8: SYNDROMES THAT MAY MIMIC PARKINSON DISEASE

Syndrome

Signs/Symptoms Resembling Parkinson Disease

Differentiating Tests

Essential tremor

Appears or worsens with movement

Symmetrical presentation

Affects distal extremities, head, and voice

Family history common

Improves with alcohol and/or beta-blockers

Dopamine transporter scan

Vascular parkinsonism

Symmetrical lower body manifestation

Gait highly affected

Rest tremor uncommon

Cognitive impairment

Poor levodopa response

Significant small vessel disease or basal ganglia lacunar infarct(s) on brain MRI

Dopamine transporter scan

Drug-induced parkinsonism

Akinesia and bradykinesia

Patient medication history, particularly for dopamine antagonists (e.g., clozapine)

Lewy body dementia

Dementia

Vivid visual hallucinations

Marked fluctuating mental status

History may be sufficient for diagnosis

Neuropsychologic testing to distinguish domains of cognitive deficits

Dopamine transporter scan to distinguish from non-Lewy body dementias (e.g., Alzheimer disease)

Progressive supranuclear palsy

Gaze palsies

Early falls within one year of diagnosis

Neurologic examination findings of vertical gaze palsy and significant postural instability

Evidence of midbrain atrophy on brain MRI (suggestive, not definitive)

Multisystem atrophy

Autonomic dysfunction with symptomatic hypotension, constipation, urinary urge incontinence, fecal incontinence, urinary retention, persistent erectile dysfunction

Speech or bulbar dysfunction

Pyramidal or cerebellar dysfunction

Poor levodopa response

Neurologic examination findings of deficits outside the extrapyramidal system

Pontine and cerebellar atrophy on brain MRI (suggestive, not definitive)

Electromyography findings of denervation and re-innervation of rectal sphincter muscle

Corticobasal degeneration

Apraxia

Alien limb phenomenon

Cortical sensory loss

No tests required

Source: [1,2,63,79,80]

Importance of Establishing a Diagnosis

Defining the presence of parkinsonism is the first step to considering therapeutic options and differentiating PD from other primary central nervous system disorders, such as progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, and vascular parkinsonism. While these alternative diagnoses will not expand the options for disease-modifying or curative therapies, arriving at a definitive diagnosis is important for purposes of patient and family education, prognosis, reassurance, and options for therapy. A definitive diagnosis gives a name to the condition. This is very important for the patient experience and helps in coming to terms with a chronic disease. An "atypical parkinsonism" or "parkinsonian syndrome" diagnosis leaves patients and family with vague uncertainty and fails to provide a clear basis for management decisions and prognosis. A hierarchical list of diagnostic possibilities should be discussed if definitive diagnosis is elusive. Diagnostic criteria for progressive supranuclear palsy, corticobasal degeneration, and multisystem atrophy allow for possible and probable diagnostic categories, according to diagnostic certainty [4].

7. TREATMENT OF PARKINSON DISEASE

Although no cure for PD is yet available, some degree of disease modification and significant alleviation of motor symptoms can be achieved with drug combinations that enhance tissue levels of dopamine, thereby promoting dopaminergic activity. Treatment strategies for PD are influenced by stage of disease, problematic symptom profile, and patient age. Clinical decision-making should balance possible efficacy with potential side-effect risk for each treatment option. Treatment decisions should be based on the best available evidence for each intervention. Pharmacotherapy should be accompanied by non-medical interventions, as needed, for gait and balance dysfunction, vocal impairment, and other motor, non-motor, and comorbid conditions [74].

Management of PD begins at the time of diagnosis but may not require immediate initiation of drug therapy. Early issues for consideration include information delivery, sources of support, counseling to facilitate a realistic view of what to expect going forward, discussion of prognosis, and potential treatment options. These conversations usually take place over several visits and should include discussion of available medical therapies for PD. When possible, these initial meetings should include family members [4].

OVERVIEW OF TREATMENT APPROACHES THROUGH DISEASE PROGRESSION

Initial treatment of early PD generally involves monotherapy, and motor control problems can be improved in many patients. Treatment of later PD becomes more complicated, with disease progression and prolonged dopaminergic drug administration. Requirements for dopamine replacement therapy become increasingly demanding as motor signs worsen. Patients initially well controlled using dopamine agonists require initiation of levodopa and, over time, increasing amounts given in higher doses with more frequent intervals. Patients initiated on levodopa will require the addition of dopamine agonists and/or other adjuncts that improve response to levodopa [81].

Levodopa therapy is commonly withheld until motor symptoms begin interfering with normal patient functioning. This is based on the assumptions that:

- The period of improved motor control is finite, and levodopa therapy is more valuable in later disease, when symptom improvement is greater.

- Deferring levodopa initiation defers the onset of dyskinesias.

- Early symptomatic treatment has no effect on disease course.

However, there is some evidence that initiating levodopa in early PD and maintaining the dose less than 400 mg/day reduces dyskinesia onset, and early use of levodopa has been shown to be the most effective treatment for motor symptoms, with long-term risk of dyskinesia minimally affected by early use of less than 400 mg/day. It appears that disease stage has a greater influence on the development of levodopa-induced dyskinesia than medication duration [81,82,83].

Some PD motor symptoms show preferential dopaminergic response. For example, bradykinesia and rigidity show the most robust levodopa response. Rest tremor severity correlates poorly with the other cardinal symptoms and extent of dopamine neuron loss and inconsistently responds to dopaminergic therapy. This sign may originate from a trigger in the basal ganglia, with contributions from cerebellothalamic pathways. Freezing gait and imbalance with frequent falls also poorly respond to dopaminergic treatment [7].

Added complexity comes with progression from later to advanced PD. The onset of motor fluctuations and motor complications (e.g., dyskinesia, freezing) create the greatest challenge to treatment efforts to maintain mobility and function in earlier disease. Predicting the onset of motor complications and fluctuations in individual patients is very difficult, but disease duration and stage, dose and duration of levodopa exposure, sex, and body weight are contributing factors [81].

Even if motor symptoms are well controlled, numerous non-motor components of PD will emerge and can be intensely burdensome to patients. Many non-motor symptoms lack response to dopaminergic medications, reflecting progression beyond the dopamine neuron motor system and extensive disease involvement in the cortical and frontal lobes and widespread central neuropathology. Only recently have non-motor symptoms received adequate research attention, and for some of these syndromes, effective treatments have been identified and become available or their final regulatory evaluation is in progress [77,81].

MEDICATION NON-ADHERENCE

An important issue, unaddressed by practice guidelines, is medication non-adherence in patients with PD. While the prevalence of non-adherence broadly varies by assessment method, the figures range from 15% to 20% using patient self-report to 67% or more using pharmacy refill data and pill counts [84]. An important dimension in PD treatment is timing adherence, as dopaminergic medications should be taken at precise and evenly spaced intervals, as instructed by the prescribing physician. Non-adherence to timing of dosage is probably very common and contributes to unwanted dopamine variability implicated in earlier onset of motor fluctuations [85]. The overall consequence of non-adherence is unsatisfactory motor control, with diminishing mobility, greater fluctuations, dyskinesias, and declining quality of life [86].

In chronic diseases, highest medication adherence occurs with once-daily formulations, but this sharply decreases with each added daily dose [87]. Polypharmacy in PD is normative, with most patients taking two or more antiparkinsonian drugs and additional medications for non-motor symptoms and comorbidities. In addition to the risk of non-adherence that directly correlates with the number of prescriptions and daily doses per prescription, many patients with PD experience depression and/or cognitive impairment, both of which are strong independent risk factors for medication non-adherence [86].

Medication non-adherence among patients with PD should be recognized as a common, under-reported, detrimental, and costly cause of suboptimal disease control. Reliance on clinical judgment to identify non-adherence is demonstrably inaccurate, and healthcare professionals should use nonjudgmental interviewing skills that encourage patient admission of their non-adherence without fear or concerns of disapproval or termination of care. Barriers to adherence should be explored and clinical resources applied to surmount them. These include simple explanations of how medications optimally work when taken correctly and referral to non-adherence counseling. To avoid unnecessary dose escalations, adverse effects, and increased patient and healthcare costs, non-adherence should be explored before a drug regimen is deemed ineffective [86].

PHARMACOTHERAPIES

Levodopa

Exogenous dopamine administration is ineffective for treating PD, because circulating dopamine does not cross the blood-brain barrier and is thus unable to reverse brain dopamine depletion. Levodopa is a dopamine prodrug that does cross the blood-brain barrier, where it is converted by aromatic amino acid decarboxylase (AAAD) to dopamine. The regular administration of oral levodopa leads to repletion of dopamine in the substantia nigra pars compacta, and to storage in presynaptic dopamine neurons for subsequent use. The majority of patients treated with levodopa realize significant and prolonged improvement in motor function, though there are side effects and, in time, many patients experience fluctuations in beneficial effects of the drug. Levodopa was introduced for use in PD in the late 1960s, and remains the criterion-standard treatment [7].

The bioavailability of orally administered levodopa is compromised by extensive metabolism to dopamine in the gut. Only 30% of an oral dose reaches systemic circulation for distribution to the brain. For this reason, Levodopa used to treat PD is always combined with carbidopa, a peripherally acting AAAD inhibitor. Carbidopa reduces the peripheral conversion of levodopa to dopamine, which triples levodopa bioavailability and lowers dosage requirements. Carbidopa 75–100 mg/day is required to inhibit peripheral conversion of levodopa to dopamine. Carbidopa also decreases acute peripheral dopamine side effects, such as nausea, vomiting, and hypotension, and improves tolerability [88].

The risk for side effects and toxicity, including troublesome dyskinesia, is high in patients on chronic levodopa therapy. For this reason, careful dose titration and tight adherence to the effective dose is important for PD symptom management. No evidence has been found that using an extended-release levodopa/carbidopa formulation, or adding a catechol-O-methyltransferase (COMT) inhibitor, delays or prevents the development of motor fluctuations [89].

Because levodopa is absorbed in the proximal small intestine, food may delay absorption. Levodopa also competes with dietary proteins for transport into the brain. High-protein meals should be kept separate from levodopa dosing, and daily dietary protein intake should be reduced to approximately 0.8 g/kg (of body weight). Levodopa is metabolized in the gastrointestinal tract, kidneys, and liver, with 70% excreted in the urine. Levodopa half-life is roughly one hour. Dosing should be reduced 10% to 30% when other dopaminergic agents are added to carbidopa/levodopa. Available formulations in the United States are [88]:

- Carbidopa/levodopa tablet (Sinemet)

- Carbidopa/levodopa orally disintegrating tablets (Parcopa ODT)

- Carbidopa/levodopa sustained-release tablet (Sinemet CR)

- Carbidopa/levodopa extended-release tablet (Rytary ER)

- Carbidopa/levodopa enteral suspension (Duopa)

- Carbidopa/levodopa/entacapone (Stalevo)

Potential adverse events associated with levodopa/carbidopa can be generally categorized as CNS, gastrointestinal, or other. Adverse effects involving the CNS include confusion, sedation, vivid dreams, dizziness, hallucinations, psychosis, and depression. Gastrointestinal effects may include nausea, vomiting, and changes in bowel habits. Orthostasis, leg edema, dyskinesia, dystonia, hemolytic anemia, and leukopenia may also occur. All patients taking levodopa should be monitored for changes in blood pressure, pulse, mental status, and clinical response.

With prolonged therapy and disease progression, the duration of benefit from each levodopa dose often becomes increasingly shorter. "End of dose deterioration," "wearing-off," "off periods," or simply "off" refers to the waning or absent effects of levodopa within four hours of the last dose. As "off" periods increase, "on" periods (levodopa-related motor symptom control) decrease [4].

Caregivers monitoring the course of a stable patient on chronic levodopa therapy for PD often face two potential therapeutic challenges. First is the development of dyskinesia, indicative of drug intolerance or excessive dosage. The second is fluctuation in motor symptoms, perhaps indicative of inadequate dosage, failing compliance, or waning therapeutic effectiveness. The frequency, or risk, of dyskinesia and motor fluctuations during chronic levodopa therapy for PD is difficult to predict. One literature review of publications spanning 1966 through 2000 showed that among patients receiving levodopa therapy, the median frequency of dyskinesia was 39%, and after a satisfactory first year of therapy, the frequency of motor fluctuations gradually increased to 40% of patients by four to six years of treatment [151].

Dopamine Agonists

Dopamine D2/3 receptor agonists bind post-synaptic striatal dopamine receptors to increase dopaminergic neurotransmission and reduce parkinsonism symptoms. Ropinirole (oral), pramipexole (oral), and rotigotine (transdermal) are the most widely used agents. In advanced disease, subcutaneous apomorphine is continuously delivered via external pump or is used for rapid rescue therapy (via injection). The ergot derivative dopamine agonists cabergoline, pergolide, and bromocriptine are not recommended as first-line dopamine agonist therapy, and bromocriptine is associated with the development of fibrotic tissue. Ergot derivatives require specialized side effect monitoring, but they remain options for patients lacking benefit or tolerability with other dopamine agonists [74,90].

Dopamine agonists are the second most potent drug class (after levodopa) for motor symptom control in PD and are effective at all stages of the condition. Initial dopaminergic therapy using dopamine agonists (versus levodopa) is associated with reduced/delayed treatment-related complications, such as levodopa-induced dyskinesia and motor fluctuations [7,91].

However, poor tolerability can limit the use of dopamine agonists. While dopamine agonists are less likely to lead to motor fluctuations in early disease than levodopa, they are less effective for motor symptoms and carry greater risk of side effects such hallucinations, psychosis, hypotension, peripheral edema, excessive daytime somnolence, and impulse control disorders. In patients older than 70 years of age, dopamine agonists should be used with caution or avoided entirely [89]. All patients taking ropinirole, pramipexole, or rotigotine should be monitored for changes in blood pressure, daytime alertness, weight, and heart rate [88].

Ropinirole

Ropinirole undergoes hepatic metabolism, with a half-life of about six hours. It is associated with various adverse effects in various systems, including the gastrointestinal system (e.g., nausea, vomiting, dyspepsia, abdominal pain, constipation) and the CNS (e.g., dizziness, somnolence, headache, syncope, confusion, hallucinations, impulse control disorders, sleep attacks). Other potential adverse effects include fatigue, asthenia, dependent/leg edema, viral infection, pain, increased sweating, orthostatic symptoms, pharyngitis, abnormal vision, and urinary tract infection [88].

Pramipexole

Pramipexole is administered orally for PD and is available in immediate- and extended-release formulations. The half-life in healthy adults is about 8 hours, but this is extended to 12 hours in elderly patients. It is excreted in the urine primarily as unchanged drug, and dose adjustment is required in renal impairment. Overnight switch from immediate- to extended-release is successful in 80% of patients [88]. Potential adverse effects include nausea, abdominal pain/discomfort, constipation, dizziness, somnolence, headache, hallucinations, impulse control disorders, dyskinesia, orthostatic hypotension, xerostomia, peripheral edema, and muscle spasms [88].

Rotigotine

Rotigotine is available as a transdermal patch for the treatment of PD. It undergoes extensive metabolism via conjugation and N-dealkylation. The initial half-life is three hours, with the terminal half-life five to seven hours after patch removal. Potential adverse effects have included nausea, vomiting, somnolence, dizziness, application-site reactions, dyskinesia, anorexia, hyperhidrosis, visual disturbance, and peripheral edema, and all patients should be monitored for skin reactions. Patients with sulfa allergy should not be prescribed rotigotine, and patches contain aluminum and should be removed prior to MRI [88].

Apomorphine

Apomorphine for PD is given as a subcutaneous injection into the abdominal wall, upper arm, or upper leg; the injection site should be rotated. It is indicated for hypomobility and "off" episodes associated with PD.

Apomorphine undergoes extensive first-pass metabolism, with a terminal half-life of about 40 minutes. Nausea, vomiting, drowsiness, somnolence, dizziness, orthostatic hypotension, hallucinations, confusion, dyskinesia, rhinorrhea, and edema/swelling of extremities may occur. It is important to avoid use of apomorphine with serotonin blockers, as co-ingestion may cause profound hypotension. All patients taking this agent should be monitored for orthostatic hypotension and drowsiness [88].

Bromocriptine Mesylate

Bromocriptine mesylate is taken orally and is metabolized by the liver. The half-life is approximately 5 to 15 hours. Potential adverse effects include nausea, vomiting, abdominal discomfort, abnormal involuntary movements, ataxia, hallucinations, confusion, "on-off" phenomenon, dizziness, syncope, drowsiness, insomnia, depression, visual disturbance, hypotension, shortness of breath, constipation, vertigo, and asthenia. Long-term treatment with this drug is associated with pleural thickening (fibrosis). As such, patients' pulmonary function should be monitored during treatment [88].

Monoamine Oxidase B Inhibitors

MAO-B is an enzyme that inactivates dopamine by breaking it down into metabolic byproducts. MAO-B inhibitors block the breakdown of dopamine, slowing the loss of dopamine and several of the effects of PD. MAO-B inhibitors are generally considered for initial treatment of early PD as monotherapy and as adjunctive therapy to augment the effects of levodopa in later PD. The preferred agents are selegiline and rasagiline, both of which have shown symptomatic benefit and multiple neuroprotective effects in pre-clinical research [7,89,92].

Selegiline

In the treatment of PD, selegiline may be used as monotherapy or combined with levodopa. This agent blocks the breakdown of dopamine via MAO-B inhibition. It is metabolized via CYP450 enzymes to amphetamines, with a half-life of 10 hours. In high doses, it may precipitate a hypertensive crisis. Other potential adverse effects include nausea, weight loss, dyspepsia, hypotension, decreased heart rate, headache, hallucinations, vivid dreams, dizziness, insomnia, flu-like symptoms, dyskinesias, dystonia, rash, and photosensitivity [93]. All patients undergoing treatment with selegiline should be monitored for rash, drug interactions, and changes in blood pressure, cardiac status, and mental status (i.e., increased anxiety) [93].

In addition to a capsule/tablet, selegiline is available as an orally disintegrating tablet. Pharmacology, potential adverse effects, and monitoring are similar, but metabolism of the disintegrating tablet bypasses the liver to reduce formations of amphetamine metabolites, which reduces the risk of insomnia side effects [93].

Rasagiline

Oral rasagiline may be used in monotherapy or combination therapy for patients with PD. This agent inhibits the breakdown of dopamine via MAO-B inhibition and is metabolized via CYP1A2. The half-life is three hours. The potential adverse effects and patient monitoring requirements are the same as with selegiline [93].

Catechol-O-Methyltransferase Inhibitors

COMT is an enzyme that converts levodopa in peripheral circulation to 3-O-methyl-DOPA (3-OMD). This metabolite cannot be converted to dopamine and accumulates in plasma during levodopa therapy. Inhibition of COMT increases the bioavailability of levodopa, allowing a larger amount of the drug to reach the brain and consequently raise dopamine levels. COMT inhibitors are always taken in combination with levodopa because they lack intrinsic dopaminergic activity. They are used in PD to potentiate levodopa effects when "wearing off" or other motor complications appear during carbidopa/levodopa therapy [93].

Entacapone

As a COMT inhibitor, entacapone inhibits the peripheral metabolism of levodopa. It is metabolized to active isomer and undergoes glucuronidation to inactive metabolites, with a half-life of two hours. Potential adverse effects include exacerbation of levodopa adverse effects, brown/orange urine, and diarrhea. All patients should be monitored for changes in blood pressure and mental status. A fixed-dose combination of entacapone with carbidopa/levodopa is available and reduces the number of tablets needed for treatment, which may improve adherence [93].

Tolcapone

Tolcapone inhibits peripheral and central metabolism of levodopa. It has a half-life of about three hours and is metabolized via glucuronidation and CYP2A6 and CYP3A4 enzymes. The adverse effects are the same as those described for entacapone, plus transient elevations in liver enzymes and fulminant liver failure. In addition to the monitoring recommended for entacapone, these patients should be regularly tested for liver enzymes and function [93].

Opicapone

Opicapone is a novel, once-daily, third-generation COMT inhibitor. Research has compared opicapone with entacapone and placebo as a levodopa adjunct. In a study involving 590 patients with PD-associated motor fluctuations, the mean reduced times in "off" state were 56 minutes for placebo, 96.3 minutes for entacapone, and 116.8 minutes for opicapone after 14 to 15 weeks. Opicapone 50 mg was statistically superior to placebo and non-inferior to entacapone, but lower-dose opicapone did not differ from placebo [94].

The most common adverse events with opicapone are dyskinesia, insomnia, and constipation. Serious adverse events were reported in six patients with placebo, eight with entacapone, and four with opicapone 50 mg. In addition to "off" time efficacy, an advantage of opicapone is the once daily dosing [94].

Anticholinergic Agents

Anticholinergic agents used in PD treatment include benztropine (Cogentin) and trihexyphenidyl. Anticholinergics may be helpful as a symptomatic treatment in younger patients with early PD and severe tremor or dystonia, but they should not be drugs of first choice due to their narrow range of efficacy. Adverse effects from nonselective cholinergic receptor blockade are a major drawback and include CNS-related side effects of cognitive impairment, exacerbation of dementia, delirium, sedation, and hallucinations. Other side effects include constipation, xerostomia, blurred vision, and urinary retention; higher doses may cause or worsen orthostatic hypotension and palpitations. Elderly patients are especially prone to these side effects plus confusion and memory difficulties, and anticholinergic agents are not recommended in this population [89].

Amantadine

Amantadine is an N-methyl-d-aspartate (NMDA) antagonist with modest benefit in early PD and efficacy in suppressing levodopa-induced dyskinesia in later/advanced PD. The mechanism of action is thought to involve augmentation of pre-synaptic dopamine release and NMDA glutamatergic antagonism. Common side effects include pedal edema and livedo reticularis (violet, lace-like coloration) [7].

Amantadine is the only agent demonstrated to suppress levodopa-induced dyskinesia without worsening parkinsonism, and the American Academy of Family Physicians recommends that amantadine should be considered for treatment of dyskinesias in patients with advanced PD [2]. However, use in frail elderly patients with advanced PD may result in confusion, hallucinations, and/or worsening motor symptoms [95].

Acetylcholinesterase Inhibitors

The acetylcholinesterase inhibitor rivastigmine is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate PD dementia. Other approved drugs for dementia, including donepezil, galantamine, and memantine, have been evaluated for the treatment of PD dementia, but their efficacy has not been clearly shown [95].

Rivastigmine has shown significant improvement in PD dementia that was maintained through 48- and 76-week follow-up in different trials. In long-term trials comparing rivastigmine capsules (12 mg/day) versus transdermal patch (9.5 mg/24 hours), the rates of adverse effects from worsening PD were 36.1% with the capsule (tremor in 24.5%) versus 31.9% with the patch (tremor in 9.7%). Both formulations showed a 2.1-point worsening on the UPDRS-III motor scale [96,97].

Novel and Investigational Agents

Istradefylline

In 2019, the FDA approved istradefylline as an add-on treatment to levodopa/carbidopa in adult patients with PD experiencing "off" episodes [155]. This agent is an adenosine receptor antagonist with evidence of significantly decreasing daily “off” time compared with patients receiving a placebo. Potential side effects include dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia [155].

Adenosine A2A Receptor Antagonists

A2A receptors are co-localized on dopamine D2 receptors and may be over-activated in PD. Thus, A2A receptor antagonism may reduce PD motor symptoms [98]. Istradefylline was the first A2A antagonist evaluated in PD, but it received a "not approvable" letter from the FDA due to lack of clinical benefit and association with dyskinesias. A subsequent review concluded istradefylline 50 mg had clinical potential as a levodopa adjunct in PD, with support from a clinical trial showing significant reduction in "off" time and good tolerance [95,99].

Riluzole

There has been interest in glutamate receptor antagonists for the treatment of PD based on the finding that PD is linked to glutamate overactivation in basal ganglia circuits, resulting in oxidative stress and cell death. Riluzole, an NMDA receptor antagonist approved for the treatment of amyotrophic lateral sclerosis, was studied in PD, but it lacked significant effects on survival or disease progression [93].

Safinamide

Safinamide is an alpha-aminoamide developed as adjunct therapy to dopamine agonist or levodopa therapy in patients with PD. This drug shows dopaminergic and non-dopaminergic activity, including MAO-B inhibition, sodium channel antagonism, and inhibition of glutamate release. Clinical trials have shown significantly improved motor symptoms versus placebo. In a six-month double blind, placebo-controlled study of patients with mid-to-late stage PD with motor fluctuations, the addition of safinamide 50–100 mg/day was shown to significantly improve "on time" without increasing dyskinesia and to improve motor function, activities of daily living, quality of life measures, and depressive symptoms [152]. Clinical benefit was sustained over an additional 18-month period of continued treatment and observation.

In 2017, the FDA approved safinamide as "add-on" treatment for patients with PD who are taking levodopa/carbidopa and experiencing "off" periods [8].

Cannabidiol

Cannabidiol, the primary non-psychoactive constituent in Cannabis, has been evaluated for treatment efficacy in several non-motor PD conditions. In patients with PD-associated psychoses of at least three months' duration, oral cannabidiol treatment ≤400 mg/day for four weeks significantly reduced psychotic symptoms. No cognitive or motor side effects were found in study participants [101].

A small case series of patients with PD and REM sleep behavior disorder examined treatment response to oral cannabidiol 75 mg/day or 300 mg/day for six weeks. In this sample, symptoms of REM sleep behavior disorder included swearing, laughing, yelling, pushing, kicking, or punching during REM sleep, occurring two to seven times per week. After six weeks of cannabidiol, REM sleep behavior disorder symptom frequency was no times per week in 75% and one time per week in 25% of patients. All patients reported elimination of nightmares. Shortly after cannabidiol cessation, symptom frequency returned to baseline level in all patients. No side effects were observed [102].

Inosine

The antioxidant urate precursor inosine has been associated with lower risk of PD and slower PD progression and was suggested as neuroprotective in laboratory assays. The effects of inosine on PD are currently in phase III clinical trial evaluation in the Safety of Urate Elevation in Parkinson Disease (SURE-PD) study [83].

Agents FDA-Approved for Other Indications

In addition to investigational new drugs, several FDA-approved medications have been studied for their off-label use in the treatment of PD. Calcium-channel blockers are one such group. In one study, the calcium-channel blocker isradipine was found to reduce risk of PD in patients 65 years of age or older [103]. Isradipine, a calcium-channel blocker in use as hypertension therapy, may be neuroprotective in PD. The drug is currently in phase III trials (known as STEADY-PD) to determine its utility in treating early PD [83].

Evidence for the role of neuroinflammation in the pathogenesis of PD have prompted trials of several anti-inflammatory agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) may be protective against PD, but the overall evidence of neuroprotective effect with aspirin or NSAIDs in PD is inconsistent [93].

The stimulant methylphenidate has been found in limited studies to improve gait hypokinesia and freezing in patients with PD receiving deep brain stimulation of the subthalamic nucleus [104].

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes. In a 12-month trial of 45 patients with moderate PD, subcutaneous exenatide showed clinically relevant improvements in PD across motor and cognitive measures versus untreated controls [105,106].

Zonisamide is an anticonvulsant with neurotransmitter effects, including stimulation of dopamine synthesis, and is approved in Japan for the treatment of PD. Use as an adjunct to levodopa found improvements in "off" time [107].

Beta-blockers are considered a therapeutic option for PD tremor, although some patients may not benefit from or tolerate these agents [108].

MANAGEMENT OF EARLY PARKINSON DISEASE

Evidence Based Practice Recommendation

The European Federation of Neurological Societies asserts that the optimal time frame for onset of therapy for Parkinson disease has not been clearly defined. Once parkinsonian signs start to have an impact on the patient's life, initiation of treatment is recommended.

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch14

Last Accessed: April 11, 2019

Level of Evidence: Expert Opinion/Consensus Statement

The therapeutic objective in patients with early PD is symptomatic treatment of motor symptoms to restore more normalized motor function and to optimize and maintain patients' ability in perform activities of daily living. Therapy initiation is individualized, based on patient age, handedness, employment status, and functional status. Tremor is often the symptom that brings patients to medical attention and diagnosis, but it is dominant at rest and infrequently a source of disability or reason to initiate treatment. Rigidity and bradykinesia are more frequently associated with the functional limitations and mobility impairments that influence a patient to initiate treatment [7]. Initial therapy should also target the most disruptive and impairing symptoms in each patient, which can differ with tremor versus rigidity [109].

Initial therapeutic options for motor symptoms, in descending order by potency of effect, are levodopa, dopamine agonists, and MAO-B inhibitors. Dopaminergic agents (levodopa and dopamine agonists) remain the mainstay of symptom control but are not always first-line treatment. The timing of dopaminergic therapy initiation depends on patient preference, degree of disability, and potential side effects. In general, early dopaminergic treatment is recommended, and the choice, depending on age and overall cognition, is between levodopa preparations, dopamine agonists, and MAO-B inhibitors [4].

The assumption that dyskinesia strictly arose from long-term levodopa use led to the common practice of delaying its initiation until the onset of significant motor symptoms in order to save the window of efficacy before dyskinesia begins. As noted, it is now thought that disease stage has greater influence than medication duration on development of levodopa-induced dyskinesia. This has led to earlier levodopa initiation, although MAO-B inhibitors or dopamine agonists are often preferred as initial early PD therapy [7].

Treatment-Naïve Patients

The initial choice of drug depends on the likelihood of improving motor function (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and the presence of neuropsychiatric complications (more common in older and cognitively impaired patients, greater with agonists). Levodopa is the mainstay of initial treatment and the most effective drug for improving motor function. One should avoid controlled-release formulations or adding entacapone, as this is not effective for delaying the onset of motor complications. Other treatments include MAO-B inhibitors (e.g., selegiline, rasagiline) or oral or transdermal dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). Initial treatment with an agonist can be recommended in younger patients. Ergot derivatives (e.g., bromocriptine, cabergoline) are not recommended due to the increased risk of fibrotic development [74]. Amantadine and anticholinergic agents are also options. Rehabilitation in early-stage disease has seldom been evaluated, and therefore a recommendation for or against its use cannot be made [74].

Dose adjustments with dopamine agonists and levodopa preparations are made in response to clinical effect, emerging symptoms, and/or side effects. Risks of psychiatric side effects and dyskinesias are greater at higher doses, and treatment with the lowest dose possible to achieve benefit is favored; this better maintains patient function and quality of life. Patients older than 50 years of age who receive levodopa doses greater than 600 mg/day are more likely to develop dyskinesia [4].

Adjustment of Initial Therapy in Patients without Motor Complications

Patients who initiate treatment with an MAO-B inhibitor, anticholinergic agent, amantadine, or their combination will, at some point, require levodopa or a dopamine agonist added. If patients on dopaminergic therapy require treatment intensification, the options are to increase the dose, switch to another agonist, or add levodopa. Patients who are initiated on levodopa may be better managed by an increase in the dose, the addition of an agonist, or the addition of a COMT inhibitor [74]. If significant tremor persists in patients with disabling tremor, add or initiate with [74]:

- Anticholinergic drug

- Clozapine

- Beta-blocker (e.g., propranolol)

- Deep brain stimulation

MANAGEMENT OF LATER PARKINSON DISEASE

Later stage PD is clinically characterized by diminished efficacy of dopaminergic therapy and the emergence of motor fluctuations and dyskinesias. In patients with PD, the initial response to carbidopa/levodopa therapy is usually positive, because dopaminergic systems are relatively intact and produce sufficient endogenous dopamine to "buffer" the exogenous carbidopa/levodopa. With disease progression, combined effects from dopaminergic neuron loss, receptor alteration, modifications in circuitry, and desensitization of receptors lead to inconsistent and unpredictable carbidopa/levodopa response and the development of motor fluctuations. At some point, virtually all patients with PD develop motor fluctuations that include wearing off, delayed onset dyskinesias and dystonias [110,111,112].

Levodopa-Induced Dyskinesias

While early PD can be effectively managed with levodopa for many years, disease progression invariably leads to peak-dose dyskinesias, including tics, tremors, and other involuntary movements [8]. In addition to levodopa, dyskinesias can also develop with dopamine agonists or MAO-B inhibitors. Men and younger patients have higher risk of dyskinesias. Mild dyskinesias do not require specific treatment, but more severe cases may respond to a reduction in levodopa dose or addition of an NMDA antagonist or dopamine receptor agonist [4].

Motor Complications

When patients develop end-of-dose deterioration (symptom relapse) or peak-dose dyskinesias, motor complications begin to dominate the clinical picture. Several potential mechanisms contribute to the development of motor complications. Low plasma levels of dopaminergic drugs lead to "off" periods, while high levels increase peak-dose dyskinesia; the levodopa therapeutic window is narrowed. Motor complications accrue in an estimated 10% of patients with PD per year, with an estimated 50% prevalence with five years of levodopa treatment. Other motor signs and symptoms can emerge, including axial motor symptoms of gait and postural abnormalities, that increase the risks of falling, dysphagia, dysarthria, and cognitive problems [8].

Emergence of Motor Symptoms

Axial motor signs/symptoms of gait impairment, postural instability, and postural abnormalities are common and debilitating in patients with later PD. Unlike the cardinal motor symptoms of rest tremor, bradykinesia, and rigidity, dopaminergic therapy and physiotherapy minimally benefit axial motor symptoms. This is probably due to mediation of motor control of axial and cardinal functions by different anatomical-functional pathways [65].

Freezing gait often appears later in the disease course and can lead to significant declines in quality of life. Walking requires shifting from one leg to the other, and patients with freezing gait experience a sense of falling every time they lift a foot up off the floor. Every step forward resembles a controlled fall. Research has shown that auditory stimuli (e.g., sound of a metronome) or visual cues (e.g., a flash of light or lines on the floor indicating stride length) can reduce episodes of freezing, but how these cues work is unknown [8].

Management

When motor complications emerge, manipulation of levodopa dose or frequency is often the first strategy, but the initial improvement is eventually precluded by the emergence of dyskinesias.

Levodopa Wearing Off

Studies comparing immediate- and modified-release levodopa found roughly 25% less levodopa absorbed with the modified-release formulation, and this should be considered when switching between preparations. Erratic levodopa absorption in later PD and significant reduction in doses per day with modified-release levodopa can result in delayed or no "on" responses. Modified-release levodopa has greatest benefit in reducing overnight wearing-off [4].

The next strategy is adding adjunctive therapies to levodopa to control fluctuating motor response. Wearing-off symptoms can be reduced by adding MAO-B inhibitors, COMT inhibitors, or dopamine agonists. The MAO-B inhibitor rasagiline reduces "off" time by around 1.5 waking hours per day; the same results were found with the COMT inhibitor entacapone [4]. The COMT inhibitors entacapone and tolcapone can improve CNS delivery of levodopa by inhibiting its peripheral degradation to 3-OMD. Entacapone is most widely used due to rare hepatic failure associated with tolcapone, although the latter agent may be more effective [7,74]. COMT inhibitors can increase ''on'' time, but these drugs lack intrinsic antiparkinsonism efficacy as monotherapy [4].

The dopamine agonists pramipexole and ropinirole reduce "off" time by around 15% but can cause problematic side effects, including drowsiness, sudden onset of sleep, and impulse control disorders, in 15% or more of patients. Patients should be screened for pre-existing drowsiness and tendencies toward compulsive disorders (e.g., gambling) before prescribing a dopamine agent. Patients should be monitored for the development of impulse control disorders throughout the course of treatment. Apomorphine can be administered by continuous infusion or intermittently to treat sudden "off" periods unresponsive to other medications [4].

Severe Motor Fluctuations

Deep brain stimulation is effective against motor fluctuations and dyskinesia [74]. However, because the risk for adverse events is elevated, this modality is only recommended in patients younger than 70 years of age without major psychiatric or cognitive problems. Other options include subcutaneous apomorphine administered via penject or pump or intrajejunal levodopa/carbidopa enteric gel administered through percutaneous gastrostomy [74].

Unpredictable "On-Off"

Deep brain stimulation of the subthalamic nucleus is effective to manage unpredictable "on-off" symptoms [74]. In treatment studies for wearing-off, patients with unpredictable "on-off" have been excluded or were uncommon. Thus, there is insufficient evidence to conclude if the results are valid for unpredictable "on-off." The strategies described for dyskinesia and wearing-off should be considered. For delayed "on," dispersible levodopa and subcutaneous apomorphine injections have some value [74]. Reducing or redistributing dietary proteins may be helpful, but a more practical approach is to take levodopa on an empty stomach one hour before, or at least one hour after, each meal.

Freezing

Management options for "off" freezing are the same as for wearing-off. However, freezing during "on" often does not respond to dopaminergic strategies. Visual or auditory cues are empirically useful for facilitating the start of motor acts [74].

Dyskinesias

The first step in managing dyskinesias is to reduce the levodopa dose. This elevates the risk of increasing "off," but it can be compensated for by increasing the number of doses or adding a dopamine agonist. MAO-B or COMT inhibitors should also be reduced or discontinued at the risk of worsening wearing-off [74].

Amantadine (an NMDA antagonist) is the sole effective agent in suppressing levodopa-induced dyskinesia without worsening parkinsonism and should be initiated at 200–400 mg/day [74,95]. In younger patients, an anticholinergic agent may be prescribed [74].

Deep brain stimulation of the subthalamic nucleus also reduces dyskinesia symptoms and dopaminergic dosing. Stimulation of the globus pallidus pars interna may reduce severe dyskinesia.

Clozapine or quetiapine may be added. Clozapine is associated with potential serious adverse events (e.g., agranulocytosis, myocarditis) and requires monitoring. Intrajejunal levodopa infusion is another option. Continuous subcutaneous infusion of apomorphine allows reduction of levodopa [74].

Biphasic Dyskinesia

Biphasic dyskinesias can be very difficult to treat, and well-designed treatment studies are sparse. Deep brain stimulation of the subthalamic nucleus appears effective [74]. The strategies described for managing peak-dose dyskinesias may also be considered.

Another option is increasing the size and frequency of levodopa dosing, at the risk of increasing peak-dose dyskinesia. However, larger and less frequent doses may give more predictable responses. Apomorphine and intrajejunal levodopa infusion may be tried [74].

Off-Period and Early-Morning Dystonias

The strategies for wearing-off can be applied to patients with off-period dystonias. Additional levodopa or dopamine agonist doses at night may be effective if the symptoms are worst in the morning. Deep brain stimulation is recommended, and botulinum toxin injection may be employed [74].

MANAGEMENT OF ADVANCED PARKINSON DISEASE

Advanced PD is defined as the onset of persistent and severe motor complications despite optimized oral pharmacologic and behavioral management [95]. The development of motor complications during later disease progresses to advanced disease. The underlying pathophysiologic mechanisms result in a narrowing therapeutic window whereby low plasma and striatal levels of dopaminergic drugs lead to "off" periods and high levels lead to increases in peak-dose dyskinesia. Patients experience increasing dose failures from absorption problems [7,95]. Dyskinesias become more frequent and severe in advanced disease, appearing in 59% of patients after 10 years of levodopa treatment. Even small dose increases in levodopa to improve motor function may produce dyskinesias. Management of dyskinesias and "off" periods by lowering the levodopa dose and shortening the time intervals between doses becomes increasingly ineffective in advanced disease [89].

Long-acting dopamine agonists taken once daily have become popular with patients. In theory, long-acting dopamine agonists should allow a stable release of drug, with continuous dopaminergic stimulation reducing plasma fluctuations and decrease motor complications. Many experts state this theory is unsupported by observations in clinical practice, and the presumptive advantage of long-acting dopamine agonists has not been proven. Dopamine agonists should not be prescribed to patients with dementia, hallucinations, autonomic dysfunction, or sleep disorders, and impulse control disorders are a potential side effect with this drug class [95].

With disease progression in advanced PD, the development of wearing-off symptoms and dyskinesias can produce severe, disabling motor fluctuations uncontrollable with oral medications. Advanced therapies are considered at this point, including deep brain stimulation or infusional therapies such as subcutaneous apomorphine or intraduodenal levodopa gel infusions. Such therapies are generally reserved for patients who no longer improve with available oral and transdermal therapies and who lack cognitive or psychiatric dysfunction [4].

Apomorphine, intraduodenal levodopa, and deep brain stimulation can substantially improve motor fluctuations by decreasing daily "off" time and dyskinesias. Despite benefits that may continue several years after initiation, the underlying pathology progresses, and even patients with excellent response can experience the emergence of advancing disease with postural instability and falls, cognitive disturbance, autonomic dysfunction, and swallowing and speech dysfunction [4].

While large head-to-head studies comparing invasive procedures are lacking, deep brain stimulation has the highest level of supportive evidence from the largest number of randomized controlled trials. Before any decision is made to use invasive therapies, a multidisciplinary team should examine the patient and carefully weigh the relative risks and potential benefits of each therapy [95].

Pharmacotherapy Interventions

With apomorphine, the rapid onset of action makes it an effective intervention for "off" periods with use as a rescue injection. Apomorphine is also available as a continuous infusion treatment, suggested by clinical trials as effective in treating motor symptoms and some non-motor advanced PD symptoms [95].

With FDA approval in 2015, intestinal gel is the most recent formulation of levodopa/carbidopa to improve its blood concentration consistency and stability. In advanced PD, delayed and unpredictable spontaneous gastric emptying interferes with the passage of oral medication from the stomach to the small intestines for absorption and circulation to the brain. Levodopa/carbidopa intestinal gel (Duodopa) was developed to bypass this problem by delivering the drug directly to the proximal jejunum via a percutaneous endoscopic gastrojejunostomy tube connected to a portable infusion pump [113].

Compared to conventional immediate-release levodopa, levodopa/carbidopa intestinal gel has been found superior in improving motor fluctuations and quality-of-life scores. For example, 71 patients with advanced PD were randomized to levodopa/carbidopa intestinal gel plus oral placebo or oral levodopa/carbidopa plus placebo intestinal gel. After 12 weeks, the levodopa/carbidopa intestinal gel group showed a significant reduction in "off" time (-4.04 hours/day), versus the active oral/placebo gel group (+2.14 hours/day). This extent of improvement was also observed in "on" time without troublesome dyskinesia, and in "on" time without dyskinesia. Most side effects involved complications related to the percutaneous gastrojejunostomy therapy pump [114].

Deep Brain Stimulation Surgery

Evidence Based Practice Recommendation

According to the European Federation of Neurological Societies, deep brain stimulation of the subthalamic nucleus is effective against motor fluctuations and dyskinesia in later-stage PD, but because of the risk for adverse events, the procedure is only recommended for patients younger than 70 years of age without major psychiatric problems or cognitive decline.

https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch15

Last Accessed: April 11, 2019

Level of Evidence: A (At least one convincing randomized, controlled clinical trial or at least two consistent, convincing prospective matched-group cohort studies)

Surgical treatment is considered in patients with advanced PD when optimized medical treatment has failed to control motor symptoms. Initial surgical interventions involved lesions to the basal ganglia, with thalamotomy for tremor and pallidotomy for levodopa-induced dyskinesias. Surgical lesions showed a high risk of permanent side effects, and while pallidotomy or thalamotomy remain options in carefully selected patients, deep brain stimulation is now the surgical treatment of choice for patients with advanced PD [2]. Unlike ablative surgery, deep brain stimulation can be modified over time to address changing disease presentation with progression, adverse effects are primarily reversible, and deep brain stimulation can be used bilaterally to improve symptoms [89].

Deep brain stimulation can reduce symptoms of motor fluctuations, dyskinesia, and tremor, but symptoms unresponsive to levodopa in advanced PD (e.g., cognitive impairment, gait instability, mood disorders, speech impairment, autonomic dysfunction) are unlikely to improve and may worsen with deep brain stimulation. Guidelines recommend that deep brain stimulation should only be performed in experienced centers [2].

The primary targets of deep brain stimulation are the subthalamic nucleus and the globus pallidus pars interna. Effectiveness of subthalamic nucleus stimulation in improving levodopa-responsive signs and symptoms has been reported by many short-term and long-term studies. The overall improvement of activities of daily living and motor UPDRS scores averaged 50% compared to pre-surgery. Levodopa-induced dyskinesias have been reduced by an average 69%. The most frequent post-surgical surgery-related adverse effects are infections (6.1%), migration or misplacement of the leads (5.1%), lead fractures (5%), intracranial hemorrhage (3%), and skin erosion (1.3%) [115].

Factors that contribute to deep brain stimulation outcome include clinical indications, patient selection, surgical targeting accuracy, stimulation programming, and medication management. The most frequently reported persistent complications possibly related to deep brain stimulation include eyelid opening apraxia (1.8% to 30%), dysarthria/hypophonia (4% to 17%), gait disturbances (14%), postural instability (12.5%), weight gain (8.4%), and verbal fluency decline (14%) [89,116]. As of 2016, more than 100,000 patients had undergone deep brain stimulation surgery for the treatment of PD and other movement disorders [117].

Timing

While deep brain stimulation was formerly offered only in late-phase disease (mean: 13 to 14 years post-diagnosis), several considerations have now moved the timing for surgery forward [117]. Deep brain stimulation produces motor improvement in symptoms responsive to dopaminergic drugs, but unresponsive features usually predominate in later disease. Performing deep brain stimulation at advanced stages of illness can alleviate some motor dysfunction features but does not benefit ongoing problems in well-being and occupational, social, and role functioning. In addition, older patients are more likely to develop surgical complications and/or worsening of axial motor functions.

Earlier deep brain stimulation surgery was studied by comparing best medical treatment with deep brain stimulation of the subthalamic nucleus in 251 patients with early-stage motor fluctuation (mean: seven years post-diagnosis). Early and sustained improvement was found in quality of life for patients who received deep brain stimulation. Deep brain stimulation of the subthalamic nucleus has been proposed in patients less than four years after diagnosis without motor fluctuation, but this approach is less compelling, as it exposes patients to potentially dangerous side effects without improving motor function or quality of life. The long-term impact is also unclear [117].

Targeting

Several trials comparing subthalamic nucleus and globus pallidus pars intera stimulation have helped define relative advantages between these two targets. While motor benefits are comparable, other parameters show advantages with subthalamic nucleus for more severe on-off symptoms and cost-efficacy, and advantages with globus pallidus pars intera for dyskinesia suppression, long-term stability of effects, and cognitive symptoms [117].

Experimental and clinical observations suggest contribution from the pedunculopontine nucleus to the pathophysiology of gait and stability impairment. However, pedunculopontine nucleus stimulation remains investigational, with several unresolved issues [117].

Long-Term Impact

Early open-label studies reporting long-term (more than 10 years) outcomes in subthalamic nucleus stimulation consistently found durable benefits in motor fluctuation, dyskinesias, and the cardinal symptoms of PD (tremor, rigidity, and to a lesser extent, bradykinesia). A survival advantage was suggested when comparing eligible patients who chose deep brain stimulation versus those who continued medical treatment. However, subthalamic nucleus stimulation does not halt disease progression, and "long-term deep brain stimulation syndrome" with axial motor problems can emerge from long-term therapy. Reappraisal of current targets and investigation of new ones is ongoing [117].

MANAGEMENT OF NON-MOTOR SYMPTOMS

As discussed, patients frequently develop diverse non-motor symptoms and syndromes throughout the clinical course of PD. Most non-motor symptoms cluster into broader groups of abnormality: neuropsychiatric disorders, autonomic dysfunction, sleep disorders, and pain.

Neuropsychiatric Disorders

Psychosis in Parkinson Disease

Psychosis in PD is common and multifactorial in etiology. Up to 60% of patients with PD develop psychosis. Following its onset, PD psychosis remains a persistent, lifelong problem for most patients [118]. Pharmacologic management is challenging, in part because dopaminergic agents required for motor control can exacerbate psychotic symptoms, and antipsychotic agents can exacerbate motor symptoms [119]. The onset of psychosis in PD predicts a poor prognosis, including increased likelihood of nursing home placement and early mortality [120].

The early clinical manifestations of PD-associated psychosis differ from other psychotic disorders in that hallucinations are common and patients initially remain lucid and connected with reality. Visual hallucinations are the most prevalent form. Functional MRI performed on patients with PD who are experiencing visual hallucinations show several abnormalities: altered cortical visual processing; decreased occipital response and increased caudate and frontal cortical activation to visual stimuli; overactive visual association cortex; and decreased primary visual cortex activity [119].

Auditory, tactile, olfactory, and gustatory hallucinations do occur, though less commonly and usually in combination with visual hallucinations. Confusion states, delusions, paranoia, agitation, and delirium may also develop.

The stage of PD at which psychotic features emerge has some diagnostic import. In newly suspected or recently diagnosed (within three months) cases of PD, the appearance of psychotic symptoms suggests early-onset dementia with Lewy bodies, but could also indicate an alternative neuropsychiatric diagnosis, such as Alzheimer disease with extrapyramidal symptoms or underlying functional (psychiatric) psychosis. Differences in the initial presentation of PD-associated psychosis do not substantively change the management approach (with some caveats) [119].

Risk factors for PD-associated psychosis include cognitive impairment, dementia, advanced age, sleep disturbances, and disease duration/severity [121]. Psychosis is unrelated to total dose or duration of dopaminergic medication, and no differences have been found in the incidence rate among patients receiving levodopa versus those on dopamine agonists or anticholinergic drugs [122].

The association between sleep disturbance and PD psychosis is sufficiently robust to suggest REM sleep behavior disorder manifests from an evolving synucleinopathy in patients with PD-associated psychosis or dementia. Both factors may develop from a single epiphenomenon, such as neurodegeneration. Evidence also suggests contribution to PD psychosis from non-dopaminergic neurotransmitters, including serotoninergic or cholinergic systems [119].

Visual hallucinations require medication adjustment and possibly specific therapies if they are troublesome, threatening, or associated with behavioral change [4]. Triggering factors, such as infection, metabolic disorders, fluid/electrolyte imbalance, and sleep disorder, should be controlled. In addition, steps should be taken to reduce polypharmacy. Tricyclic antidepressants and anxiolytics/sedatives should be reduced or stopped. Antiparkinsonism drugs should also be reassessed. Anticholinergics and amantadine should be halted, while dopamine agonists and MAO-B and COMT inhibitors should be reduced or halted. The levodopa dose may be reduced [74,123].

Unfortunately, most commonly used antipsychotic drugs have side effects that exacerbate PD. Consequently, atypical antipsychotics are often key in the management of PD-associated psychosis. Almost all antipsychotic drugs can exacerbate PD. Clozapine is the only antipsychotic with high-level evidence of efficacy; in some patients, it also improves motor function [124]. Clozapine is widely recommended as the first-line choice, but it is associated with potentially fatal agranulocytosis, which develops in 1% of patients and makes routine blood neutrophil counts mandatory. Less serious side effects include sedation, tachycardia, orthostatic hypotension, and sialorrhea. Low-dose clozapine (less than 50 mg) also has efficacy, with less frequent and more tolerable side effects and rare agranulocytosis [125,126].

The AAN states quetiapine can be considered in the treatment of PD-associated psychosis [76]. However, some studies have found quetiapine no better than placebo in antipsychotic effect in this group of patients [127,128]. Despite clozapine superiority, quetiapine is the most frequently used antipsychotic for PD-associated psychosis in the United States, due to better safety and despite inconsistent antipsychotic benefit [75,119].

First-generation antipsychotics (e.g., haloperidol) should not be used. This drug class is a common cause of drug-induced parkinsonism, shows little to no psychotic symptom relief, and can worsen motor symptoms [119]. Other atypical antipsychotic agents (e.g., olanzapine, risperidone) can worsen parkinsonism and should not be used [75]. The FDA requires all atypical antipsychotics to carry black box warnings for increased risk of death in elderly patients with dementia [119].

Adding a cholinesterase inhibitor (e.g., rivastigmine, donepezil) is an option [74]. In patients requiring sedation for severe agitation, non-neuroleptics such as lorazepam should be considered over standard agents like haloperidol [75,76].

Pimavanserin is an investigational drug with a novel mechanism of antipsychotic action as a selective serotonin 5-HT2A receptor inverse agonist. The activity of this drug does not block dopamine receptors and does not adversely affect PD. In clinical trials for the treatment of PD-associated psychosis, pimavanserin has shown efficacy and tolerability, including significant improvements in positive symptoms of psychoses, caregiver burden, and overall clinical improvement without worsening of motor function. No safety signals have emerged [95,129].

Dementia

Dementia is the progressive decline in cognitive function (i.e., thinking, planning, organizing, problem solving) beyond what might be expected from normal aging. The dementia of PD takes two forms: an early, more rapidly progressive dementia characterized pathologically by an abundance of Lewy bodies within the brain (i.e., dementia with Lewy bodies), and a later onset, less rapid form characterized by neurodegenerative change and fewer Lewy bodies (i.e., PD dementia) [8]. The cognitive signs of dementia with Lewy bodies begin within one year of motor symptom onset, while the cognitive problems associated with PD dementia begin one or more years after motor symptom onset.

Dementia affects a substantial portion of people with PD and has virtually no effective treatment [8]. Cognitive impairment, autonomic dysfunction, and falls are all features of PD dementia that substantially affect function and quality of life and incompletely respond to medication manipulation [4].

In patients with typical PD dementia, there is an initial rapid loss of midbrain dopamine neurons followed by slow progression of Lewy body infiltration into the brain over decades. Dementia manifests later when Lewy bodies invade the neocortex. Patients diagnosed with PD after 70 years of age develop dementia earlier in the disease, show more alpha-synuclein-containing Lewy bodies throughout the brain, and often have additional age-related plaque pathology. In contrast, dementia with Lewy bodies occurs with PD diagnosed at a younger age, is more rapidly progressive, and shows substantial amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that age at symptom onset and the extent and type of age-related, Alzheimer-type pathology influence pathologic progression in PD [8].

Management involves discontinuation of potential aggravators, including anticholinergics, amantadine, tricyclic antidepressants, tolterodine, oxybutynin, and benzodiazepines [74,123]. A cholinesterase inhibitor, such as rivastigmine, donepezil, or galantamine, should be initiated. With idiosyncratic clinical response or side effects, an alternate agent may be tried. If cholinesterase inhibitors lack tolerability or efficacy, memantine should be added or substituted.

Depression

As many as 90% of patients with PD experience depression, which can appear in early and advanced disease. This neuropsychiatric problem has a major impact on both patients' and caregivers' quality of life. With many overlapping features between depression and PD before and during dopaminergic treatment (e.g., loss of facial expression, hypophonic speech, slowed movement, reduced appetite, sleep disorders), depression in PD often goes on unrecognized [89,130].

Tricyclic antidepressants may be the best choice for depression treatment in PD, followed by selective serotonin or norepinephrine reuptake inhibitors (SSRIs/SNRIs) or dopaminergic agonist therapy. Cognitive-behavioral therapy also appears promising. Most PD experts use an SSRI, SNRI, or tricyclic antidepressant and follow the patient closely for four to six weeks, adjusting as needed [95,131].

The potential of antidepressants to worsen PD motor symptoms has been debated, but studies show no significant increase in risk of motor deterioration. A review of tricyclic antidepressant and SSRI/SNRI treatment of depression in PD concluded possible efficacy in reducing levodopa-induced dyskinesia [132]. There is a minor risk of impairing levodopa motor control, but this finding is inconsistent. The effect is usually minor when it happens and can be resolved by increasing levodopa dose [132]. Nortriptyline has no effect on dyskinesia or motor symptoms.

Tricyclic antidepressants and SSRIs/SNRIs are probably effective for depression [132]. The strongest evidence is for nortriptyline and paroxetine. SSRIs may not be the preferred drug class when rapid effect is needed, and quicker onset of therapeutic benefit is achieved with noradrenergic antidepressants. Tricyclic antidepressants and SSRIs/SNRIs are also beneficial in treating anxiety in patients with PD.

In other drug classes, the dopamine agonist pramipexole (up to 1 mg three times per day) significantly improved depression compared to placebo, an effect unrelated to motor improvement [95,131]. Depression symptoms confined to "off" time may respond well to any treatment that reduces motor fluctuations and improves "on" time. Electroconvulsive therapy remains a potentially lifesaving treatment in major depression and has been used successfully in PD, but sufficient trials in PD depression do not exist [95,131].

Apathy

Apathy in non-demented and non-depressed patients with PD is not associated with dopamine transporter activity in the striatal sub-regions. It is more likely the result of extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits [133].

No established treatment for apathy is available. Levodopa, selegiline, and antidepressants have been suggested as useful. In a small clinical trial, rivastigmine 9.5 mg/day transdermal significantly improved apathy symptoms beyond placebo response. There was also improvement in activities of daily living and caregiver burden, but not quality of life. Methylphenidate is probably effective in treating apathy and fatigue in later PD [132]. There is a lack of literature on the subject, many experts use a dopamine agonist for severe apathy, but with caution for impulsive behaviors [95,134].

Impulse Control Disorders

Impulse control disorders and aberrant behaviors can develop during dopamine agonist treatment in PD and worsen patient and caregiver quality of life. Often, patients lack insight into the negative consequences of their behavior. Risk factors include male sex, younger age at onset, personality traits of high impulsivity and novelty seeking, and personal or family history of addictive disorders. In predisposed patients, overstimulation of mesocorticolimbic dopamine receptors by dopamine agonists leads to impulse control disorders and compulsive medication use. Impulse control disorders are more likely in early PD with normal-range medication dosing, while compulsive medication use is more commonly associated with fluctuations in advanced disease. Affected patients often lack noteworthy psychiatric histories and cognitive impairment, making identification difficult. Management requires reducing dopaminergic therapy, and psychosocial support is often necessary. SSRIs may help, while atypical antipsychotics have limited benefit. Prevention is based on the identification of at-risk individuals and active monitoring [135].

In a study of 203 patients with PD, the most common impulse control disorders were compulsive eating (14%), hypersexuality (10%), compulsive shopping (6%), and pathologic gambling (3%). Age younger than 68 years and exposure to dopamine agonists or MAO-B inhibitors were identified as risk factors for developing disorders of impulse control. Affected patients on dopamine agonists received a daily dose 60% higher than those without the disorders. Impulse control disorder symptoms showed a nonlinear dose-response relationship with dopamine agonists [136].

Autonomic Dysfunction

Constipation

In patients with PD, constipation may develop due to impaired gastrointestinal motility and medication side effects. Treatment is often behavioral, with a focus on increasing fluid ingestion, fiber intake, and physical activity. If additional treatment is necessary, polyethylene glycol solution, fiber supplements (e.g., psyllium, methylcellulose), and/or osmotic laxatives are recommended. Short-term irritant laxatives may help in selected patients [74,123].

Dysphagia

Management of dysphagia requires optimization of motor control approaches. Speech therapy is indicated for assessment, swallowing advice, and further investigations, if needed. Videofluoroscopy may be conducted in selected cases to exclude silent aspiration. In severe cases, enteral feeding options (e.g., short-term nasogastric tube, percutaneous endoscopic gastrostomy) may be considered [74,123].

Orthostatic Hypotension

Orthostatic hypotension is a symptomatic drop of 20 mm Hg systolic or 10 mm Hg diastolic blood pressure when rising to standing from sitting or lying down. Orthostatic hypotension is associated with lightheadedness, syncope, or nonspecific complaints including fatigue, unsteadiness, headache, neck tightness, or cognitive slowing. Because supine hypertension often accompanies orthostatic hypotension, the first step of treatment should be non-pharmacologic to avoid worsening supine hypertension. Patients should avoid, reduce, or eliminate large meals, alcohol, warm environments, volume depletion, diuretics, antihypertensive drugs, tricyclic antidepressants, nitrates, dopaminergic drugs (if possible), and alpha-blockers used for benign prostatic hypertrophy. Increasing salt intake may also help. Tilting the head of bed at night (30° to 40°) is recommended, as is exercise, as tolerated. Waist-high elastic stockings, abdominal compression bands, and counter-maneuvers (e.g., leg crossing, toe raising, thigh contraction) are effective prevention measures.

Midodrine has the greatest level of evidence in terms of pharmacotherapy. Fludrocortisone is also possibly effective, but it is important to monitor for side effects [74,95,123].

Urinary Dysfunction

Urinary incontinence in patients with PD is thought to result from hyper-reflexia caused by basal ganglia dysfunction. When symptoms appear suddenly, it is important to rule out urinary tract infection. If incontinence occurs mainly at night, fluid intake should be reduced after 6 p.m. and the head of the bed should be tilted up for sleep.

Night-time dopaminergic therapy should be optimized, and if necessary, an anticholinergic drug may be added. Guidelines recommend trospium chloride (10–20 mg two to three times per day) or tolterodine (2 mg twice per day) [74,123]. However, trospium is less able to penetrate the blood-brain barrier, and cognition may worsen. Botulinum toxin type A injected in the detrusor muscle is also an option [74,123].

Sexual Dysfunction

Sexual dysfunction is common in men and women with PD and is a complex problem from diverse etiologies, including motor dysfunction, medication side effects, mood disorders, and autonomic dysfunction manifesting in erectile dysfunction, reduced genital sensitivity and lubrication, and difficulty reaching orgasm [123].

Erectile dysfunction is widespread in PD and affects at least 50% to 75% of men with PD. Good evidence supports the use of sildenafil citrate, and similar drug class members, such as tadalafil and vardenafil, are also likely to be effective [89].

Sleep Disorders

Excessive Sleepiness

Excessive daytime somnolence and sudden sleep onset can originate from the disease process, medications, or other sleep disorders. Excessive daytime somnolence can result from dopaminergic medications—more commonly dopamine agonists than levodopa. Patients with these symptoms should be assessed for nocturnal sleep disturbances. Nocturnal sleep may be improved by reducing akinesia, tremor, and urinary frequency.

Sedative drugs should be reduced or discontinued. All dopaminergic drugs may induce daytime somnolence, so the dose of the current dopamine agonist may be reduced or the patient may switch to another dopamine agonist. Modafinil and/or other wake-promoting agents (e.g., methylphenidate) should be added [74,123]. Patients with excessive daytime somnolence should be advised to stop driving.

Restless Legs Syndrome

Restless legs syndrome (RLS) is a movement disorder of the limbs whereby patients have a bothersome, irresistible urge to move the legs. RLS often interferes with sleep, leading to chronic sleep deprivation and stress. The prevalence of RLS was 12% in one study of patients with PD [137]. Drugs considered the most efficacious for RLS include levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin; second-line options include rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, and clonidine [138].

Insomnia

Insomnia in PD may be the result of mood disturbances, persistent tremor, night-time re-emergence of PD symptoms, nocturia, and reversal of sleep patterns [123]. Levodopa/carbidopa may contribute to insomnia while improving sleep-related motor symptoms. Melatonin may be effective in improving patients' perception of sleep quality [123].

REM Sleep Behavior Disorder

As discussed, REM sleep behavior disorder is a type of parasomnia characterized by the behavioral enactment of dreams during REM sleep. REM sleep behavior disorder is one of the most robust predictors of PD development and is very prevalent throughout the motor symptom phase of disease progression. Standard treatment is clonazepam or melatonin [54].

Pain

Among non-motor symptoms, 60% to 83% of patients with PD report pain of heterogeneous presentation and disabling effect on quality of life. Pain has received minimal attention in PD due to its association with the reappearance of motor symptoms and dystonic muscle contraction with dissipation of levodopa dose response. Pain also occurs as skeletal-muscle or neuropathic (peripheral or central) pain. Evidence suggests patients with PD have abnormal nociceptive processing in pain-free states, independent of parkinsonism motor symptom presence, that is unaffected by levodopa stimulation. Few therapeutic strategies for pain management in PD have been developed [139,140].

A concern in using opioids to treat pain in patients with PD is potential exacerbation of constipation, a common, burdensome symptom of autonomic dysfunction. To possibly mitigate this issue, an oral formulation combining prolonged-release oxycodone with naloxone has been evaluated. In an eight-week trial, patients with PD-associated chronic pain received low-dose oxycodone/naloxone (5 mg/2.5 mg) twice daily. Of the 87.5% who completed the trial, significant pain reduction was achieved, no adjustment of dopaminergic therapy was required, no significant changes were observed in bowel function and constipation symptoms, no changes were observed in sleep symptoms, and improvements were recorded in clinician impression of therapeutic effect [141].

END-STAGE PARKINSON DISEASE

A little-studied area of PD has been symptom manifestation with approaching death and factors related to their severity and progression. The course of non-dopaminergic PD symptoms in relation to age and death was prospectively studied in 378 patients with PD over five years. Patients who died (11%) during follow-up had more severe non-dopaminergic symptoms. The progression of cognitive and axial symptoms accelerated in older patients, and the progression of axial, cognitive, and psychotic symptoms accelerated before death. Improving understanding of these factors will hopefully make a positive impact on end-of-life care [142].

End-of-Life Care

During end-stage PD, the focus of care is on palliation of symptoms and comfort. Patients with end-stage PD often exhibit cognitive impairment and progress to the point of requiring assistance with most activities. The best approach for patients with PD at the end of life is multidisciplinary palliative care with adequate physical, psychologic, and spiritual support. In earlier stages, the goal is to maintain patient independence for as long as possible; however, in end-stage PD, the focus is mainly on comfort and supportive care [149].

Non-motor symptoms such as depression, psychosis, urologic dysfunction, pain, and respiratory depression, become more common in end-stage PD. Over time, these symptoms may become the most prominent medical problem, leading to increasing decline in quality of life [149]. The first step in managing these symptoms may be reduction or discontinuing triggering pharmacotherapeutic agents, such as anticholinergics, MAO-B inhibitors, and opioids.

In the last days, the goals of the healthcare team are to ensure a peaceful death for the patient and to support the family during the dying process and throughout grief and mourning. The focus for the patient is management of symptoms and emotional and spiritual ease, and the focus for the family is education to prepare them for the dying process.

ADJUNCTIVE TREATMENT MODALITIES

Evidence Based Practice Recommendation

The American Occupational Therapy Association recommends engagement of patients with PD in exercise and physical activity, specifically multisession, repetitive physical exercise (diachronic) to improve motor and sensory-perceptual performance skills.

https://www.guidelinecentral.com/summaries/occupational-therapy-practice-guidelines-for-adults-with-neurodegenerative-diseases

Last Accessed: April 11, 2019

Level of Evidence: A or B (There is strong or moderate evidence that occupational therapy practitioners should routinely provide the intervention to eligible clients.)

A variety of nonpharmacologic, adjunctive interventions have been evaluated for management of PD. These include exercise programs and occupational, physical, and speech therapies. While clinical study design and control group issues have confounded the quality of evidence, clinical experience suggests that these approaches have value. The American Academy of Family Physicians recommends physical therapy, speech therapy, and occupational therapy be offered to patients with PD as part of an overall strategy for improving or maintaining function [2]. The specific benefits for allied health professional interventions to patients with PD include [143]:

Physical Therapy

- Gait re-education, improving balance and flexibility

- Increasing aerobic capacity

- Improving movement initiation

- Improving independent functioning, mobility, and daily activities

- Advising on safety in the home environment

Occupational Therapy

- Maintaining work and family roles, home care, and leisure activities

- Improving and maintain transfers and mobility

- Improving self-care activities such as eating, drinking, washing, and dressing

- Addressing environmental issues to improve safety and motor function

- Cognitive assessment and appropriate intervention

Speech/Language Therapy

- Improving vocal loudness and pitch range (with programs such as Lee Silverman voice treatment)

- Teaching strategies to optimize speech intelligibility

- Ensuring effective means of communication maintained throughout the disease course, including use of assistive technologies

- Reviewing and managing safe and efficient swallowing to minimize risk of aspiration

When capable of doing so, persons with PD should be encouraged to maintain a regular program of stretching and other physical exercise. In a randomized, controlled trial, tai chi training was seen to be more effective than resistance training or stretching in reducing balance impairments and falls in patients with mild-to-moderate PD [153]. The American Parkinson Disease Association has developed a free, web-based training program designed to teach fitness professionals how to best meet the unique needs of persons with PD [154]. Cognitive training is likely helpful for other patients. Patient and family member education is a key component of PD management, as is the use of support groups [93].

PRACTICE CONSIDERATIONS

Avoiding Inappropriate Medications

Many patients with PD require hospital admission for problems unrelated to motor pathology. Their medical care is typically received on non-neurology wards from staff unfamiliar with PD management, increasing the risk of inappropriate medications that exacerbate PD. Among inpatients with PD, 43.8% received inappropriate anti-dopaminergic medication at some point, primarily haloperidol and metoclopramide. The highest prevalence occurred in patients with PD on chronic antipsychotics [75].

Nausea and vomiting, common adverse effects of levodopa and dopamine agonists, may require antiemetic use. The centrally acting dopamine antagonists metoclopramide and prochlorperazine should not be used; the peripheral dopamine antagonist domperidone is the antiemetic of choice. The serotonin receptor antagonist ondansetron is another option [74,75].

Healthcare professional education is suggested to improve the care of inpatients with PD. Pharmacists can play a key role in identifying inappropriate medications and in educating non-PD specialist professionals [75].

Safety Precautions with Dopaminergic Agents

With disease progression, patients with PD become more reliant on medication to maintain their ability to function. In addition to regular monitoring for drug-specific side effects, clinicians should be careful not to abruptly withdraw dopaminergic medication [89]. Patients and family should be educated on the importance of medication compliance and regular dosing so as to avoid rapid changes in efficacy. Special attention is required during periods of intercurrent illness, such as gastroenteritis or abdominal surgery, which may result in interruption of dosage or poor intestinal absorption. These measures help to avoid the potential development of acute akinesia or neuroleptic malignant syndrome. "Drug holidays" are not recommended due to the risk of developing neuroleptic malignant syndrome.

Considering the risks of sudden changes in dopaminergic medication, patients with PD admitted to hospitals or care facilities should receive their medication at the appropriate times or be allowed self-medication. Medication adjustment should be reserved for specialists in PD management [89].

Clinician-Patient Communication

In managing newly diagnosed patients, healthcare professionals should exhibit great sensitivity and understanding in describing disease symptoms and progression. As it progresses, PD complicates every aspect of daily living. Formerly routine tasks demand full attention and often cause frustration and anxiety. Over time, PD reduces work capacity, erodes earning potential, and may compromise social and family relationships. Disease progression leads to increased dependency and fosters feelings of being a burden to others. Increasing difficulties with writing and speaking, coupled with the loss of independence, often lead to social withdrawal, isolation, depression, frustration, and anger. Access to primary care, speech therapists, exercise programs, and emotional support is critical to managing the disease and living with dignity, and people living with PD require understanding and support as they struggle to maintain independence and adapt to living with a chronic condition [89].

Good communication is the foundation of care between patients with PD, their caregivers, and health professionals. Healthcare professionals' commitment to clear, compassionate communication can make a meaningful difference to their patients. When patients with PD understand healthcare professionals' recommendations, they can know what to expect and are better prepared to navigate the system, ask the right questions, and make the best personal choices [89].

Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 31 million Americans speak a language other than English in the home, with approximately 9.4 million of them (11.7% of the population) speaking English less than "very well" [144]. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" [145]. In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [145]. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [146,147].

"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters [148]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [70]. A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters [147].

Care decisions should be based upon best available evidence and provided by applicable professional standards. Issues to consider when communicating with people with PD and their caregivers include [89]:

- Style, manner, and frequency of communication that is compassionate and respectful

- Ease of access for those receiving information in a timely and appropriate manner throughout the progression of the disease

- Honesty and sensitivity in tailoring information to meet changing medical needs

- Encouragement of self-management to meet individual needs and preferences

- Inclusion of caregivers who are also impacted by PD and require information and support

Hospice

Traditionally, management of PD has focused on drug treatment and interdisciplinary care for a long-term, slowly progressive disorder. Palliative care specialists have not routinely been involved. Due to the long duration of the disease and the difficulty in predicting the time of death, patients with PD are frequently refused access to hospice and palliative care services [89].

8. CONCLUSION

PD is an important, increasingly prevalent neurodegenerative disease of aging. Although the defining motor abnormalities are relatively easy to recognize after the syndrome of parkinsonism is fully manifest, the onset and progression of clinical features are variable and often preceded or followed by non-motor symptoms of disease. The pathogenesis of PD remains vague, but the pathophysiology is clear enough to provide the basis for treating the motor dysfunction of PD and to lend hope for future development of more effective and innovative therapies.

On average, patients with PD live for well over a decade with their disease, which usually follows a slowly progressive and debilitating course. The likelihood of intercurrent complications is high, and at each stage, there are new issues of chronic disease management that challenge healthcare providers and family alike. All involved should have a basic understanding of the clinical features of PD, the sources of suffering, principals of treatment, importance of compliance, and potential for drug-drug interactions and side effects. Best practice outcomes require the coordinated effort of well-informed primary care physician and nurse, subspecialist, pharmacist, and home health provider—an interprofessional healthcare team approach.

9. RESOURCES

National Institute of Neurological Disorders and Stroke

https://www.ninds.nih.gov/Disorders/All-Disorders/Parkinsons-Disease-Information-Page

American Parkinson Disease Association

https://www.apdaparkinson.org

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103. Pasternak B, Svanström H, Nielsen NM, Fugger L, Melbye M, Hviid A. Use of calcium channel blockers and Parkinson's disease. Am J Epidemiol. 2012;175(7):627-635.

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122. Fox SH, Visanji NP, Johnston TH, Gomez-Ramirez J, Voon V, Brotchie JM. Dopamine receptor agonists and levodopa and inducing psychosis-like behavior in the MPTP primate model of Parkinson disease. Arch Neurol. 2006;63(9):1343-1344.

123. Zesiewicz TA, Sullivan KI, Arnulf I, et al. Practice parameter: treatment of nonmotor symptoms of Parkinson disease. Neurology. 2010;74(11):924-931.

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129. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540.

130. DeMaagd G, Philip A. Parkinson's disease and its management. Part 5: treatment of nonmotor complications. PT. 2015;40(12): 838-846.

131. Troeung L, Egan SJ, Gasson N. A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease. PLoS One. 2013;8(11):e79510.

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135. Antonini A, Cilia R. Behavioural adverse effects of dopaminergic treatments in Parkinson's disease: incidence, neurobiological basis, management and prevention. Drug Saf. 2009;32(6):475-88.

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137. Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease. Mov Disord. 2006;21(3):380-384.

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139. Antonini A, Tinazzi M. Targeting pain in Parkinson's disease. Lancet Neurol. 2015;14(12):1144-1145.

140. Tinazzi M, Del Vesco C, Defazio G, et al. Abnormal processing of the nociceptive input in Parkinson's disease: a study with CO2 laser evoked potentials. Pain. 2008;136(1-2):117-124.

141. Madeo G, Schirinzi T, Natoli S, et al. Efficacy and safety profile of prolonged release oxycodone in combination with naloxone (OXN PR) in Parkinson's disease patients with chronic pain. J Neurol. 2015;262(9):2164-2170.

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Evidence-Based Practice Recommendations Citations

1. Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES recommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013;20(1):16-34. Available at https://www.movementdisorders.org/MDS-Files1/MDS-ES/MDS-ES--EFNS/BerardellietalEFNSMDSESene12022.pdf. Last accessed April 11, 2019.

2. Wippold FJ II, Brown DC, Broderick DF, et al. ACR Appropriateness Criteria: Dementia and Movement Disorders. Reston, VA: American College of Radiology; 2015. Available at https://acsearch.acr.org/docs/69360/Narrative. Last accessed April 11, 2019.

3. Oertel WH, Berardelli A, Bloem BR, et al. Early (uncomplicated) Parkinson's disease. In: Gilhus NE, Barnes MP, Brainin M (eds). European Handbook of Neurological Management. 2nd ed. Oxford: Wiley-Blackwell; 2011: 217-236. Available at https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch14. Last accessed April 11, 2019.

4. Oertel WH, Berardelli A, Bloem BR, et al. Late (complicated) Parkinson's disease. In: Gilhus NE, Barnes MP, Brainin M (eds).European Handbook of Neurological Management. 2nd ed. Oxford: Wiley-Blackwell; 2011: 237-267. Available at https://onlinelibrary.wiley.com/doi/abs/10.1002/9781444328394.ch15. Last accessed April 11, 2019.

5. Preissner K. Occupational Therapy Practice Guidelines for Adults with Neurodegenerative Diseases. Bethesda, MD: American Occupational Therapy Association, Inc.; 2014. Summary retrieved from Guideline Central at https://www.guidelinecentral.com/summaries/occupational-therapy-practice-guidelines-for-adults-with-neurodegenerative-diseases. Last accessed April 11, 2019.

94101 • Low Back Pain

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2019 NetCE, All rights reserved.

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

Table of Contents

94101 • Low Back Pain

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. EPIDEMIOLOGY

INCIDENCE AND PREVALENCE

PERSONAL IMPACT

ECONOMIC AND SOCIETAL COSTS

3. RISK AND PROGNOSTIC FACTORS

RISK FACTORS FOR DEVELOPING BACK PAIN

RISK FACTORS FOR PROGRESSION OF ACUTE LBP TO CHRONIC LBP

IATROGENIC RISK FACTORS

PROGNOSTIC FACTORS OF UNSATISFACTORY TREATMENT RESPONSE

4. CLINICAL COURSE

5. PATHOPHYSIOLOGY

PAIN PHYSIOLOGY

CHRONIC LOW BACK PAIN

PATHOANATOMIC BASIS OF COMMON LBP CONDITIONS

6. ASSESSMENT AND DIAGNOSIS

HISTORY AND PHYSICAL EXAM

DIAGNOSTIC IMAGING AND TESTING

LABORATORY TESTS

ENHANCING ASSESSMENT AND DIAGNOSIS

7. TREATMENT OPTIONS

TREATMENT OF ACUTE AND SUB-ACUTE LBP

TREATMENT OF CHRONIC LBP

NON-DRUG THERAPIES

COMPLEMENTARY AND ALTERNATIVE THERAPIES

PHARMACOTHERAPIES

INTERVENTIONAL PAIN MEDICINE THERAPIES

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

LIMITATIONS IN PAIN THERAPY RESEARCH

DECLINING AVAILABILITY OF MULTIDISCIPLINARY PAIN PROGRAMS

THE RISE OF INTERVENTIONAL PAIN MEDICINE

FINANCIAL AND MONETARY INFLUENCES

HEALTHCARE PROVIDER EDUCATION

PATIENT SATISFACTION RATINGS

COMMUNICATION WITH NON-ENGLISH-PROFICIENT PATIENTS

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

94101 • Low Back Pain

Education Category. Infection Control / Internal Medicine

Release Date. 08/01/2019

Expiration Date. 07/31/2022

Course Overview

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

Audience

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

Course Objective

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

Learning Objectives

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

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

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

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

4. Describe the clinical course of low back pain.

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

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

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

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

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

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

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

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

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

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

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

Faculty

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

Faculty Disclosure

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

Division Planners

John M. Leonard, MD

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

Division Planners Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

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

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

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

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

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

2. EPIDEMIOLOGY

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

INCIDENCE AND PREVALENCE

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

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

Type of Pain

Experienced in the Past Three Months

Difficulty with Basic Actionsa

Complex Activity Limitationb

Low back pain

28.1%

51.6%

55.0%

Severe headache or migraine

16.1%

31.0%

33.5%

Neck pain

15.1%

30.2%

34.4%

Knee pain

19.5%

37.3%

38.6%

Shoulder pain

9.0%

17.7%

21.4%

Finger pain

7.6%

14.3%

16.3%

Hip pain

7.1%

15.0%

18.4%

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

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

Source: [12]

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

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

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

PERSONAL IMPACT

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

ECONOMIC AND SOCIETAL COSTS

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

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

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

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

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

3. RISK AND PROGNOSTIC FACTORS

RISK FACTORS FOR DEVELOPING BACK PAIN

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

Smoking

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

Obesity

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

Evidence Based Practice Recommendation

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

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

Last Accessed: July 28, 2019

Strength of Recommendation: Systematic review

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

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

Age

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

Vitamin D Deficiency

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

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

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

RISK FACTORS FOR PROGRESSION OF ACUTE LBP TO CHRONIC LBP

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

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

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

- Negative belief that pain is harmful or potentially severely disabling

- High levels of "fear avoidance" behaviors

- Poor or maladaptive coping strategies

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

- Excessive focus on pain

- High emotional distress levels

- Depressed mood, low morale, and social withdrawal

- Resistance to change

- Low self-efficacy

- Family reinforcement of illness behavior

- Concurrent social or financial problems

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

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

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

Specific work-related factors that may predict chronicity include:

- Job dissatisfaction

- Conflict with supervisors or coworkers

- High physical demands

- Inability to modify work

- High levels of job stress

- Disputed or unresolved workers' compensation claim

IATROGENIC RISK FACTORS

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

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

PROGNOSTIC FACTORS OF UNSATISFACTORY TREATMENT RESPONSE

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

- Medical comorbidities

- Psychiatric and psychologic comorbidity

- Another pain condition

- Substance abuse

- Previous surgeries

- Tobacco use

- Head trauma history

- BMI

- Sleep disorders

- Employment status

- Concurrent pharmacotherapies

- Social support

- Physical conditioning

- Current pain intensity

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

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

Pre-Operative

- Anxiety

- Depression

- Misidentification of pain origin

- Obesity

- Cigarette smoking

- Unresolved litigation or claims

Surgical

- Revision surgery

- Poor candidate for surgical technique

- Incorrect spinal level of intervention

Post-Operative

- Central sensitization

- Progressive spinal disease

- Epidural fibrosis

- Nerve injury

- Infection

- Hematoma

- Myofascial pain

4. CLINICAL COURSE

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

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

5. PATHOPHYSIOLOGY

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

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

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

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

- Pain is not an accurate measure of tissue state.

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

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

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

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

PAIN PHYSIOLOGY

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

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

Peripheral Nociception

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

Inflammatory Pain

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

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

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

Spinal Cord Transmission

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

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

Brain Projections of Pain Pathways

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

Descending Modulatory Pain Pathways

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

CHRONIC LOW BACK PAIN

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

Development of Chronic LBP

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

Peripheral Sensitization

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

Central Sensitization

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

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

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

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

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

Neuropathic Involvement in Chronic LBP

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

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

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

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

Psychologic Factors

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

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

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

Neuroscience Findings

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

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

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

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

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

Heritable Factors

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

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

PATHOANATOMIC BASIS OF COMMON LBP CONDITIONS

Definitions

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

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

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

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

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

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

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

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

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

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

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

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

Anatomic Pathogenesis of LBP

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

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

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

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

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

Myofascial Pain Syndrome

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

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

Failed Back Surgery Syndrome

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

6. ASSESSMENT AND DIAGNOSIS

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

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

HISTORY AND PHYSICAL EXAM

Red Flag Assessment

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

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

Possible Etiology

Red Flags

Malignancy

History of or current cancer diagnosis

Systemically unwell

Unexplained weight loss in the past six months

Constant, progressive, nonmechanical pain

Altered sensation from trunk down

Vertebral fracture

Age older than 70 years

Significant age-relative trauma

Long-term corticosteroid use

Altered sensation from trunk down

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

Cauda equina syndrome

Acute-onset urinary retention

Loss of anal sphincter tone or fecal incontinence

Saddle anesthesia

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

Gait disturbances

Vertebral infection

Systemically unwell

Constant, progressive, nonmechanical pain

Recent bacterial infection or spinal region wound

Intravenous drug abuse

Immunosuppression from steroids, transplant drugs, or HIV

Altered sensation from trunk down

Source: [36,130,131,132]

History

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

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

Physical Examination

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

- Gait:

- Heel walking (L4–L5)

- Toe walking (S1)

- In standing position:

- Movement testing, flexion and extension

- Trendelenburg test (L5)

- Repeat toe raise (S1)

- In sitting position:

- Patellar reflex (L3–L4)

- Quadriceps power (L3–L4)

- Ankle dorsiflexion strength (L4–L5)

- Great toe extension (L5)

- Flexion strength (S1)

- Plantar response

- Upper motor test

- Kneeling position:

- Ankle reflex (S1)

- Supine lying position:

- Passive straight leg raise

- Prone lying position:

- Femoral nerve stretch (L3–L4)

- Gluteus maximus power (S1)

- Saddle sensation testing (S2–S4)

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

- Dermatomes

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

- Non-anatomic superficial tenderness

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

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

- Non-anatomic motor or sensory loss

- Verbal over-reaction or exaggerated body language

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

DIAGNOSTIC IMAGING AND TESTING

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

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

MRI Finding

Frequency of Finding

Disk bulge

24% to 53%

Disk protrusion

20% to 63%

Disk extrusion

1% to 18%%

Any disk pathologya

57% to 64%

Nerve root deviation or compression

4%

aAny bulge, protrusion, extrusion, or sequestration

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

Evidence Based Practice Recommendation

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

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

Last Accessed: July 28, 2019

Strength of Recommendation: 2 (Usually not appropriate)

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

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

LABORATORY TESTS

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

ENHANCING ASSESSMENT AND DIAGNOSIS

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

Subgrouping Patients with Nonspecific LBP

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

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

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

Nociceptive Pain

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

- Usually intermittent and sharp with movement or mechanical provocation

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

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

Peripheral Neuropathic Pain

- Pain referred in a dermatomal or cutaneous distribution

- History of nerve injury, pathology, or mechanical compromise

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

Central Sensitization

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

- Pain disproportionate to the extent of injury or pathology

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

- Diffuse non-anatomic areas of pain tenderness on palpation

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

Table 4: LOW BACK PAIN DIAGNOSTIC CATEGORIES AND KEY INFORMATION

Category

Definition

Key Findings

Diagnostic Standard Used

Screening

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

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

N/A

Functional instability

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

Positive prone passive lumbar extension

Hypermobile lumbar segment(s)

Absence of hypomobile lumbar segment

Radiographic measurements of intervertebral motion

Nociceptive (pain from noxious stimulation of peripheral tissues)

Discogenic

Pain from the posterior annulus and near the endplate

Centralization with repeated end-range loading

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

Lumbar discography

Sacroiliac joint

Pain from the sacroiliac joint and/or supporting ligaments

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

Fluoroscopically guided, controlled anesthetic block

Zygapophyseal joint

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

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

Fluoroscopically guided, controlled anesthetic block

Myofascial

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

Pain with use of involved muscle and trigger points

None

Neuropathic (pain from peripheral or central nervous system tissues)

Compressive radiculopathy

Pain from compression and inflammation of a nerve root

Absent ankle/knee reflex

Pain worse in lower extremity than in back

Dermatome distribution (cough, sneeze, straining)

Paresis (extremity motor strength loss)

Finger to floor distance >25 cm

Clinical findings in individuals with nerve root compression confirmed by MRI

LANSS score >12

Expert opinion

Non-compressive radiculopathy

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

LANSS score >12

Expert opinion

Compressive radiculopathy criteria are not met

N/A

Neurogenic claudication

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

Age older than 60 years

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

Symptoms worsened by standing or extension

Urinary incontinence

Expert opinion

Negative ABI

Doppler ultrasound

Central

Pain from a lesion or dysfunction within the central nervous system

Disproportionate pain

Unpredictable symptom aggravation and relief

Maladaptive psychosocial factors

Non-anatomic distribution

Expert opinion

Other

Other diagnoses

Diagnoses not categorized above

Dependent on suspected condition

N/A

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

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

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

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

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

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

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

Prognostic Factors

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

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

7. TREATMENT OPTIONS

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

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

TREATMENT OF ACUTE AND SUB-ACUTE LBP

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

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

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

Acute LBP

Nonspecific Acute LBP

Evidence Based Practice Recommendation

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

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

Last Accessed: July 29, 2019

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

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

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

- Avoid twisting and bending.

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

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

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

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

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

Acute/Sub-Acute Lumbar Disk Herniation with Radiculopathy

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

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

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

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

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

Sub-Acute LBP

Nonspecific Sub-Acute LBP

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

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

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

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

TREATMENT OF CHRONIC LBP

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

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

Nonspecific Chronic LBP

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

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

Pharmacotherapies with proven efficacy include [47,115]:

- NSAIDs

- Norepinephrine reuptake inhibitors

- Oral mu agonist opioids

- Tramadol

- Short-term benzodiazepine trial

- Duloxetine

- Topical lidocaine patch

- Muscle relaxants (e.g., tizanidine)

- TCAs

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

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

- Salix alba (white willow bark)

- Neuroreflexotherapy

- Acupuncture

- Yoga

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

Specific Spine Conditions

Lumbar Spinal Stenosis

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

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

Myofascial Back Pain

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

The pharmacotherapy with the strongest evidence for myofascial pain is benzodiazepines combined with ibuprofen or amitriptyline (not as monotherapy) [122,161,162]. Second-line options include topical methyl salicylate, menthol, and diclofenac patch. Although antiepileptics, antidepressants, muscle relaxants, NSAIDs, and tramadol are widely used, they are largely lacking evaluation.

Trigger point injection with local anesthetic may also be used [116,158]. Efficacy depends on accurate identification of trigger points and needle placement and is enhanced by physiotherapy. There is less injection pain with lidocaine 0.25% than 1%, with comparable efficacy. Botulinum toxin may also be effective in treatment-resistant trigger points. The addition of a steroid to the local anesthetic is common but lacks supportive evidence and should be avoided due to risks of muscle necrosis, skin depigmentation, and other adverse events. Long-term pain relief requires resolution of underlying pathology, such as abnormal posture/muscle imbalance, depression, anxiety, sleep disturbance, metabolic abnormalities, psychosocial stressors, and fear avoidance behavior [122,161,162].

Failed Back Surgery Syndrome

Evidence Based Practice Recommendation

According to the American Society of Interventional Pain Physicians, spinal cord stimulation is indicated in chronic low back pain with lower extremity pain secondary to failed back surgery syndrome, after exhausting multiple conservative and interventional modalities.

https://www.painphysicianjournal.com/2013/april/2013;16;S49-S283.pdf

Last Accessed: July 29, 2019

Level of Evidence: Fair (Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, size, or consistency of included studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes)

As noted, failed back surgery syndrome is not a single entity, but a complex syndrome of multiple potential etiologies, including poor surgical technique, mechanical factors, central sensitization, or a combination. Successful identification of the pain mechanism and pain control outcome is best achieved by assessing the time frame of symptom development [115]. Spinal cord stimulation is recommended [115].

Other Conditions

Implantable intrathecal opioid infusion and spinal cord stimulation are recommended for severe, intractable LBP [4]. For patients with facet joint pain, radiofrequency denervation is recommended when previous diagnostic or therapeutic injection of facet joint or medial branch nerve have provided temporary relief [47,146,158]. Facet joint injection is not recommended [47,133,163,399].

Neuropathic Chronic LBP

The Canadian Pain Society recommends a fourth group of medications for patients with neuropathic LBP lacking benefit or tolerability to TCAs or gabapentinoids (first-line), SNRIs or topical lidocaine (second-line), or tramadol/traditional opioids (third-line) [164]. This group includes cannabinoids, methadone, mexiletine, clonidine, the SSRIs citalopram or paroxetine, and the anticonvulsants lamotrigine, topiramate, or valproic acid.

Intravenous lidocaine is recommended in patients unresponsive to oral analgesic therapy [4]. A trial of 5–7.5 mg/kg may provide pain relief from several hours to four weeks. Alternatively, intravenous ketamine is recommended for short-term pain relief. If used, it should be infused in a hospital setting under specialist care.

Considerations for Analgesia in Elderly Patients

Acetaminophen is recommended for initial and ongoing treatment of persistent musculoskeletal back pain in older patients [165]. There is a strong recommendation against the use of NSAIDs, amitriptyline, and imipramine due to the possible adverse effects. Systemic corticosteroids should only be used in pain from systemic inflammatory disease or metastatic bone pain.

Opioids are recommended for most elderly patients with moderate-to-severe pain, pain-related functional impairment, or diminished quality of life due to pain [165]. If opioids are warranted, around-the-clock dosing should be used to achieve steady-state in frequent or constant pain. If extended-release/long-acting opioids are used, it is vital to anticipate, assess, and prevent breakthrough pain or add short-acting or immediate-release opioid formulations. Do not exceed safe acetaminophen or NSAIDs limits with fixed-dose opioid combination agents [165].

Nonpharmacologic therapies and adjuvant analgesic drugs should be considered for all elderly patients with neuropathic back pain or refractory chronic LBP to enhance analgesia. In cases of localized neuropathic or non-neuropathic chronic LBP, consider topical NSAIDs or lidocaine. For regional back pain syndromes, capsaicin, menthol, or other topical agents may be beneficial. Clinicians are advised to cautiously consider glucosamine, chondroitin, cannabinoids, botulinum toxin, alpha-2 adrenergic agonists, calcitonin, vitamin D, bisphosphonates, and/or ketamine for specific pain syndromes.

NON-DRUG THERAPIES

Mattress Type

For chronic LBP, a randomized controlled trial found that a medium-firm mattress was superior for pain while lying in bed and was associated with greater improvement in pain-related disability after 90 days compared to a firmer mattress [166].

Patient Education

Educating patients with LBP about their condition and treatment options is essential in order to reduce misconceptions of therapy and, ultimately, to reduce disability. Education facilitates communication and allows the clinician to understand patient needs, goals, and beliefs or attitudes that can impose barriers to recovery. Addressing patient needs and goals can include discussion of pain concerns, rehabilitation options, pharmacotherapy, and smoking cessation. Education is also important for helping patients attain optimal pain outcomes. Without slow titration and education on prescribed drugs, patients are likely to abandon even the most established, high-evidence drugs when adverse effects begin [95,167].

Therapeutic Pain Neuroscience Education

With central sensitization present in chronic LBP, the brain produces pain, fatigue, and other "warning signs" of tissue harm without actual tissue damage or nociception. Explaining the mechanism of central sensitization with evidence from neuroscience to patients with chronic LBP is a therapeutic strategy known as therapeutic pain neuroscience education or TPNE [93,94].

TPNE helps patients with chronic pain understand their pain and make sense of the lack of objective biomarkers or imaging findings. A main goal is changing pain beliefs through the reconceptualization pain. This involves patient knowledge that pain persists without tissue damage, is disproportionate to tissue damage and/or that tissue damage (and nociception) does not by itself result in pain. The distinction between "hurting versus harming" is addressed [93,94].

Exercises and physical activity are introduced under time-contingent (e.g., perform for five minutes regardless of pain) instead of symptom-contingent (e.g., stop when painful) conditions. Research shows that symptom-contingent approaches can facilitate brain production of nonspecific warning signs, while time-contingent approaches can deactivate brain-orchestrated top-down pain facilitatory pathways. Reduced CNS hyperexcitability and increased prefrontal cortical volume have also been found in response to time-contingent therapy [168,169].

To reconceptualize pain and convince patients that CNS hypersensitivity, rather than tissue damage, is the likely cause of pain symptoms, TPNE is delivered in two to three sessions over two to three weeks. Potential patient misunderstanding of being told the pain is "all in their head" can be prevented by front-end coverage of pain neurophysiology and chronic pain, before discussing potential sustaining factors such as emotions, stress, illness perceptions, pain cognitions, and pain behavior [170].

Cognition-Targeted Neuromuscular Training

TPNE is optimally used in tandem with a time-contingent, cognition-targeted approach to daily activity and exercise therapy to address pain beliefs and cognitions before, during, and after exercise therapy. Neuroscience-informed exercise for chronic LBP involves a cognition-targeted neuromuscular training approach incorporating several modifications to conventional physical therapy that have been shown to improve patient outcomes. As noted, all exercises should be performed in a time-contingent instead of symptom-contingent manner. Progression to the next exercise level can be preceded by motor imagery for retraining brain circuitry responsible for successful execution of the targeted movement. The physical therapist should address patient pain cognitions to help patients attain positive perceptions about their pain, treatment, and exercise outcome. Discussion of patient perceptions about each exercise should include anticipated consequences (e.g., pain increase, further low back damage) and should challenge patient cognitions concerning the exercises. Pre-exercise communication reinforces the principles of TPNE and their application [93,94,171].

Patient Self-Management

Improving patient self-management is considered an important goal to decrease patient burden and service utilization. Patient self-management involves strategies to manage and monitor spinal health, assume a primary role in LBP management, and learn skills for daily use in managing back pain. Self-management of LBP is nearly universal in clinical practice guidelines for back pain, but patients often do not appreciate the improvements in their condition resulting from this approach [172].

In a meta-analysis of 13 randomized controlled trials of self-management in LBP, average improvement was calculated using a 0–100 scale. Evidence shows that patients with chronic LBP require a 20% to 30% pain and disability reduction to view an intervention as worthwhile, and the average improvement with self-management was 6% [173]. Therefore, patients are unlikely to consider the benefits from self-management efforts as meaningful. The small benefit in pain and disability challenges treatment guideline endorsement of self-management for LBP [172].

Exercise and Activity-Based Therapy

Exercise therapy produces moderate pain reduction in patients with chronic LBP independent of increases in musculoskeletal strength and significantly reduces work disability, regardless of exercise type [174,175]. Pain reduction can occur with physical therapy, but functional improvement is the primary goal. In patients with chronic LBP, studies have demonstrated positive outcomes with aggressive exercise. Exercise has been favorably compared with surgical intervention and has eliminated the need for spinal surgery in some patients. Patient care should include appropriately aggressive exercise as a core element in chronic LBP management [176].

The goal of returning patients to previous activity level is best achieved by increasing strength, flexibility, endurance, and balance. Resistance (strength) training is the only approach that improves all four factors at the same time and reduces kinesiophobia, depression, vertebral fractures, and recidivism [176].

Outcomes of core stabilization exercises are equivocal, but lumbar extensor strengthening has shown benefit by reducing pain and healthcare utilization and increasing quality of life. Motivational issues can detract from gains in function, and patients should receive time and distance guidelines and specific, measurable goals to help prevent engaging in progressively less intense home exercise [176]. Exercise frequency has been found more important than the type, duration, or intensity of the exercise [177]. A review of randomized controlled trials found that, compared with usual care, exercise therapy improved post-treatment pain intensity and disability and long-term function in chronic LBP [178].

It is important to consider that exercise worsens pain and symptoms in some patients. Poor exercise response is thought to reflect dysfunctional endogenous analgesia, with exercise failing to help restore homeostatic balance. This deficit of endogenous analgesia in some patients with chronic pain should be considered in order to help these patients avoid the detrimental effects of exercise-induced pain and distress [179].

Manual- and Physiotherapy-Based Therapies

Spinal Manipulation Therapy

Evidence Based Practice Recommendation

The American Physical Therapy Association asserts that thrust manipulative and nonthrust mobilization procedures can be used to improve spine and hip mobility and reduce pain and disability in patients with subacute and chronic low back and back-related lower extremity pain.

https://www.jospt.org/doi/full/10.2519/jospt.2012.42.4.A1

Last Accessed: July 29, 2019

Strength of Recommendation: A (Strong evidence)

Spinal manipulation therapy is performed by mobilization, whereby spinal joints are passively moved by a therapist, and by manipulation, whereby a manual impulse or thrust is applied to a joint at the end of a passive range of motion, often accompanied by a cracking sound [180]. For acute LBP, spinal manipulation therapy was found no more effective than inert interventions, sham spinal manipulation therapy, or use as adjunct therapy. Spinal manipulation therapy also seems no better than other recommended therapies [181].

For chronic LBP, spinal manipulation therapy has been found to produce a small but significant short-term effect on pain relief and functional status in comparison with other interventions. Spinal manipulation therapy has a significant short-term effect on pain relief and functional status when added to another intervention. No serious complications have been observed [182]. Spinal manipulation therapy is cost-effective as treatment of chronic back pain, either alone or in combination with general primary care, exercise, and physiotherapy [183,184].

Therapeutic Massage

A Cochrane review concluded therapeutic massage had no serious side effects and resulted in more beneficial pain relief than joint mobilization, relaxation, physical therapy, self-care education, or acupuncture for LBP [185]. Acupressure or pressure point massage provided more relief than Swedish massage. In another study, Chinese massage combined with herbal ointments was found more effective than massage plus placebo ointment among athletes with nonspecific LBP [186].

Psychologic Therapies

Encouraging patients with chronic LBP to participate in psychologic pain treatments can be difficult, because patients often insist on somatic interventions and regard psychologic interventions as inferior. Information on neurophysiologic changes associated with psychologic interventions can be presented to patients as a strategy to motivate acceptance and dispel preconception [187]. Information related to pain-related neurophysiologic alteration and treatment effects of psychologic therapies on brain and peripheral measures of pain is especially useful to enhance treatment motivation and facilitate treatment [187,188]. This is similar to pain neuroscience education.

CBT and behavioral therapies are the most widely used psychologic treatments for chronic pain. Operant-behavioral treatments, such as exposure treatment and acceptance- and commitment-based approaches, are also used. While relatively few studies have examined the neurophysiologic correlates of these therapies in patients with chronic LBP, CBT has been found effective in sub-acute or chronic LBP across a range of dimensions [184,187].

Cognitive-Behavioral Therapy

Interventions that use CBT include creative visualization, imagery, progressive muscle relaxation techniques, and problem-solving techniques. The goal of CBT is to promote patient understanding, acceptance, and self-management of chronic LBP through the development of adaptive coping behaviors and strategies, which eventually empowers the patient. CBT is effective for subacute and chronic LBP, and there is moderate-to-strong evidence for CBT use early in recovery in patients with specific biopsychosocial issues. Strong evidence indicates that CBT should be used in most patients with nonspecific LBP lasting longer than 12 weeks. Comparable outcomes have been found between fear-avoidance training and spinal fusion in chronic LBP. CBT is cost effective, adds 20% efficacy to usual rehabilitation, and reduces the duration of recurrence [42,189,190].

Studies have identified core brain regions that mediate effective cognitive interventions. These include increased rostral anterior cingulate cortex activation and decreased dorsal anterior cingulate cortex activation with cognitive distraction; involvement of the ventral lateral prefrontal cortex, mid-cingulate cortex, thalamus, amygdala, and post-central gyrus with cognitive reappraisal; and correlation of right anterolateral prefrontal cortex and the dorsal anterior cingulate cortex activation with increased self-control over pain [191,192,193].

Cognitive and learning factors contribute to placebo analgesia, considered a type of psychologic modulation of pain that is mediated by descending spinal pathways involving the anterior cingulate cortex and periaqueductal gray that alters transmission of nociceptive input at the spinal cord level [194,195]. CBT specifically alters prefrontal cortex activity in response to pain in patients with fibromyalgia [196]. Operant-behavioral therapies have been advocated for patients with low activity levels, with prominent pain behaviors that are reinforced by significant others [197,198]. Patients with fibromyalgia who received operant-based pain extinction training displayed a shift from greater anterior insula to posterior insula activation post-treatment. Changes in pain-related interference were closely related to changes in blood oxygen level-dependent activation of the posterior insula, primary somatosensory cortex, thalamus, and striatum [199]. These findings suggest that different behavioral treatments may impact different brain circuits [187].

Stepped Care in the Primary Care Setting

Measurement-based stepped care is a management approach for patients with chronic LBP in primary care that blends the stepped care approach used for many chronic diseases with the system of pain assessment and care used by pain specialists. Stepped care is well established in managing complex chronic illness, increasing treatment intensity levels for patients with no response to lower-level treatment intensity. This approach moves beyond the biomedical paradigm by systematically evaluating complex biopsychosocial factors associated with chronic pain. Systematic measurement enhances identification of specific problem areas at baseline and throughout treatment, assisting clinicians in deciding to intensify treatment or make specialist referral [200]. Relevant biopsychosocial domains are measured at baseline and during treatment with specific instruments [200]. Input from the results of these instruments helps guide the primary care provider to make referrals specific to the problem domain (Table 5) [200,400].

Table 5: BIOPSYCHOSOCIAL ASSESSMENT AND REFERRAL OF PATIENTS WITH CHRONIC LOW BACK PAIN

Domain

Instrument

Measurement-Based Score

Step Care Referral

Pain intensity

Intensity numerical rating scale (1–10)

Score ≥7 without diagnosis/plan

Pain specialist

Pain interference

Interference numerical rating scale (1–10)

Score >4

Physiatry, occupational therapy, and/or physical therapy or vocational rehabilitation

Mood

PHQ-4, PHQ-9, or PC-PTSD

PHQ-4 score ≥6 or PC-PTSD score ≥3a

Behavioral health specialist

Sleep quality

STOP-BANG

STOP-BANG score ≥3, high morphine equivalent dose, or the use of opioids and sedatives

Sleep specialist

Risk of opioid misuse

ORT

ORT score ≥8, more than four minor urinary drug test aberrancies, or any serious aberrancies

Addiction specialist

ORT = Opioid Risk Tool, PC-PTSD = Primary Care-PTSD Screen, PHQ = Patient Health Questionnaire, STOP-BANG = sleep apnea questionnaire.

aBased on DSM-V diagnostic criteria for PTSD. If using DSM-5 criteria, >3 is considered optimally sensitive and >4 is considered optimally efficient.

Source: [200]

Multidisciplinary and Functional Restoration Programs

Evidence Based Practice Recommendation

The Colorado Division of Workers' Compensation asserts that interdisciplinary rehabilitation programs are the gold standard of treatment for individuals with low back pain who have not responded to less intensive modes of treatment. There is good evidence that interdisciplinary programs that include screening for psychologic issues, identification of fear-avoidance beliefs and treatment barriers, and establishment of individual functional and work goals will improve function and decrease disability.

https://www.colorado.gov/pacific/sites/default/files/MTG_Ex1_LBP.pdf

Last Accessed: July 29, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Multidisciplinary pain programs are used for chronic LBP with the goal of restoring and improving physical and emotional functioning and quality of life. In contrast to other pain programs, multidisciplinary pain programs provide interdisciplinary care, with collaboration by providers from different program components to develop and implement patient care. Core components of multidisciplinary pain programs are medical and behavioral therapy, physical reconditioning, and education; adjunctive modalities can be added. Multidisciplinary pain programs are often viewed as the last resort for intractable pain, and many enrolled patients have exhausted most other non-invasive options. However, they may be considered earlier in the disease course. Multidisciplinary pain programs may improve chronic LBP outcomes by simultaneously addressing multiple contributing factors to chronic pain [201]. These programs cause few if any adverse effects, in contrast to surgery or long-term opioid therapy [202]. The biopsychosocial model of chronic pain (the theoretical basis of multidisciplinary pain programs) describes psychosocial factors as part of a complex system with dynamic and reciprocal inter-relationships between biologic, psychologic, and sociocultural factors that shape patient pain experience and therapeutic response [203].

A review of 41 randomized controlled trials examining chronic LBP found that multidisciplinary pain programs resulted in significantly less pain and disability than usual care or physical modalities; these benefits persisted at long-term follow-up. A positive benefit was also found on work status versus physical modalities [204]. Multidisciplinary pain programs were found cost-effective as therapy for sub-acute or chronic LBP [184].

Multidisciplinary pain programs have been expanding in other countries, but have been declining in the United States. The most pressing problems are declining access and lack of reimbursement from third-party payers. The decline in multidisciplinary pain programs and their lack of recognition as the standard of care for chronic pain has been attributed to three dichotomies whereby the multidisciplinary pain program model inherently contradicts prevailing healthcare financing and provision [202,205,206]:

- Interdisciplinary collaboration in multidisciplinary pain programs versus the discipline-segmented organization of major medical centers: Multidisciplinary pain programs require integrated care across several disciplines; in contrast, major medical centers are aligned in silos by field and are increasingly competitive with each other for resources, including patients, space, and research dollars.

- Collaborative care in multidisciplinary pain programs versus the fee-for-service model of healthcare payments: Multidisciplinary pain programs face obstacles in adequate reimbursement for essential but time-intensive assessments and collaborative meetings. The pervasive fee-for-service model preferentially rewards spinal procedures and surgery over assessments and behavioral therapy.

- Rehabilitative therapy with focus on individualized patient assessment and behavioral change in multidisciplinary pain programs versus the curative medical model of treatment: This aspect of multidisciplinary pain programs is not only resisted by healthcare payers and providers wanting higher compensation, but also by patients with chronic pain, who may prefer to obtain "cure" from interventional, surgical, or drug therapy approaches than the intensive cognitive and behavioral changes required by multidisciplinary pain programs.

An intensive, multidisciplinary functional restoration program was prospectively evaluated in 87 patients with up to two-year follow-up. Results found a 60% reduction in the number of sick days [207]. Patient outcomes with the same functional restoration program were compared to less intensive ambulatory-based individual physiotherapy in a randomized controlled trial of 132 patients with chronic LBP. The more intensive functional restoration program was superior in reduction of sick days and physical capacity, but improvements in pain intensity and quality of life were comparable [208,209].

Predictive factors of positive functional outcome were studied in 524 patients with chronic LBP admitted to a two-week intensive multidisciplinary pain program with CBT, physical therapy, and educational components. Patients had a mean 13-year LBP duration. At one-year follow-up, employed patients with mild-to-moderate disability showed greatest benefit. Baseline psychologic factors were unrelated to outcome, indicating that highly distressed patients equally benefited. However, patients with formal psychiatric disorder were excluded from enrollment [210].

Lumbar spinal stenosis is considered most effectively treated by surgery. Although surgery may provide the best outcomes among therapeutic options in restoring function and reducing pain, surgery is often less than effective and a sizeable proportion of patients do not regain good function. Active rehabilitation has been found the most effective post-surgical rehabilitation approach for improving short- and long-term (back-related) functional status and secondary outcomes such as short-term improvement in LBP and long-term improvement in LBP and leg pain [211].

Functional Restoration

Functional restoration is a variant of multidisciplinary pain programs, with an emphasis on preventing disability and returning to work and previous functioning. Functional restoration programs incorporate the following approaches [212]:

- Repeated quantification of physical deficits to guide, individualize, and monitor physical rehabilitation progress

- Psychosocial and socioeconomic assessment to guide, individualize, and monitor pain, disability, behavior, and outcomes

- Multimodal disability management programs using CBT approaches

- Psychopharmacologic interventions, as needed, for detoxification and psychosocial management

- Ongoing outcome assessment using standardized outcome criteria and objective data collection through structured interviews

- An interdisciplinary, medically directed team approach with frequent conferences and collaboration

Systematic reviews and randomized controlled trials have found strong evidence of pain reduction and improved function with functional restoration compared with less intensive programs or usual care in patients with LBP [213,214]. Randomized controlled trials have shown prevention of progression to chronic LBP in patients with acute pain, and in patients with chronic LBP, substantially lower rates of chronic pain disability, healthcare utilization, medication use, self-reported pain variables, and back pain treatment costs relative to usual care. These positive outcomes have been consistent in studies conducted in states and countries with markedly different economic and social conditions and workers' compensation systems and in studies enrolling patients with unresolved workers' compensation claims [212]. Less intensive programs have no advantage over non-multidisciplinary outpatient therapy or usual care [215].

The primary deterrent to broader use of this approach is the reluctance of third-party payers to authorize its use because of its perceived high cost. These perceptions are misguided in terms of the potential long-term cost savings of such a program. Similarly, cost-saving efforts by third-party payers to reimburse for only a portion of functional restoration programs diminish effectiveness [212].

COMPLEMENTARY AND ALTERNATIVE THERAPIES

Complementary and alternative medicine (CAM) is widely used in the United States. In 2012, more than 59 million Americans made out-of-pocket CAM expenditures totaling $30.2 billion [216]. Of this, 60% was for manipulative and body-based therapies (e.g., chiropractic or osteopathic manipulation, massage therapy), 24% for mind-body therapies, 10% for alternative medical systems, and 6.4% each for biologically based and energy healing therapies [217]. Integrative medicine combines appropriate healthcare strategies and disciplines for patient benefit, typically by blending traditional medicine and CAM [218]. Many CAM modalities address LBP mechanisms, stress response, or both, and use as monotherapy or combined with other modalities may diminish chronic stress response and interfere with the pain-stress cycle [218,219].

Acupuncture

Evidence Based Practice Recommendation

According to the Colorado Division of Workers' Compensation, there is good evidence that acupuncture, true or sham, is superior to usual care for the reduction of disability and pain in patients with chronic nonspecific low back pain.

https://www.colorado.gov/pacific/sites/default/files/MTG_Ex1_LBP.pdf

Last Accessed: July 29, 2019

Level of Evidence: Expert Opinion/Consensus Statement

Acupuncture is a Chinese medicine technique whereby needles are slightly inserted in particular points on the body to stimulate energy fields and meridians. There is now greater understanding of the mechanisms that mediate successful acupuncture therapy, specifically stimulation of the fascia, a web of connective tissue that envelops muscle fiber and surrounds, separates, and connects organs and allows them to slide past one another when necessary [220]. Thoracolumbar fascia mediates force transfer, and disruption of its self-regulatory features may contribute to LBP. Stimulation by acupuncture needles inserted into muscle fascia induces the realignment of fibroblasts [221,222,223].

A review of acupuncture randomized controlled trials in chronic LBP found significant reductions in pain and disability with acupuncture or sham acupuncture versus conventional therapy or no therapy; a significant difference in acupuncture versus no treatment or routine care at 8- and 12-week follow-up; and a significant improvement in pain, function, and quality of life with acupuncture versus routine care at three months. The results suggest benefit from acupuncture beyond improvement from usual care in chronic LBP [224]. Acupuncture was also evaluated in a low-income, urban healthcare setting in 226 patients with chronic pain (60% with chronic back pain). Treatment once weekly up to 18 weeks led to statistically significant but clinically modest improvements in pain and physical well-being [225]. Acupuncture has been found to be a cost-effective therapy for sub-acute or chronic LBP [184].

Reviews and clinical practice guidelines have broadly concluded acupuncture in acute LBP lacks evidence. However, a randomized controlled trial of 58 patients with severely disabling acute LBP compared diclofenac injection to motion-style acupuncture treatment, an approach whereby part of the body moves passively or actively while retaining acupuncture needles. Following a single session of both treatments, motion-style acupuncture treatment led to a 3.12 greater mean pain reduction (on a 0–10 scale) and a 33% greater reduction in disability than diclofenac. These differences remained significant two and four weeks post-treatment. Motion-style acupuncture treatment showed immediate pain relief and functional recovery in disabling acute LBP [55]. A Mayo Clinic review stated that acupuncture efficacy is difficult to evaluate under controlled conditions because of the individualized and tailored approach of acupuncture to specific patient needs [226]. Bias has also been identified in Cochrane reviews of acupuncture [227]. Positive response to acupuncture and other CAM therapies has long been attributed to placebo response from high patient expectations, but this has been generally disproven [228]. Due to ongoing interest in acupuncture as a therapy for LBP, a proposal was announced in July 2019 in which Medicare will cover acupuncture as an alternative to opioids for LBP research. If the proposal is accepted, participants must be enrolled in an approved study and agree to have outcomes data collected [408].

Yoga

Yoga is an ancient discipline, originating in the Indian subcontinent, designed to restore balance and health to the physical, mental, emotional, and spiritual dimensions of the practitioner. Yoga has gained popularity in the United States, and proponents claim benefits from yoga that include reduced inflammation and decreased heart rate and blood pressure [229]. Yoga has also become increasingly used in patients with chronic musculoskeletal pain, including back pain, and has been investigated in several trials [230]. A review of randomized controlled trials in chronic LBP found that yoga showed a medium-to-large effect size in reducing disability and pain. The same benefits remained at follow-up, with somewhat smaller effect sizes. Despite differences in yoga style and duration in the reviewed trials, treatment outcomes were consistent [231]. Little is known of the mechanisms in yoga benefit [232]. Generalizability to diverse populations was assessed in 95 low-income urban minorities with moderate-to-severe chronic LBP. Following 12 weeks of once- or twice-weekly yoga classes, both groups showed significant reductions in pain (30% and 36%, respectively) and disability (36% for both) [233].

Yoga is not free of potential injury. A survey of 1,336 yoga instructors found the most frequent and severe injuries involved the neck, lower back, shoulder, wrists, and knees. Risk factors for yoga injury include poor technique or alignment, previous injury, excessive effort, and improper instruction. Specific yoga forms were associated with specific injuries, including neck injuries from headstand and shoulder stand, and low back injuries from forward bends, twists, and backbends. Recommendations to reduce yoga injuries include population-specific instructor training, appropriate placement of new students, improved understanding of appropriate effort levels, improved teacher detection of overzealous students and improper alignment, and the use of assistants to watch for overzealous and poorly aligned students in large classes [234].

Mindfulness-Based Stress Reduction

Mindfulness is an approach derived from Buddhist spiritual tradition that has been secularized and integrated into behavioral treatment approaches. Mindfulness is described as a specific state of consciousness that is non-elaborative with non-judgmental moment-to-moment awareness. It helps achieve acceptance and trust in one's own experience. The most widely used of these interventions is mindfulness-based stress reduction, developed as a component of behavioral medicine for patients with chronic pain and stress-related complaints. Components of mindful-based stress reduction include sitting meditation, walking meditation, hatha yoga, and body scan, a mindfulness practice in which attention is sequentially focused on different parts of the body. Mindful-based stress reduction also instructs on applying mindfulness to everyday life [235].

A review of three mindful-based stress reduction trials involving 117 patients with chronic LBP found statistically and clinically significant short-term improvements in pain and disability compared with usual care in patients with failed back surgery syndrome, and no improvements in pain or disability but greater short-term improvements of pain acceptance in two trials of elderly patients with specific or nonspecific chronic LBP. In aggregate, these outcomes were inconclusive in pain reduction but suggest greater pain acceptance with mindful-based stress reduction in patients with chronic LBP [235].

Tai Chi

Tai chi is a traditional mind-body exercise that enhances balance, strength, flexibility, and self-efficacy. It has been found to reduce pain, depression, and anxiety in diverse groups of patients with chronic pain conditions. The physical component provides exercise consistent with guideline recommendations, while the mental component addresses the cognitive and emotional well-being of the patient. Tai chi is a safe and economical option that helps reduce disability without introducing an intrinsic risk and addresses the cognitive, emotional, and social needs associated with chronic pain and disability [236,237].

Therapeutic Ultrasound

Ultrasound involves the application of high-frequency sound waves up to 3 MHz to the low back surface (above the pain source). A randomized controlled trial found ultrasound effective in chronic LBP compared with placebo ultrasound [238]. A case series of patients with acute pain from lumbar disk herniation and radiculopathy found that 41% of subjects were free of pain following ultrasound, compared with 12% following sham ultrasound and 6.8% with analgesics [239]. However, a 2014 Cochrane review did not find any convincing evidence of the efficacy of ultrasound for LBP, and there was no high-quality evidence of improvement of pain or quality of life [401].

Low-Level Laser Therapy

Low-level laser therapy involves application of laser at wavelengths of 632–904 nm to the skin in order to direct electromagnetic energy to soft tissues. While the mechanism and optimal treatment parameters are unclear, low-level laser therapy may alter fibroblast function to reduce inflammation and accelerate tissue repair. A review of seven small studies in patients with nonspecific LBP found low-level laser therapy more effective in reducing pain versus sham laser [115,180,240].

Neuroreflexotherapy

Neuroreflexotherapy involves temporary superficial implantation of small staples into the skin over trigger points in the back and referred tender points in the ear. Similar to acupuncture, neuroreflexotherapy uses devices for skin puncture but is believed to stimulate different zones. In patients with chronic LBP, several randomized trials found neuroreflexotherapy substantially superior to sham therapy or usual care for short-term pain relief [115].

Interferential Therapy

Interferential therapy applies medium-frequency alternating current modulated to produce low frequencies of 150 Hz or less and is suggested to provide analgesia by increasing blood flow to tissues. Randomized controlled trials have found no difference in LBP outcomes with interferential therapy versus spinal manipulation, traction, or TENS [115,241].

Transcutaneous Electrical Nerve Stimulation

TENS uses a small, battery-operated device to provide continuous electrical impulses to the site of the most severe pain via surface electrodes. TENS is thought to reduce pain by modifying pain perception and possibly by raising spinal fluid endorphins. Despite widespread use, there is little published evidence from randomized controlled trials of efficacy in chronic LBP [115,242]. One meta-analysis of TENS for chronic LBP included 267 patients with a mean treatment period of six weeks and a mean follow-up of seven weeks. This study showed significant pain reduction when using TENS [402]. However, more studies are required to determine the efficacy of TENS on chronic LBP.

Percutaneous Electrical Nerve Stimulation

With percutaneous electrical nerve stimulation, low-level electrical stimulation is applied though acupuncture-like needles inserted into points that target dermatomal levels for local pathology. In chronic LBP with or without radiculopathy, research has shown superior pain reduction versus TENS and minimal exercise intervention, with benefit duration of two months or less [115].

Cranial Electrical Stimulation

Cranial electrical stimulation uses microcurrent therapy, with a mechanism that differs from TENS. A review found cranial electrical stimulation effective in the treatment of chronic pain, including headaches, and intractable pain conditions. It is promising as a treatment for chronic LBP, but little evidence has been published [242,243].

Biofeedback

Biofeedback has been widely used for managing chronic pain, especially tension and migraine headaches. EMG electrodes are placed on the involved muscle, and the patient learns to reduce muscle contractions through a feedback procedure. Biofeedback has shown benefit in pain with a muscle component, including some forms of back pain, and has been used as a component in stress reduction. Biofeedback can train patients to reduce bracing of posture and improve self-regulation of body physiology that impacts pain. However, biofeedback requires multiple sessions and trained personnel [242]. Electroencephalography (EEG) biofeedback is a newer approach and is little studied in chronic LBP.

Hypnosis

An analgesic effect from hypnosis has been confirmed, believed to result from selective reduction of pain-related affect, reductions in sensory pain, and inhibition of pain signaling at the spinal level of processing. However, little research is available in patients with LBP [242].

Ozone Therapy

Ozone (O_3) is an allotropic form of oxygen primarily used in Europe as an alternative treatment option for patients with LBP from disk herniation. Ozone is administered percutaneously as an oxygen-ozone gas mixture at nontoxic concentrations of 1–40 mcg ozone per mL of oxygen. Proposed mechanisms of analgesia include anti-inflammatory and antioxidant action on the nucleus pulposus. The safety and efficacy of percutaneous ozone injection in LBP secondary to disk herniation was reviewed using four randomized controlled trials and eight observational studies. Based on pain reduction at six-month follow-up, the authors strongly recommended intradiscal and paravertebral ozone therapy [384].

Another systematic review of 439 references selected seven studies reviewing ozone therapy for LBP from disk herniation [403]. Of these seven studies, researchers found that there was an improvement in pain and functional scores in all, but only three studies evaluated side effects, leading researchers to conclude that complications, both minor and serious, are under-reported. Due to inconsistent methodologies and findings, researchers in this study recommend additional studies to determine safety and efficacy of ozone therapy [403].

Essential Oxygenated Oil

Essential oxygenated oil is a topical analgesic new to the U.S. market, but used in Europe for decades. Essential oxygenated oil is obtained by subjecting corn or nut oil to an accelerated peroxidation process, producing triglycerol-oxyester oil. Its mechanism is not fully known but likely involves the microcirculatory system and inhibition of lipid peroxidation, inhibition of the arachidonic acid pathway, or both [244,385]. Several randomized controlled trials have evaluated essential oxygenated oil as an alternative to NSAIDs or opioids in patients with moderate-to-severe acute, chronic, or degenerative pain from sciatica, post-traumatic pain, tendonitis, back pain, or sprain. Treatment for 7 to 28 days showed positive analgesic effects in acute and chronic pain, improved oxygen content in the skin, few side effects, and no allergic reactions [244].

Comfrey Root

The root of comfrey (Symphytum officinale) has been used for centuries as a medicinal treatment of muscle and joint pain. It is thought that the root constituents of allantoin and rosmarinic acid contribute to the anti-inflammatory effects in back pain treatment. A safety concern involves pyrrolizidine alkaloids present in the raw plant material, which possess genotoxic properties. In Europe, all medicinal comfrey root products are required to be pyrrolizidine alkaloid-depleted or pyrrolizidine alkaloid-free [245].

In one study, patients with acute upper or lower back pain received comfrey root extract or placebo cream, applied three times per day for five days. Pain intensity on active challenge decreased a median 95.2% with comfrey and 37.8% with placebo. A rapid-onset effect (within one hour of application) was reported. Mild adverse events occurred in 5% of participants [246].

In another study, patients with acute back pain received comfrey extract plus methyl nicotinate, methyl nicotinate only, or placebo cream applied three times per day for five days. Average pain scores and pain at rest were significantly lower with combination therapy than methyl nicotinate alone, with both significantly lower than with placebo. Investigator assessment of "good" or "excellent" global efficacy was 93.3% with combination therapy, 51.2% with methyl nicotinate, and 7.6% with placebo. Application site reactions occurred in 5% of subjects, mostly with methyl nicotinate [247].

Patient Expectation and CAM Outcomes

Positive patient outcomes in CAM therapies have long been attributed to nonspecific placebo response, reflecting an expectation of benefit. In 64 patients with chronic LBP evaluated before CAM therapy, baseline treatment outcome expectations clustered into pain relief, improved function, improved physical fitness, and enhanced well-being. Patients were modest in expectation level of positive therapy outcomes and reluctant to articulate optimistic expectations, and many drew the distinction between expectation and hope. Improvements from therapy in pain level, function, physical fitness, and well-being were strongly inter-related, with improvement in one domain benefiting other domains. These findings contradict the belief that positive CAM benefit is solely explained by high pre-treatment expectations [228].

Likewise, in acupuncture-naïve patients with chronic LBP, higher pre-treatment expectations for success did not predict pain or functional improvement. An association did develop with ongoing treatments, but positive pre-treatment attitude toward acupuncture was not associated with superior outcomes [248].

PHARMACOTHERAPIES

There are few current, comprehensive practice guidelines for back pain therapy with analgesics. Therefore, this section will emphasize research identifying promising analgesic approaches, challenging current assumptions of the safety or efficacy (or the lack of) in established analgesic therapies, or modifying use or delivery of established therapies to improve safety or efficacy.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs represent the foundation of back pain pharmacotherapy. Anti-inflammatory activity accounts for a proportion of analgesia from NSAIDs. Cell injury generates enzymes that release arachidonic acid from cell membranes, and arachidonic acid is converted into prostaglandins, thromboxanes, leukotrienes, and other eicosanoids. The prostaglandins PGE2 and PGF2a contribute to inflammation and sensitize nociceptors innervated by A-delta and C nerve fibers. Other prostaglandins are needed for homeostasis. NSAIDs inhibit the enzyme cyclooxygenase (COX) required for synthesis of arachidonic acid into prostaglandins and other eicosanoids. COX-1 is noncontributory to inflammation but is involved in homeostatic functions and mediates gastrointestinal protection by the gastric mucosa. COX-2 is induced during inflammation and amplifies inflammatory response, but it also contributes to kidney and cardiovascular homeostasis and helps maintain vascular integrity. Thus, COX inhibitors reduce inflammation and pain but can interfere with homeostatic functions, such as proper renal blood flow and gastric mucosa protection. NSAID analgesia also results from central activity, possibly through substance P and NMDA inhibition [63,249,250].

NSAIDs are subgrouped by dominant COX isoenzyme activity. NSAIDs that inhibit COX-1 and 2 are termed non-selective NSAIDs. NSAIDs with greater COX-2 inhibition are termed coxibs, COX-2 selective NSAIDs, or COX-2 inhibitors. COX-2 inhibition is not an absolute NSAID characteristic, as COX-2 selective agents also possess varying degrees of COX-1 inhibition [250,251].

Gastrointestinal Toxicity

Nonspecific NSAIDs were the first to enter commercial use. However, evidence began accumulating that associated non-selective NSAIDs use with gastrointestinal bleeding and toxicity, and in 1997, nonspecific NSAIDs were linked to 107,000 hospitalizations and 16,500 fatalities from upper gastrointestinal morbidity [63,252]. All-cause mortality rates fell from 11.6% pre-1997 to 7.4% post-1997, while NSAID-induced mortality rates from upper gastrointestinal bleed or perforation increased from 14.7% before 1997 to 20.9% after 1997. Thus, mortality per event has fallen when unrelated to NSAIDs, while NSAID-associated mortality has increased [256].

Up to 40% of NSAIDs users develop upper gastrointestinal symptoms, most frequently gastroesophageal reflux and/or dyspeptic symptoms. Serious and potentially fatal upper gastrointestinal toxicities, including symptomatic and/or complicated peptic ulcer, bleeding, perforation, or obstruction, occur in 1% to 2% of NSAID users and are influenced by dose and exposure [253]. COX-2 inhibitors are associated with significantly lower risks of upper gastrointestinal perforation, obstruction, and bleeding compared with non-selective NSAIDs plus proton pump inhibitors [254]. The highest risk of serious gastrointestinal morbidity is found with piroxicam, azapropazone, and ketorolac; the lowest risk is with aceclofenac, ibuprofen, and celecoxib [253,255].

Piroxicam's half-life of greater than 30 hours may explain its propensity for gastrointestinal toxicity, and oral ketorolac dosing is limited to five days due to well-recognized gastrointestinal and renal toxicity profile. Ketorolac is a highly potent analgesic. While it is unsuitable to manage acute or chronic LBP, a role in hyperacute LBP is worth consideration, especially when opioid analgesia is not the best option [251].

The incidence of lower gastrointestinal toxicity with NSAID use has been increasing, likely due to enhanced detection by new diagnostic modalities (e.g., capsule endoscopy, device-assisted enteroscope). Evidence suggests comparable risks of lower gastrointestinal and upper gastrointestinal bleeding and perforation from NSAIDs. The most frequent lower gastrointestinal morbidities include increased gut permeability, gut inflammation, blood loss and anemia, malabsorption, and mucosal ulceration. Lower gastrointestinal complications from NSAIDs can be fatal [253].

Cardiovascular Toxicity

The COX-2 inhibitor celecoxib was introduced in 1999, quickly followed by rofecoxib and valdecoxib, to retain the benefits of non-selective NSAIDs without the associated upper gastrointestinal toxicity. However, rofecoxib and valdecoxib were withdrawn from the market in 2004 and 2005 due to adverse cardiovascular events [250,251]. Nonspecific NSAIDs have been assumed to carry the greatest risk of upper gastrointestinal morbidity with little risk of cardiovascular morbidity, with the reverse true for coxibs [257]. However, this was challenged by a meta-analysis that found comparable cardiovascular risks between coxibs, high-dose diclofenac, and possibly ibuprofen. The incidence of major cardiovascular events was increased 33% with diclofenac, primary from non-fatal myocardial infarction or coronary death. Ibuprofen increased the risk of major coronary event, while naproxen did not elevate the risk. Use of any NSAID roughly doubled the risk of heart failure [257,258].

Another meta-analysis found naproxen the least harmful NSAID in cardiovascular risk, with coxibs displaying the highest risk of myocardial infarction. Ibuprofen and diclofenac are associated with the highest risk of stroke, and diclofenac is associated with a high risk of cardiovascular fatality. Naproxen may be safer in risk for cardiovascular events but carries a very high risk of gastrointestinal complications. The authors concluded that no NSAID is safe for cardiovascular risk and prescribing any NSAID requires assessment of patient cardiovascular risk factors [259,260].

Efficacy

NSAIDs are effective in reducing acute LBP and pain associated with several chronic LBP conditions, though no benefit has been found in LBP with radiating symptoms [261]. The data on acute LBP are less convincing than with non-radicular chronic LBP, but, given the toxicity potential with acetaminophen, NSAIDs seem preferable in acute LBP [251]. NSAIDs have a ceiling effect, where further dose escalation increases side effects but not analgesia [263]. Analgesic efficacy between coxibs and non-selective NSAIDs is comparable, and consistent differences in pain reduction for specific NSAIDs have not been found [261]. For unknown reasons, up to 70% to 80% of patients preferentially respond to a specific NSAID. Response cannot be predicted, but some patients lacking response to one NSAID will achieve full benefit from another [262].

NSAIDs remain among the most commonly prescribed drugs for neuropathic LBP despite repeated demonstration of ineffectiveness, reflecting prescribers' unfamiliarity with the mechanistic basis of LBP [95]. Short-term use of NSAIDs for acute LBP is appropriate in most cases, but NSAIDs in chronic back pain should only be used in carefully selected patients for occasional use to manage pain flares, and never for long-term therapy [251].

Acetaminophen

Acetaminophen is a nonsalicylate antipyretic analgesic that may be used alone or combined with other agents (usually opioids). Unlike aspirin, it lacks antiplatelet effects and gastric mucosa compromise. Acetaminophen does not have peripheral anti-inflammatory effects and produces analgesia that is additive to NSAIDs. Despite decades of use, the exact mechanism of action for acetaminophen remains unclarified [63,263].

Acetaminophen is widely recommended as first-line analgesia for acute and chronic LBP because of enduring assumptions of efficacy and safety. However, research has challenged these assumptions. In one study, 1,649 patients with acute LBP were randomized to regular dosing (three times per day, ≤4,000 mg/day), as-needed dosing (take as needed for pain relief, ≤4,000 mg/day), or placebo. All groups were instructed continue as needed, up to 28 days. Average time to recovery was 17 days in the regular and as-needed groups, and 16 days in the placebo group. The average number of tablets consumed per day was about four in all groups. Side effects in each group were also similar [264].

With increasing evidence of liver toxicity, the U.S. Food and Drug Administration (FDA) recommends a maximum 3,250 mg/day dose ceiling for acetaminophen, and McNeil Consumer Healthcare voluntarily lowered the maximum dose of its 500-mg tablets of acetaminophen to 3,000 mg. Acetaminophen is usually well tolerated, but overdose can result in fatal hepatic necrosis, and patients with alcoholism or liver impairment risk hepatotoxicity at standard doses. Acetaminophen has a lower risk of gastrointestinal toxicity than NSAIDs and is rarely associated with renal toxicity [263,265].

TCAs

TCAs are subgrouped into amines and their demethylated amine derivatives. Common TCAs include amitriptyline, imipramine, trimipramine, clomipramine, doxepin, nortriptyline, desipramine, and protriptyline [266]. The mechanism of analgesic action includes norepinephrine and serotonin re-uptake inhibition in descending inhibitory pathways, and sodium channel blockade with amitriptyline and doxepin. Analgesic action is independent of antidepressant action, occurs at lower doses, and is much more rapid in onset. TCAs can enhance opioid analgesia and are more commonly used with neuropathic LBP [266]. TCAs are not FDA-approved for pain treatment due to possible side effects, which are more likely and consequential in frail patients [95]. Amitriptyline is approved solely for depression, but its off-label use is among the highest of all medications, primarily from use in pain therapy [267].

In chronic LBP, nortriptyline and desipramine are preferred over amitriptyline and imipramine as they show fewer side effects with comparable efficacy. TCA advantages include once-daily dosing and low cost [266]. However, TCAs exhibit a wide range of adverse effects, which differ among the various agents. Common adverse effects include anticholinergic effects, antihistaminergic effects, and orthostatic hypotension (α-1 adrenergic receptor blockade). Anticholinergic side effects include urinary retention, dry mouth, and constipation. Cardiac complications are described as a possible TCA side effect in patients with a history of coronary artery disease, more likely with doses greater than 100 mg/day. Potential side effects and overdose risks should be considered when prescribing antidepressants for chronic LBP; in TCAs, risks include weight gain, driving impairment, falls, and greater overdose lethality potential than other analgesic antidepressants [263,268].

Selective SNRIs

SNRIs are thought to alleviate pain through norepinephrine and serotonin re-uptake inhibition in descending inhibitory spinal pathways [269]. Duloxetine is efficacious in chronic LBP treatment, with significant pain reduction and improved function compared with placebo at 60 and 120 mg/day, with 120 mg more effective [270,272]. Responders in a randomized controlled trial showed further improvements in pain, physical function, and quality of life during open-label extension through one-year follow-up [271]. A database review found that patients with chronic LBP initiating duloxetine versus standard of care for pain management were less likely to use opioids, had fewer days on opioids, and initiated opioids later than the standard care cohort, suggesting an opioid-sparing effect of duloxetine in chronic LBP [269].

Venlafaxine has efficacy in several neuropathic pain conditions, but it is not as well researched in chronic LBP. At doses less than 150 mg/day, venlafaxine has greater serotonergic activity and behaves more like an SSRI; at doses greater than 150 mg, SNRI activity becomes dominant, suggesting a 150-mg dose "basement" as pain treatment. Venlafaxine requires tapering instead of abrupt cessation due to the potential for a withdrawal syndrome. Anticholinergic effects are virtually nonexistent from SNRIs, making them favorable in elderly or comorbid patients [273].

Anticonvulsants

Anticonvulsants produce analgesia through diverse mechanisms, including voltage-gated calcium or sodium channel modulation, glutamate antagonism, enhancement of GABA inhibitory systems, or a combination of these actions [263]. Gabapentin is the most widely prescribed anticonvulsant for chronic pain in the United States. Neuropathic pain efficacy with gabapentin was first demonstrated in 1998, along with analgesic synergism when combined with morphine. Gabapentin and its analog pregabalin lack hepatic enzyme induction and adverse drug-drug interactions. Common side effects include somnolence, dizziness, fatigue, and weight gain. Gabapentin is considered benign in overdose. The older anticonvulsants phenobarbital, phenytoin, valproic acid, and carbamazepine may be beneficial but are seldom used due to the risks for side effects, drug interactions, and toxicity [263,274]. Combining gabapentin or pregabalin with other analgesics has been recommended to target multiple pain pathways and increase analgesia over monotherapy [275].

Benzodiazepines

Benzodiazepines have intrinsic analgesic properties due to GABAA receptor binding that facilitates GABA activity in the CNS. These drugs are effective as muscle relaxants and may facilitate recovery from acute back pain. Patients with chronic LBP and comorbid anxiety, mood, or sleep disorders may benefit from short-term benzodiazepines, but long-term use is constrained by drowsiness, ataxia, and tolerance. Co-use with opioids may increase analgesia but potentiate respiratory depression, potentially leading to life-threatening consequences. Patient selection should consider history of substance abuse or addiction, as benzodiazepines possess abuse liability [263,276].

Skeletal Muscle Relaxants

Skeletal muscle relaxants are widely prescribed for relief of painful and disabling muscle spasms that can occur with LBP or myofascial pain syndrome [277]. Baclofen, dantrolene, and tizanidine are FDA-approved for spasticity and act through different mechanisms. Baclofen blocks pre- and post-synaptic GABAB receptors; tizanidine is a CNS α2 receptor agonist; and dantrolene inhibits calcium release from muscle sarcoplasmic reticulum. Diazepam, clonidine, gabapentin, and botulinum toxin are also used off-label for muscle spasticity [277].

Carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine are approved for musculoskeletal disorders. Their broad diversity can guide clinical use. Cyclobenzaprine, closely related to TCAs, should be avoided in patients at risk for arrhythmia or with lowered seizure threshold. Therapeutic actions of most are vague, but sedative effects may contribute [263,276,277].

Most skeletal muscle relaxants have similar efficacy and show superiority to placebo in acute and chronic LBP. With cyclobenzaprine or diazepam, significantly more patients attained moderate-to-marked improvement in muscle spasm compared with placebo. Patient preference was found greater for baclofen or dantrolene vs. diazepam. Side effects include drowsiness, dry mouth, and dizziness. Comparative studies of opioids and skeletal muscle relaxants have not been published [263,276,277].

Opioid Therapy

A variety of issues are encountered when prescribing opioids for back pain. This section will discuss the long-term use of opioids to manage chronic severe pain, use in specific LBP populations, and other information relevant to primary care practice.

The use of opioids to manage acute and cancer pain is established and relatively straightforward, but their appropriateness for chronic pain is sometimes disputed [202]. The most common side effects are dry mouth, constipation, and nausea. A substantial minority of subjects in randomized controlled trials of opioids for chronic noncancer pain drop out due to side effects (20% to 30% with opioids vs. 5% to 15% with placebo) [202].

Some patients on long-term opioid therapy receive increasing opioid doses over time. Potential causes include pain increase from progression of underlying disease, development of opioid tolerance, or development of opioid-induced hyperalgesia (i.e., increased pain sensitivity). In some cases, dose escalation may reflect addiction or drug diversion, though studies suggest fewer than one in five patients receiving opioids for chronic noncancer pain develop problems with abuse or addiction [202]. Still, opioids possess abuse liability, and use without medical supervision can be hazardous, despite the misperception of greater safety as a pharmaceutical versus a street drug. The abuse liability also requires patients to ensure safe storage of their opioid medication. Due to their abuse potential, opioids are strictly regulated at the federal and state level, imposing barriers for patients to receive appropriate opioid treatment. When prescribing opioids, extensive documentation should be maintained. A systematic review of abuse-deterrent and non-abuse-deterrent opioid formulations concluded that both produced significantly greater pain reduction than placebo and showed comparable efficacy and safety profiles [278].

Opioid Efficacy in Nonspecific Chronic LBP

A 2013 meta-analysis reviewed randomized controlled trials of analgesics for nonspecific chronic LBP, with emphasis on opioids. Opioid trials using opioid control groups were excluded. Tramadol, oxycodone, and oxymorphone studies had 12-week follow-up, while buprenorphine trials had 8- to 24-week follow-ups [279]. The magnitude of pain reduction was marginally greater with tramadol, comparable with oxycodone, dramatically greater with oxymorphone, and significantly greater with buprenorphine compared with placebo. Global improvement in patient functioning was substantially greater with tramadol, oxycodone, and oxymorphone, and comparable with buprenorphine. The side effect risk (vs. placebo) was significantly greater with tramadol and buprenorphine, marginally greater with oxymorphone, and comparable with oxycodone [279]. In this study, oxymorphone showed the greatest magnitude of improvement from baseline on measures of pain intensity and overall patient functioning, with side effects nominally higher than placebo [279]. Patients receiving placebo were as likely to also use acetaminophen or NSAIDs as those assigned opioids.

Another meta-analysis reviewed 15 placebo-controlled randomized trials of opioids in chronic LBP. The researchers found that tramadol was superior to placebo in improving pain and functioning in five studies, and comparable to celecoxib in one trial [280]. Transdermal buprenorphine was somewhat superior to placebo in pain control but not meaningfully different in improved function in two trials. The magnitude of pain reduction with strong opioids (i.e., morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) was large for ≥30% (moderate) reduction and for ≥50% pain reduction. One trial each showed comparable improvement in pain and function with morphine compared with TCAs in chronic radicular LBP and tramadol compared with TCAs in chronic LBP. In this meta-analysis, adverse events were not reported. Tramadol, buprenorphine, and strong opioids all showed efficacy in controlling chronic LBP for up to 15 weeks [280].

Long-Term Opioid Therapy

Although there is moderate evidence that opioids provide short-term relief for patients with chronic LBP, evidence of long-term effectiveness is poor, based on small-scale, uncontrolled studies [391]. One long-term (median: 8.5 years) study assessed opioid therapy in 84 patients with intractable, severe chronic pain [281]. Twenty-four patients with chronic LBP and radiculopathy were maintained on a median 510 mg/day morphine equivalent dose. The most commonly used opioids were oxycodone, morphine, transdermal fentanyl, and hydromorphone. The median duration of current opioid dose was 3.5 years. At baseline, all patients had severe or very severe pain. At last follow-up, 46% rated their pain as mild, 49% as moderate, and 5% as severe but reduced from baseline. After reaching stable analgesia, 81% rated pain reduction as ≥50%, and 42% rated their pain reduction as ≥70% [281]. In total, 26% reported significant side effects of constipation, fatigue/drowsiness, dry mouth, or weight gain. One event each of constipation, dry mouth, weight gain, urinary retention, memory impairment, vomiting, and reduced libido were described as intolerable.

In 78 patients with disability comparisons, the greatest changes occurred in 65 patients who were bedridden, chair bound, or incapable of any activity of daily living at baseline who became capable of doing some or all activities of daily living or returning to work at follow-up [281]. Quality of life ratings were slightly below normative age-matched population values and not indicative of significant impairment in health-related quality of life. Composite overall physical and mental health scores were slightly below normal.

No increase in infections was found relative to population norms. Sexual function was at least moderately impaired in 85%, but opioid attribution was obscured by age, concomitant medications, and serious medical comorbidity. Problematic opioid use developed in four patients (about 5%) with histories of alcohol use disorder or bipolar disorder early in treatment [281]. All regained opioid stability with good long-term pain control after comorbid psychiatric conditions were addressed.

In 95% of patients, pain levels were reduced from severe/very severe to mild or moderate [281]. Most did not report significant adverse effects; of those who did, few were intolerable. Unexpectedly, 70% reported mild or absent constipation, and hyperalgesia or immune impairment was not detected. Most patients were older than 65 years of age and/or had significant comorbidity, such as diabetes or vascular disease. Although uncontrolled, this long-term study provides information unobtainable by randomized controlled trials in a patient population with severe intractable chronic pain closely monitored over time. This small study shows that immune impairment, tolerance, or hyperalgesia may not develop from long-term opioid therapy in some patients. A caveat is that patients required opioid therapy before enrollment; those lacking opioid response or tolerability were unlikely to enroll [281].

Levorphanol

Termed the "forgotten opioid," levorphanol is not often prescribed but may be effective in hospice and palliative care or for neuropathic pain syndromes requiring opioids [282,283]. Although levorphanol has been available in the United States since 1953, it is largely unknown to most pain clinicians, in part because levorphanol is not marketed or promoted [284,285]. The unique, non-opioid properties of levorphanol suggest a potentially important role in pain therapy.

Advances in pain research during the 1990s began identifying the mechanistic basis of neuropathic and treatment-resistant chronic pain, and the centrality of NMDA receptor activation in both. Further research found that levorphanol and methadone possessed potent NMDA receptor activity [286]. Levorphanol and methadone are both potent mu opioid receptor agonists with unique non-opioid mechanisms. Both are NMDA receptor antagonists and serotonin and norepinephrine reuptake inhibitors [284]. Levorphanol differs from methadone by its more powerful NMDA antagonism (comparable in potency to ketamine), greater NMDA and mu opioid receptor affinity, lower serotonin and norepinephrine receptor affinity, and full kappa-opioid receptor agonism [287,288]. These properties suggest levorphanol efficacy in chronic neuropathic LBP and severe treatment-refractory nociceptive or mixed nociceptive-neuropathic back pain conditions.

Importantly, levorphanol has many safety advantages over methadone. Methadone's complex pharmacology imposes a hazard when prescribed without sufficient knowledge and experience to mitigate the risks that arise from the extended half-life (15 to 60 hours) exceeding analgesia (4 to 8 hours); numerous drug interactions, which may delay clearance with resultant accumulation to fatal levels; risk of prolonged QTc interval; and activity as a P-glycoprotein substrate. Between 2000 and 2007, methadone prescribing for pain increased dramatically , often by providers lacking sufficient training. By 2009, methadone accounted for 2% of written opioid prescriptions but more than 30% of prescribed opioid-related deaths [289,404]. In contrast, levorphanol lacks metabolic competition with most drugs, lacks known cardiac toxicity, and is not a P-glycoprotein substrate [283]. However, levorphanol does possess a half-life (11 to 16 hours) exceeding analgesia (6 to 15 hours), and safe prescribing requires dose titration spaced four days apart to avoid drug accumulation [290].

Few studies of levorphanol have been published; its generic status eliminates market incentive for drug company-funded research [285]. An eight-week trial randomized 81 patients with severe, chronic, treatment-refractory neuropathic pain to high-dose (0.75 mg) or low-dose (0.15 mg) levorphanol capsules, titrated to a maximum 21 mg per day. Pain reduction was 36% with high-dose (mean: 8.9 mg/day) and 21% with low-dose (mean: 2.7 mg/day) therapy. Both dose groups showed comparable improvement in sleep and affective distress. Pain levels returned to baseline after levorphanol taper. No addictive behavior was observed [291]. In a separate case series, 31 patients with severe, chronic neuropathic pain received levorphanol following treatment failure with other opioids, including methadone. Pain relief was rated excellent by 52% and fair by 22%, for a response rate of 74%. Some levorphanol responders were methadone nonresponders [285].

An extended-release levorphanol formulation has been developed and is undergoing evaluation by Relmada Therapeutics [292]. While the levorphanol molecule is intrinsically long acting, the extended-release formulation is proprietary, and the patent protection makes the development, evaluation, and marketing (assuming FDA approval) commercially viable.

Methadone

As noted, methadone was increasingly prescribed for the treatment of chronic pain beginning in 2000. Deaths related to methadone peaked in 2007 and have been gradually declining since, mostly due to increased education and stricter prescribing guidelines [404]. This focus on safety was prompted by data showing large increases in methadone-associated overdose deaths paralleling its increasing use for chronic pain. Clinical practice guidelines were developed to promote safer methadone prescribing for chronic pain. Among the recommendations are [293]:

- Educate patients on methadone safety.

- Use electrocardiogram to identify patients at greater risk for methadone-related arrhythmia.

- Use alternative opioids in patients at high risk of QTc interval prolongation.

- Use careful dose initiation and titration.

- Be diligent in monitoring and patient follow-up.

Cannabinoids

Cannabinoids, which include the plant Cannabis and several pharmaceutical products that mimic the analgesic molecular constituents of Cannabis, have shown increasing promise in alleviating severe LBP and neuropathic LBP in particular. However, evidence of efficacy is preliminary. If used, it should be considered an adjunctive option for patients for whom first-line options have failed [7,405].

Combination Pharmacotherapy

When managing chronic LBP, the use of multiple analgesics with complementary pharmacologic mechanisms—termed rational polypharmacy—may offer advantages of additive pain control, fewer adverse events, and reduced opioid dosing (when opioids are included) [283]. Despite a robust theoretical basis, few well-designed, randomized controlled trials using a combined mechanism approach in chronic LBP have been published, and chronic LBP guidelines have not addressed it. Scarcity in the literature is likely the result of difficulty and complexity in performing clinical trials of multiple active treatments, the inherent inflexibility of clinical trial protocols in allowing individualized dosing and titration, and the absence of an economic incentive [294]. However, the findings of published studies suggest an added benefit with combined pharmacotherapies [294].

Celecoxib Plus Pregabalin

Patients with chronic neuropathic or nociceptive LBP from disk prolapse, lumbar spondylosis, and/or spinal stenosis treated with celecoxib and/or pregabalin for 12 weeks showed significantly greater pain reduction with combined therapy than with monotherapy. Pregabalin dose requirements were significantly lower when combined with celecoxib. Monotherapy and combination treatment showed similar incidence of adverse events [295].

Buprenorphine Plus Pregabalin

In one study, patients with chronic neuropathic or nociceptive LBP received buprenorphine transdermal system for four weeks and were then randomized to additional pregabalin 150 mg or placebo for four weeks. After one month, transdermal buprenorphine produced significant pain reduction. After two months, further reductions in pain scores were only significant in patients receiving transdermal buprenorphine plus pregabalin [296].

Morphine Plus Nortriptyline

A trial randomized 61 patients with chronic lumbar radiculopathic pain to morphine (15–90 mg), nortriptyline (25–100 mg), morphine plus nortriptyline, or active placebo (benztropine) therapy for nine weeks. More patients attained moderate or better pain reduction with combination treatment (67%) than placebo (37%), morphine alone (42%), or nortriptyline alone (40%). The additive benefits from morphine plus nortriptyline may reflect successful targeting of multiple pain pathways in this difficult-to-treat pain condition [297].

Topical Analgesics

Some analgesics are now formulated to bypass the systemic distribution produced by oral administration through transdermal delivery. Topical analgesics are used for the delivery of locally effective drug concentrations to the peripheral application site, with low systemic exposure and, presumably, lower risk of systemic adverse effects [298]. Potential benefits of topical analgesic delivery include reduced side effects, painless drug delivery, improved patient adherence and acceptance, ease of discontinuation, avoidance of first-pass metabolism, and direct access to the peripheral tissue target [299].

Although most topical analgesics produce clinically effective drug concentrations at the peripheral site without clinically relevant systemic concentrations, the therapeutic effects may not be strictly limited to the peripheral target. For example, topical morphine and fentanyl produce analgesia through central and peripheral mechanisms of action despite low systemic concentrations. Factors that influence penetration and absorption of topical analgesics include the biochemical properties of adjuvants in the topical formulation and inter-individual variability in skin absorption [300,301]. Compounding pharmacies often include dimethyl sulfoxide in topical formulations of drugs that lack the properties for optimal cutaneous absorption [298].

In general, topical opioids, NSAIDs, and salicylates have not shown the systemic side effects that limit the use of their oral counterparts [302]. However, topical analgesics are not without side effects, most commonly skin irritation or dryness. Penetration enhancers (e.g., dimethyl sulfoxide) are associated with significant skin dryness resulting from lipids dissolving on the skin surface [303].

NSAIDs

Effort has been made to improve NSAID tolerability for elderly and medically comorbid patients by shifting from oral to topical NSAIDs. As of 2009, topical NSAIDs were recommended in seven of nine clinical guidelines for pain [304].

NSAIDs are the most widely studied topical analgesics [302]. Topically applied NSAIDs are suitable for the treatment of many back pain conditions as they penetrate the muscle and joint tissues proximal to and below the site of application. A comparison study of topical NSAIDs, topical salicylate, and capsaicin in chronic musculoskeletal pain found highest rates of significant pain control with topical NSAIDs [305,306,307].

Of all topical NSAIDs, diclofenac has the most evidence supporting its use and is the sole NSAID with FDA approval for topical use. Approved formulations include diclofenac sodium 1% and 3% gel, diclofenac sodium 1.5% topical solution in 45.5% dimethyl sulfoxide, diclofenac epolamine topical patch 1.3%, and diclofenac sodium topical solution 2% [298,310]. Topical diclofenac has shown efficacy in pain reduction superior to placebo; comparable to topical NSAIDs indomethacin, ketoprofen, and piroxicam; and comparable to oral NSAIDs diclofenac, ibuprofen, and naproxen. The effectiveness, safety, and tolerability of topical diclofenac support its use for a variety of inflammatory chronic back pain conditions [305,308]. Randomized controlled trials of diclofenac applied three times daily showed that benefits began at 1 week, were fully apparent by 4 weeks, and were maintained to 12 weeks [309].

The most common adverse effects with diclofenac are mild site reactions, such as erythema or pruritus. No severe or systemic gastrointestinal effects have been observed with topical diclofenac or other topical NSAIDs, and skin irritation is significantly less common with patch versus gel [302]. Systemic exposure from diclofenac epolamine topical patch is 1% that of an oral 75-mg dose. The steady-state plasma concentrations are also significantly lower and unlikely to result in COX-1-mediated effects [311]. From 1993 to 2008, 46 million patients worldwide received diclofenac epolamine topical patch, and adverse events were reported in 108 patients. Most were skin reactions or lack of efficacy; six were serious gastrointestinal events, but none were believed causally related to the diclofenac epolamine topical patch [312]. The FDA requires that manufacturers incorporate standard NSAID warnings of serious liver disease risks into the labeling of topical diclofenac; however, to reach systemic levels from one 150-mg oral dose of diclofenac, 100 patches would need to be worn simultaneously [251,283,313].

NSAIDs are recommended for analgesia in many LBP conditions, and topical formulations should be considered for use in patients with acute or chronic back pain conditions for which oral NSAIDs are indicated [302,314]. It is important to note that, unlike oral NSAIDs, topical NSAIDs cannot target central and peripheral pain mechanisms, are ineffective for neuropathic pain and widespread musculoskeletal pain, and lack sufficient penetration for use in chronic LBP caused by arthritis [283].

Anesthetic Analgesics

Aberrant ion channel (particularly sodium channel) activity contributes to chronic pain conditions involving neuropathy. Topical anesthetic analgesics produce analgesia by disrupting pain signal transmission between afferent nerve fibers and the CNS, primarily from binding affinity to voltage-gated sodium and/or potassium ion channels. Lidocaine is nonselective for sodium and potassium ion channels, while tetracaine is more selective for sodium ion channel binding. Binding to these receptor sites reversibly inhibits neuronal action potential to prevent transmission and conduction of nerve impulses, producing analgesia through inhibition of ectopic discharge in sensitized and hyperactive subcutaneous nociceptors. Lidocaine also shows widespread nerve fiber activity suppression, while tocainide is more selective to C-afferent conductivity suppression [298,315,316].

Topical analgesic agents that interact with sodium and potassium channels include lidocaine 5% patch; a self-heating patch containing 70 mg each of tetracaine and lidocaine; a eutectic mixture of 2.5% each of lidocaine and prilocaine; and a cream with 7% concentrations of lidocaine and tetracaine [298]. Lidocaine-containing creams show a maximum skin penetration depth of 3–5 mm, and circulating lidocaine levels following topical application vary broadly across patients. Systemic absorption of topical anesthetics does occur but has not been associated with side effects or toxicity. The primary side effects are application-site reactions, such as skin discoloration, erythema, and irritation [298,317].

Lidocaine 5% patch or plaster has efficacy superior to placebo and comparable or superior to oral pregabalin in pain reduction with postherpetic neuralgia or diabetic neuropathy. It has also shown greater improvements in quality of life and fewer side effects than oral pregabalin [302]. In patients with post-traumatic peripheral neuropathy, lidocaine 8% pump spray significantly reduced pain and tactile allodynia for a median five hours after application [318].

In some patients with chronic back pain with neuropathic contribution, lidocaine 5% patch may be effective in reducing pathologic pain from abnormally increased sodium channel expression, although patient response is variable [315]. A placebo-controlled trial of 5% lidocaine patch in chronic LBP found no difference between active and placebo patch; however, 50% of subjects in both groups experienced substantial pain reduction, and the high placebo-response rate to the inert patch created difficulty in appraising true lidocaine efficacy [315].

Capsaicin

Capsaicin is a constituent of hot peppers and a topical analgesic with efficacy in several musculoskeletal and neuropathic pain conditions. The mechanism of analgesia is mediated by action on TRPV1 receptors, temperature sensors that regulate pain signaling on peripheral sensory neurons. TRPV1 receptors are initially activated and then desensitized by capsaicin, leading to reversible loss of C fiber function [309]. Capsaicin also inhibits the activity of bradykinin, a neuropeptide involved in the inflammatory process [298].

Capsaicin is available as 0.75% or 0.5% cream or 8% patch. The 8% patch is associated with significant local reactions, including pain, pruritus, and swelling. Instructions for its use state that application should only be performed under physician supervision, and pre-treatment of the application site with a local anesthetic is recommended [298]. A single 60-minute application of the 8% capsaicin patch has shown significantly greater pain relief compared to a low-concentration 0.04% capsaicin patch, a difference that was sustained as long as 12 weeks [319].

Opioids

Peripheral tissue inflammation upregulates opioid receptors and stimulates local endogenous opioid peptide production in immune cells. These cells provide the targets for opioid binding and activation by opioid drugs and the rationale for topical opioid analgesia. Topical application also bypasses systemic distribution and side effects [320].

Topical opioids are not commercially available and require compounding pharmacist preparation [321]. Most studies have evaluated morphine and have found side effects of application site itching and burning with morphine and placebo vehicle-gel [321,322]. Case series trials found rapid reduction of pain from tumor skin infiltration, malignant and non-malignant skin ulcers, severe oral mucositis, knee arthritis, and tenesmoid pain. Randomized controlled trials in painful skin ulcers found significantly lower pain scores with topical opioids compared with placebo [322].

In a small study, patients with chronic, intractable pain (due to disk degeneration in 61% of cases) received topical morphine, oxycodone, or hydromorphone for six months to apply as needed. Treatment was used at least once per day by 100% of participants and for breakthrough pain by 67%. Effective pain relief up to three hours per application was reported by 85%, and reductions in oral opioids, pain flare-ups, and stiffness were reported by at least 30% of participants [323]. In a separate study, patients with severe back pain received morphine cream, applied one to three times per day. Following application, 88% reported pain reduction of 40% to 50% lasting four or more hours; 19% reported relief lasting longer than one day. Responders were then randomized (double-blind) to active or placebo cream. Twenty-four hours post-treatment, pain-free movement was experienced by 44% with morphine vs. 0% with placebo [324].

TCAs

Although recommended as a treatment option for chronic LBP, TCAs are inappropriate for many patients, and others may find the side effects intolerable. Topical TCA formulations have been developed to offset these potential risks, and other topical formulations combine TCAs with another analgesic acting through complementary pain pathways. A 2% amitriptyline/1% ketamine formulation has shown efficacy in various neuropathic pain conditions in the absence of meaningful systemic concentrations. Topical 3.3% doxepin/0.025% capsaicin has also been found effective in other types of neuropathic pain [303,325,326].

Injection, Intravenous, and Infusion Therapies

Lidocaine

Lidocaine has been used systemically as an analgesic in diverse chronic back pain conditions, typically as single IV infusion at sub-anesthetic doses ranging from 1 mg/kg to 6 mg/kg over 30 to 120 minutes [327]. Lidocaine relieves pain by blocking spinal dorsal horn sodium ion gate channels and by inhibiting neuronal ectopic discharge and aberrant electrical discharge in peripheral neuromata and dorsal root ganglia. The analgesic effect of IV lidocaine is unrelated to its anesthetic mechanism, as lidocaine half-life is 120 minutes and analgesia substantially longer [327,328,329,330].

A review of IV lidocaine found that lidocaine 5 mg/kg showed clear benefit in reducing chronic pain immediately post-infusion, but pain relief did not persist longer than one week. The most common side effects were somnolence, light-headedness, headache, nausea, dry mouth, and perioral numbness [327].

Ketamine

Ketamine infusion has demonstrated efficacy in chronic pain, including chronic neuropathic LBP, but side effects have limited its use. The most common of these are hallucinations or depersonalization/derealization. Other less troublesome side effects include somnolence, feelings of insobriety, nausea or vomiting, and drowsiness. Benzodiazepine co-administration may eliminate or dramatically reduce the development of hallucinations, depersonalization/derealization, and insobriety [331]. In addition to pain alleviation, trials of ketamine infusion in severe chronic LBP have demonstrated opioid-sparing effects, reductions in opioid tolerance, and suppression of opioid-induced hyperalgesia [332].

Botulinum Toxin A

Botulinum toxin A was evaluated in 31 patients with chronic LBP randomized to injections of botulinum or saline at five lumbar paravertebral sites on the side with pain. After three weeks, pain reduction of 50% or greater was attained by 73.3% of patients treated with botulinum and 25% of those treated with saline. At eight weeks, ≥50% pain reduction was reported in 60% of patients who received botulinum toxin A, compared with 12.5% of those who received saline. Improved functioning at eight weeks was found in 66.7% with botulinum toxin A and 18.8% with saline. No patients reported side effects [333].

A single-blind, randomized clinical trial study of 50 patients with refractory chronic LBP similarly assigned patients to receive either botulinum toxin or saline injections in the paraspinal muscles where the pain localized [334]. After four weeks, 76% of the participants receiving botulinum reported improvements in pain, compared with 20% of patients receiving saline. After eight weeks, the botulinum treatment group was significantly more likely to report improvements in functionality (68% vs. 12%) [334]. The American Academy of Neurology has concluded botulinum toxin A is possibly effective for chronic, predominantly unilateral LBP, but its role in chronic LBP treatment should be clarified by larger randomized controlled trials in homogenous populations [335,406].

Bisphosphonates

A randomized, placebo-controlled study evaluated the analgesic effect of IV pamidronate in 44 patients with chronic LBP and evidence of degenerative spine disease. Pamidronate administered as two 90-mg infusions decreased pain intensity for six months, with significantly different improvements from placebo in daily average pain score, proportion of responders, changes in worst pain, and pain interference of daily function. No serious pamidronate-related adverse events or other significant safety findings were observed [336].

Zoledronic acid was evaluated in a study of 40 patients with chronic LBP of moderate-severe intensity, with MRI-detected modic changes (i.e., pathologic vertebral endplate and bone marrow changes). After one month, single-infusion zoledronic acid 5 mg led to significantly greater reduction in pain and disability compared with placebo, but no differences were observed at one year. NSAIDs were used by 20% of patients randomized to zoledronic acid and by 60% of those receiving placebo. Acute fever, flu-like symptoms, or arthralgia occurred in 95% with zoledronic acid and 35% with placebo [337].

Anti-Nerve Growth Factor

Nerve growth factor (NGF) is a neurotrophic factor associated with pain signaling, active in several mechanistic pathways to initiate and maintain hypersensitivity and persistent pain. Clinical trials have shown pain reduction using NGF antagonists in osteoarthritis and interstitial cystitis, and agents with anti-NGF activity may be efficacious in chronic back pain [338]. In a review of four randomized controlled trials of anti-NGF agents in back pain treatment, two studies of tanezumab in chronic non-radicular LBP showed significant pain and disability reduction at 12 weeks compared with naproxen or placebo controls. Reduction was greater in pain than disability. Trials of fulranumab or REGN475 did not show benefit. Possible anti-NGF side effects include headache, hyperesthesia, abnormal peripheral sensation, and dizziness. Serious side effects were not observed in any trial [338,339].

Tumor Necrosis Factor Antagonists

In a review of randomized controlled trials of anti-TNF in discogenic lumbar radiculopathy, a significant reduction in LBP and/or leg pain was found in 60% of epidural etanercept participants compared with placebo. A three-arm study found adalimumab superior to etanercept in LBP, and a dose-response study found significant pain reduction only with the lowest (0.5 mg) etanercept dose. Subcutaneous adalimumab led to significantly decreased back pain scores from six weeks through six months and less need for surgery than patients receiving placebo. No differences from placebo were found in oral REN-1654, subcutaneous etanercept, intravenous infliximab, or intradiscal etanercept. Adverse events with epidural etanercept were similar to placebo. In aggregate, the data are promising, but further research is needed to clarify optimal dose, route of administration, and anti-TNF agent [340].

Endocrine-Targeted Therapy in Chronic Refractory Pain

A subgroup of patients with chronic pain is refractory to standard drug and non-drug therapies. Uncontrolled pain profoundly impacts endocrine function, and normalization of key hormones may reduce pain. Hormone abnormalities were assessed in 61 patients with treatment-resistant chronic pain. Most (80.3%) had at least one abnormality, most commonly related to adrenocorticotropic hormone (27.3%), cortisol (32.8%), pregnenolone (20.8%), progesterone (20.8%), dehydroepiandrosterone (37.2%), and testosterone (37.2%); 11.5% showed significant hypothalamic-pituitary-adrenal suppression. Therapy was targeted at normalizing hormone elevations or deficiencies. Within 60 days, hormone abnormalities were normalized, and pain alleviated to the extent that all patients resumed normal function. This suggests that patients with chronic pain who lack pharmacotherapy response may have profound hormone abnormalities that, once corrected, can facilitate effective pain control from standard approaches. While not specific to chronic LBP, these results may be relevant due to shared physiologic effect of severe uncontrolled pain and common mechanisms of chronic pain [341].

Pharmacotherapy for Neuropathic LBP

Confirmation of neuropathic involvement in chronic LBP has challenged conventional assumptions and management [151]. Evaluation of 7,772 patients with chronic LBP found predominant pain contribution from neuropathic causes in 37%, with higher pain intensity experienced by this subgroup [342].

Patients with radiculopathy pain are five times more likely than patients with non-radicular LBP to receive pharmacotherapy, but most lack sufficient evidence to explain their widespread use [36,343,344]. Radiculopathy and other neuropathic LBP types are often undertreated or ineffectively treated. Treatment paradigms have come under increasing scrutiny as a result of the greater understanding of neuropathic mechanisms, including those of radiculopathy. Mediocre pain outcomes in radiculopathy may be largely due to failure in using mechanism-based treatment approaches [345]. Medications effective in other neuropathic conditions (e.g., nortriptyline, morphine, pregabalin, topiramate) are largely ineffective for lumbosacral radiculopathy, and departure from suggested first- and second-line medications may be required [346].

INTERVENTIONAL PAIN MEDICINE THERAPIES

Use of interventional pain medicine in back pain increased 11.8% per year between 2000 and 2009, but began declining at a rate of 0.6% per year between 2009 and 2016. Even with the decline in interventional pain medicine, there were 5,509,306 procedures performed in the Medicare population in 2016, a275% increase compared with the number performed in 2000 [19,393]. In contrast, the Medicare beneficiary population grew 42.6% between 2000 and 2016. In 2016, 58% of interventional pain medicine interventions were epidural adhesiolysis procedures, 52% were SI joint and facet joint injections, and 45% were other nerve blocks [19,393]. All were for spinal pain. Again, these figures apply to the Medicare population only, and exclude continuous epidurals, intra-articular injections, trigger point and ligament injections, peripheral nerve blocks, vertebral procedures, and implantables [19,393].

There is a vast array of interventional approaches to the diagnosis and treatment of LBP. Few have been rigorously evaluated, and fewer still have shown consistent benefit. However, several non-interventional pain medicine organizations have included interventional approaches in their clinical practice guidelines for severe intractable pain.

Spinal Surgery

Roughly 80% of patients evaluated by neurosurgeons are referred for spinal pain, but surgery is indicated in fewer than 10% [347]. In many cases, primary care providers lack an understanding of back pain amenable to surgery. Patients in pain may wait for extended periods for initial consult, only to be sent back to primary care; improved knowledge can limit inappropriate patient referral. Spinal surgery in acute LBP is limited to patients with severe or progressive motor weakness or cauda equina syndrome. Surgical options and appropriate chronic LBP indications include spinal compression surgery, fusion surgery, and disk arthroplasty [347,348].

Spinal decompression surgery involves complete or partial removal of lumbar spine structures causing neural impingement, such as large disk herniations and spinal stenosis. This includes open discectomy, microdiscectomy, and laminectomy. Fusion surgery joins adjacent vertebrae in an unstable vertebral motion segment to alleviate pain in advanced spinal degeneration. Disk arthroplasty treats degenerative changes confined to one vertebral motion segment by disk removal with artificial disk replacement.

Evidence supports laminectomy for disabling leg pain due to spinal stenosis and open discectomy or microdiscectomy for radiculopathic pain associated with lumbar disk herniation. Post-surgery symptom relief seldom persists longer than two years. Better outcomes with radiculopathy and lumbar disk herniation are associated with patient age younger than 40 years of age and symptom duration less than three months [154,347]. Fusion surgery has a weak recommendation for non-radicular chronic LBP associated with degenerative disk disease, with greatest benefit in patients with moderately severe pain or disability, one or more years of conservative management without improvement, and absence of psychiatric or medical comorbidities [115,347].

Epidural Steroid Injection

Epidural steroid injection involves corticosteroid plus local anesthetic injection into the space between the dura and the spine. Arachidonic acid release from tissues is induced by phospholipase A2. Metabolism of arachidonic acid by the COX and lipoxygenase pathways generates prostaglandins, prostacyclins, thromboxanes, and leukotrienes. Prostaglandins and other arachidonic acid byproducts initiate or exacerbate pain by inducing inflammation and sensitizing peripheral nociceptors. Corticosteroids inhibit phospholipase A2, accounting for their anti-inflammatory properties. Steroids may also inhibit pain by suppressing ectopic discharge from injured nerve fibers and blocking conduction of normal unmyelinated C fiber [349].

Some potential mechanisms of epidural steroid injection benefit do not actually involve steroids. Local anesthetic injection can increase blood flow to ischemic nerve roots and, similar to steroids, suppress ectopic discharges from injured neurons to inhibit or block nociceptive transmission. In addition, epidural administration of any injectate, including saline, can promote analgesia through washout of inflammatory molecules. A significant correlation has been found between epidural volume and pain relief, regardless of steroid dose, at 6- and 12-week follow-up [349,350].

Epidural Steroid Injections for Lumbar Radiculopathy

Corticosteroid injection into the epidural space for LBP treatment was first reported in 1953, and despite numerous publications and exponential increases in use, its efficacy and safety remain controversial [349]. Interventional pain medicine specialists strongly believe in the efficacy of this intervention for lumbar radicular pain, reinforced by more than five decades of use and centrality in numerous pain programs [351]. The benefit of epidural steroid injection varies, with efficacy best demonstrated in short-term pain relief of persistent radiculopathy with lumbar disk herniation [47]. Evidence for epidural steroid injection in spinal stenosis is less robust than for herniated disk, but greater than with failed back surgery syndrome and axial back pain without radiating symptoms [349]. The conceptual appeal of epidural steroid injection is that subsequent pain relief allows the body time to heal while avoiding the long-term consequences of central sensitization. However, more than 70% of radiculopathies recover within six months, and a similar proportion of disk herniation undergoes resorption within one year [349].

Epidural steroid injection is also advocated as an effective means to reduce lumbar surgery. This is contradicted by epidemiologic data showing increased lumbar surgery in those receiving epidural steroid injections, especially with more than three epidural steroid injections over a two-year period [11]. Some advocate for epidural steroid injection as a non-addictive LBP treatment that eliminates or seriously reduces need for opioids, but this is not yet supported by evidence [11].

Clinical practice guidelines generally support the use of epidural steroid injections for patients with disk herniation and persistent lumbar radiculopathy who are experiencing pain severe enough to cause functional impairment with failure of noninvasive care after four weeks [47,133,155]. Contrast-enhanced fluoroscopy is suggested for accurate delivery [154]. There is no evidence that any specific injection approach (e.g., interlaminar, transforaminal, caudal) influences the risks or effectiveness [154]. This approach is suggested only for short-term (two to four weeks) pain relief in lumbar radiculopathy; epidural steroid injection has no impact on functional impairment, need for surgery, or pain relief beyond three months [4,154,155,352].

Epidural Steroid Injections for Spinal Stenosis

Roughly 25% of the estimated 2.2 million lumbar epidural steroid injections performed annually in Medicare patients are for lumbar spinal stenosis [353]. Epidural steroid injection is presumed to relieve pain by reducing nerve root inflammation and ischemia, and it is widely used for lumbar spinal stenosis despite the lack of rigorous evidence and the despite the fact that clinical practice guidelines have found insufficient evidence to evaluate the benefits and harms of this use [4,133,354,355].

In a multisite, randomized controlled trial, 400 patients (mean age: 68 years) with lumbar spinal stenosis and moderate-to-severe leg pain and disability (duration of three months or longer in 80% to 88%, respectively) were randomized to receive an epidural injection of corticosteroid plus lidocaine or lidocaine alone. At six weeks, patients in both groups had improved, with no between-group differences with respect to improvement in functional status or leg pain intensity scores; no differences were noted with different sites of injection (interlaminar vs. transforaminal) either. A greater number of participants in the epidural steroid injection group reported treatment satisfaction (67% vs. 54%) and depression symptom improvement. Those who received epidural steroid injection showed higher cortisol suppression levels at three and six weeks, possibly from systemic steroid absorption [354]. Despite modest benefit at three weeks, the anticipated longer-term benefits never materialized, raising serious questions regarding the benefits of this approach in lumbar spinal stenosis [354,355].

In another study, researchers reviewed data from 13,741 patients in the six-month period before and after epidural steroid injection for LBP. Roughly 64% of patients used opioids before epidural steroid injection and 67% used opioids after. About 38% were prescribed opioids after but not before epidural steroid injection, while 16% were prescribed opioids before but not after. Those receiving more than three epidural steroid injections were significantly more likely to begin opioids and undergo lumbar surgery than those who received three or fewer injections [11,356].

Ketamine-Augmented Epidural Steroid Injection

To evaluate ketamine-augmented epidural steroid injection, 200 patients with lumbar disk herniation and radiculopathic pain were randomized to epidural steroid injection (triamcinolone/bupivacaine) plus ketamine (30 mg) or placebo. Mean pain scores were significantly lower with ketamine-augmented therapy compared with placebo at every follow-up point from 1 month to 12 months. Likewise, at every follow-up, disability scores were significantly lower in the ketamine group. Ketamine side effects included post-injection delusions lasting a mean 45 minutes; none required intervention [357]. It is important to note that racemic ketamine should be avoided for epidural use because the preservatives have shown neurotoxicity [357].

Adverse Events

In 2014, the FDA issued a warning regarding rare but serious adverse events associated with epidural steroid injection use. Serious adverse events included death, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, stroke, seizures, nerve injury, and brain edema. Many cases were temporally associated with the epidural steroid, occurring within minutes to 48 hours post-injection. Many patients did not recover. Healthcare professionals should include this information when discussing benefits and risks of epidural steroid injections with patients [358].

Neuromodulation Interventions

Implantable devices are available for patients with severe refractory chronic LBP. Positive response to a temporary trial is required before permanent implantation.

Spinal Cord Stimulation

Spinal cord stimulation is primarily used to reduce severe and persistent neuropathic pain from lumbosacral radiculopathy or failed back surgery syndrome. It acts by modulating spinal cord and CNS afferent input. A comparison of spinal cord stimulation with conventional medical management in failed back surgery syndrome with radicular pain found greater than 50% pain reduction at one- and two-year follow-up in 48% and 47% of patients with spinal cord stimulation vs. 9% and 7% of patients managed conventionally. During the trial, 31% of patients undergoing spinal cord stimulation required device-related surgical revision [47,359,360]. As such, spinal cord stimulation should be considered in patients with failed back surgery syndrome who are not candidates for corrective surgery and have failed conservative evidence-based treatment [4].

The most challenging aspect of spinal cord stimulation therapy is patient selection. In order for patients to be considered for spinal cord stimulation, other options should have been ineffective or be contraindicated. Spinal cord stimulation is indicated for severe neuropathic pain persisting at least six months [4]. Psychologic assessment is required to identify motivational, social, psychologic, and social support factors that predispose to poor treatment outcome. Failure of spinal cord stimulation treatment is associated with active substance abuse, secondary gain, unrealistic expectations, personality disorders, litigation, and depression. These factors may account for previous treatment failures to a greater extent than sole inability to control the biologic cause of the pain [116].

Implantable Intrathecal Drug Delivery

Implantable intrathecal drug delivery systems are routinely used for cancer pain when oral or transdermal analgesics are ineffective or intolerable. In LBP, implantable intrathecal drug delivery is reserved for severe, chronic, refractory axial or neuropathic radicular pain, most frequently in failed back surgery syndrome, spinal stenosis, and intractable LBP with or without radicular pain. Similar to spinal cord stimulation, implantable intrathecal drug delivery is reserved for patients who have exhausted other options, with psychologic screening for negative prognostic factors [116]. Evidence in chronic LBP is limited, but several trials have found significant pain relief lasting longer than one year [361]. Pain control usually requires multiple analgesics, typically an opioid, local anesthetic, and alpha-2 agonist. Baclofen is often added for refractory spasms and additional analgesia. Patients are seen at least monthly for pump reservoir refill. Symptoms consistent with spinal cord or nerve root compression, known adverse events with implantable intrathecal drug delivery, require prompt, aggressive investigation [116].

8. BARRIERS TO EFFECTIVE CARE OF CHRONIC LBP

Over the past two decades, healthcare expenditures for LBP have increased dramatically. While a large volume of pre-clinical and clinical research, review papers, and practice guidelines on chronic LBP have been published, patient outcomes remain unimproved. Chronic LBP remains a frustrating condition for clinicians and for patients, who often obtain little improvement in pain and functioning with standard therapies. Data indicate that more effective patient care is hampered by several factors, including:

- Flaws and limitations in pain therapy research

- Biased or deficient clinical practice guidelines

- Declining availability of multidisciplinary pain programs

- Increasing dominance of interventional pain medicine and replacement of the biopsychosocial approach by the biomedical treatment model

- Conflicting interests that supersede delivery of patient-centered care

- Fundamental structural flaws in health care, reimbursement, and compensation systems

The International Association for the Study of Pain has identified areas of crisis in pain care in the United States: poor evidence base in most treatment approaches; inadequate primary care provider pain education; the unknown value of opioid therapy for chronic pain; pain provider reimbursement; and declining access to multidisciplinary pain programs [5].

LIMITATIONS IN PAIN THERAPY RESEARCH

A frequent criticism of opioid therapy for chronic pain is the publication of few long-term (i.e., longer than one year) randomized controlled trials, cited as proof that long-term opioid safety and efficacy lacks evidence. However, this is not unique to opioids, as no analgesic used in chronic pain has evidence of long-term efficacy [392]. Pharmaceutical randomized controlled trials usually do not extend past 8 to 12 weeks, and long-term randomized controlled trials are difficult to perform for many reasons. The complexity and expense of evaluating combined drug therapies create obstacles for investigators and are unattractive to industry funding [294,362]. Ethical constraints interfere with initiating long-term placebo-controlled analgesic trials, such as the necessary encouragement of patients in moderate-to-severe pain to remain adherent to possibly inert placebo therapy for study duration [291].

Randomized controlled trials are considered the "gold standard" in evidence-based medicine, but possess important limitations. Trial outcomes may have limited clinical use because typical patients with chronic LBP often bear little resemblance to tightly screened participants. With complex comorbidity, older age, and requirement of multiple medications the norm, patients with chronic LBP seen in practice more closely resemble patients excluded from enrollment. Randomized controlled trials also typically use strict, inflexible dosing parameters. This can lead to dropout by patients lacking benefit or tolerance who would otherwise show good therapeutic response using a tailored approach. Opioid randomized controlled trials often have high dropout rates, which can drive down efficacy to result in underestimation of true patient benefit [362].

Long-term observational studies provide clinically important information unobtainable by randomized controlled trials [5]. Although non-blinded trials have the potential for confounding by subject and observer bias, multiple-year trial durations make dissipation of earlier placebo response from investigator enthusiasm or subject expectation highly probable [281]. Spontaneous remission in the natural history of pain is also unlikely in a cohort with intractable chronic pain [362]. Placebo-controlled randomized trials have long been the preferred study design, but comparative effectiveness research is becoming emphasized to address numerous concerns over the process of new technology entrance into clinical practice.

DECLINING AVAILABILITY OF MULTIDISCIPLINARY PAIN PROGRAMS

The inadequate care of chronic LBP is in part the result of the demise of multidisciplinary pain programs and the dominance of interventional pain medicine, a reflection of a movement away from biopsychosocial-based care and toward the biomedical model. With sole emphasis on the neurophysiologic aspects of pain and the pain experience, the biomedical model is reductionistic in its approach to chronic pain [363]. The old biomedical model viewed LBP causation as tissue pathology involving structural, anatomic, and biomechanical factors. Largely ineffective for chronic LBP, the biomedical approach led to unacceptable failure rates, adverse iatrogenic effects, and escalating costs [17,127]. Recognition of a need for an alternative model of care coincided with breakthrough insights in back pain mechanisms, evolution of the biopsychosocial pain model, and development of biopsychosocial-based multidisciplinary chronic pain management programs, also termed multidisciplinary pain programs [364].

Earlier multidisciplinary pain programs were generally located in academic medical centers and staffed by scientist-practitioners, attracted by the resources and opportunities to improve chronic pain patient care. With increasing popularity and demand, some programs began delivering diverse, uncoordinated, and ineffective care while remaining highly profitable. The efficacy and cost-effectiveness shown in the published research increasingly did not apply to many programs calling themselves "multidisciplinary," because the positive outcomes in the literature reflected multidisciplinary pain programs in academic medical centers, where quality of care (not profit) was the objective. Erosion in quality and patient outcomes in many multidisciplinary pain programs led to declining reimbursement, the closing of effective academic multidisciplinary pain programs, and conversion of others to interventional pain medicine centers. Fueling this trend were changes in reimbursement and health insurance practices and financial incentives in anesthesiology residency programs, which also began using interventional pain medicine procedures as a primary measure for pain medicine competence [50,365].

THE RISE OF INTERVENTIONAL PAIN MEDICINE

Against the backdrop of preferential reimbursement for procedure-based patient care in the current healthcare system, a small but influential subgroup has been remaking the care of patients with spinal pain. The American Society of Interventional Pain Physicians (ASIPP) is the largest and most influential interventional pain medicine professional organization. Aggressive interventional pain medicine advocacy by the ASIPP has fueled guideline conflict with the American Pain Society (APS), which some see as a battle by proxy between interventional and medical pain practitioners. Following publication of guidelines by the APS that concluded interventional pain medicine therapies were not recommended for nonspecific chronic LBP, the ASIPP has refuted the APS's conclusions and underlying evidence, essentially challenging the tenets of evidence-based medicine, comparative effectiveness research, and guideline development [115,366,367,368,369]. All back pain clinical practice guidelines lacking key contribution by interventional pain medicine physicians have been declared invalid by the ASIPP [370]. (Note: The APS voted to file for Chapter 7 bankruptcy dissolution in 2019, partially due to the national public attention of opioid overprescribing and lawsuits against pharmaceutical companies, leading to withdrawal of financial support to such societies [407].)

The growth of interventional pain medicine has fundamentally altered the nature of medical care for patients with chronic LBP by shifting the orientation from a patient-centered to a modality-centered model. The premise of interventional pain medicine is that targeted peripheral tissue intervention alleviates LBP and broadly improves patient mood, physical function, and quality of life. Maladaptive pain behaviors and psychosocial dysfunction associated with chronic pain are largely unaddressed. Patients may be referred to an allied pain therapist, but benefits from combining therapies may be undermined by lack of coordinated and integrated pain care. Peripheral target identification relies on imaging findings, despite the lack of correlation between imaging results and pain and the discouragement of imaging in most patients with LBP [50,371,372].

As discussed, research indicates that psychosocial factors largely influence patient outcomes across the spectrum of LBP interventions. The highly variable outcomes of interventional pain medicine and the inability of imaging and physical findings to predict nerve blockade outcomes for chronic LBP suggest benefit from using psychologic predictors of interventional pain medicine outcome [50].

Maladaptive pain beliefs may be encouraged by the interventional pain medicine approach. For patients with unrelenting LBP, interventional pain medicine may seem to be the only means for achieving cure, leading patients to believe that return to more normal function requires dramatic pain reduction and relieving them of responsibility for their own pain management. Desperation for pain relief, and unrealistic expectations of interventional pain medicine, can trigger dysfunctional pain behaviors and a cycle of unneeded diagnostic testing, repeated ineffective interventional pain medicine, doctor shopping, delay or avoidance of pain therapy emphasizing functional improvement, risk for iatrogenic complications, and eventual disability and hopelessness.

Any modality that views chronic LBP in strictly physiologic terms deviates from modern understanding of pain pathophysiology and the principles of effective pain management [50,373,374]. An effective pain management plan acknowledges that perceived belief of one's ability to control pain is associated with less severe pain and higher levels of functional activity. Self-efficacy is the conviction that one can perform a specific task or induce a desired outcome and is strongly associated with reduced pain, disability, and depression. Self-efficacy and confidence in one's ability to control pain can be attained with psychologic interventions in a multidisciplinary context [50].

It is important to remember that some patients with chronic LBP clearly obtain meaningful and prolonged pain relief from interventional pain medicine, and some techniques seem uniquely effective in specific severe, chronic conditions. This indicates the best interests of pain medicine are served by interventional pain medicine as a partner in the family of pain therapies [50].

FINANCIAL AND MONETARY INFLUENCES

The quality of pain treatment is adversely impacted when patient-centered care is superseded by conflicting financial interests or lack of reimbursement for needed care. Numerous technologies have been developed for minimally invasive intervention in LBP, only to be later found as inferior to existing therapies [11,375].

Full discussion of funding and reimbursement for LBP care is beyond the scope of this course. However, inadequate pain care is facilitated by a reimbursement system structured to favor procedures over assessment, problem-solving, and patient support related to psychosocial issues. This reimbursement system has contributed to interventional pain medicine proliferation over the past 20 years [5]. Along with rewarding procedure-based care, there is a corresponding disincentive, through lack of reimbursement, for taking the time to listen and understand the social and cognitive concerns of patients [376].

HEALTHCARE PROVIDER EDUCATION

The high prevalence of patients with LBP dictates that primary care clinicians provide the majority of care. According to the Institute of Medicine, provider education deficits remain the primary contributor to inadequate pain treatment in the United States [12]. The hours for teaching cannot be increased, and replacement of any existing curricular content with pain education is unlikely [5]. Similar gaps in knowledge regarding chronic pain have been noted in nurses, occupational therapists, and physical therapists [377,378,379]. Improvements in knowledge and practices regarding chronic pain management would directly impact patient outcomes and appropriate prescribing practices.

PATIENT SATISFACTION RATINGS

Patient satisfaction is an essential aspect of clinical care, and patient satisfaction surveys are increasingly used as a benchmark of quality of care; however, their use can have unintended consequences, such as the promotion of opioid prescribing. Clinical practice guidelines suggest taking necessary time to inquire about psychosocial concerns and to discuss the range of more appropriate alternative approaches when patients request opioids [380]. Such encounters can be challenging and time-consuming. Patients may lack interest in non-opioid alternatives and may be dissatisfied if their requests are not met. Fulfilling patient expectations usually results in a more satisfied patient, while nonfulfillment correlates with dissatisfaction [381].

Compensation may partially depend on the quality of services provided, which is increasingly measured by achieving patient satisfaction targets. Patients may become frustrated or angry when they do not receive the treatment they want and confuse getting what they want with good medical care [381,382]. While patient satisfaction is important, it should not be sought at the expense of quality of care.

COMMUNICATION WITH NON-ENGLISH-PROFICIENT PATIENTS

Pain is a subjective experience, and strong patient-clinician communication is a cornerstone of effective pain management. Communicating effectively is more challenging when the patient's primary language differs from that of the practitioner. According to the U.S. Census Bureau, more than 64 million Americans speak a language other than English in the home, with approximately 25.6 million of them (8.5% of the population) speaking English less than "very well" [386]. It has been suggested that when patients are first evaluated, they should be asked what language is spoken at home and if they speak English "very well" [387]. In addition, patients should also be asked what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss symptoms in English [387]. Many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [388,389].

"Ad hoc" interpreters (untrained staff members, family members, friends) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, the reliability and specificity of information obtained through ad hoc interpreters is less than with professional interpreters [390]. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members. A systematic review of the literature has shown that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters [389].

9. CONCLUSION

Back pain in general, and LBP in particular, is highly prevalent and is associated with substantial economic expenditures (mainly health care) and losses (e.g., absenteeism, lost productivity). It can incur serious and prolonged patient suffering, diminished quality of life, and disability. LBP is the chronic pain syndrome responsible for the greatest clinical, social, economic, and public health burden in the United States [6,393]. By completing this course, healthcare professionals should have a greater understanding of the pathophysiology and differential diagnosis of LBP conditions, the distinction between acute and chronic back pain and its management implications, and knowledge of appropriate treatment options that are guided by advances in pain neuroscience.

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400. Reference: Prins A, Bovin MJ, Kimerling R, et al. Primary Care PTSD Screen for DSM-5 (PC-PTSD-5). Available at https://www.ptsd.va.gov/professional/assessment/documents/pc-ptsd5-screen.pdf. Last accessed July 18, 2019.

401. Ebadi S, Henschke N, Nakhostin Ansari N, et al. Therapeutic ultrasound for chronic low-back pain. Cochrane Database Syst Rev. 2014;3:CD009169.

402. Jauregui JJ, Cjerian JJ, Gwam CU, et al. A meta-analysis of transcutaneous electrical nerve stimulation for chronic low back pain. Surg Technol Int. 2016;28:296-302.

403. Costa T, Linhares D, Ribeiro da Silva M, Neves N. Ozone therapy for low back pain: a systematic review. Acta Reumatol Port. 2018;43(3):172-181.

404. Jones CM, Baldwin GT, Manocchio T, White JO, Mack KA. Trends in methadone distribution for pain treatment, methadone diversion, and overdose deaths—United States, 2002–2014. MMWR. 2016;65:667–671.

405. Fitzcharles MA, Baerwald C, Ablin J, et al. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis). Schmerz. 2016;30:47.

406. Machado D, Kumar A, Jabbari B. Abobotulinum toxin A in the treatment of chronic low back pain. Toxins. 2016;8(12):374.

407. American Pain Society. Update on the Society. Available at http://americanpainsociety.org/335-update-on-the-society. Last accessed July 18, 2019.

408. Centers for Medicare and Medicaid Services. CMS Proposes to Cover Acupuncture for Chronic Low Back Pain for Medicare Beneficiaries Enrolled in Approved Studies. Available at https://www.cms.gov/newsroom/press-releases/cms-proposes-cover-acupuncture-chronic-low-back-pain-medicare-beneficiaries-enrolled-approved. Last accessed July 18, 2019.

Evidence-Based Practice Recommendations Citations

1. Toward Optimized Practice. Guideline for the Evidence-Informed Primary Care Management of Low Back Pain. Edmonton: Toward Optimized Practice; 2011. Summary retrieved from Guideline Central at https://www.guidelinecentral.com/summaries/guideline-for-the-evidence-informed-primary-care-management-of-low-back-pain. Last accessed July 28, 2019.

2. Patel ND, Broderick DF, Burns J, et al. ACR Appropriateness Criteria: Low Back Pain. Reston, VA: American College of Radiology; 2015. Available at https://acsearch.acr.org/docs/69483/Narrative. Last accessed July 28, 2019.

3. Thorson D, Campbell R, Massey M, et al. Adult Acute and Subacute Low Back Pain. Bloomington, MN: Institute for Clinical Systems Improvement; 2018. Available at https://www.icsi.org/wp-content/uploads/2019/01/March-2018-LBP-Interactive.pdf. Last accessed July 29, 2019.

4. Manchikanti L, Abdi S, Atluri S, et al. An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part II: guidance and recommendations. Pain Physician. 2013;16(2 Suppl):S49-S283. Available at https://www.painphysicianjournal.com/2013/april/2013;16;S49-S283.pdf. Last accessed July 29, 2019.

5. Delitto A, George SZ, Van Dillen LR, et al. Low back pain. J Orthop Sports Phys Ther. 2012;42(4):A1-A57. Available at https://www.jospt.org/doi/full/10.2519/jospt.2012.42.4.A1. Last accessed July 29, 2019.

6. Colorado Division of Workers' Compensation. Low Back Pain Medical Treatment Guidelines. Denver, CO: Colorado Division of Workers' Compensation; 2014. Available at https://www.colorado.gov/pacific/sites/default/files/MTG_Ex1_LBP.pdf. Last accessed July 29, 2019.

41030 • Burnout in Physicians

Lori L. Alexander, MTPW, ELS, MWC

www.netce.com

Copyright © 2016 NetCE, All rights reserved.

Burnout is a syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment. Levels of burnout are high among physicians range from 27% to 60%, with even higher rates among physicians in training. High degrees of job dissatisfaction and stress precede burnout, making it incumbent on physicians to recognize stress early to help prevent burnout before it occurs. Preventing burnout is vital not only for the well-being and professional preservation of physicians but also for ensuring optimal patient outcomes. Several personal and professional lifestyle strategies can help physicians cope with stress, achieve better work-life balance, and become more engaged in their work.

Table of Contents

41030 • Burnout in Physicians

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. HISTORY AND DEFINITION OF BURNOUT

3. DEVELOPMENT OF BURNOUT

CAUSES OF STRESS AND BURNOUT

4. IDENTIFICATION AND MEASUREMENT OF BURNOUT

DISTINGUISHING BURNOUT FROM OTHER ENTITIES

SIGNS AND SYMPTOMS OF STRESS AND BURNOUT

MEASURING BURNOUT

5. BURNOUT AMONG PHYSICIANS

PREVALENCE OF BURNOUT

MOST COMMON CAUSES OF BURNOUT

6. FACTORS ASSOCIATED WITH BURNOUT

ALCOHOL ABUSE/DEPENDENCE

DEPRESSION AND SUICIDAL IDEATION

REDUCING HOURS/LEAVING PRACTICE

PATIENT SAFETY, QUALITY OF CARE, AND PATIENT SATISFACTION

7. STRATEGIES TO PREVENT AND COPE WITH STRESS AND BURNOUT

PERSONAL AND PROFESSIONAL LIFESTYLE STRATEGIES

CALLS FOR ACTION

8. CONCLUSION

Works Cited

41030 • Burnout in Physicians

Education Category. Management

Release Date. 10/01/2016

Expiration Date. 09/30/2019

Course Overview

Burnout is a syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment. Levels of burnout are high among physicians range from 27% to 60%, with even higher rates among physicians in training. High degrees of job dissatisfaction and stress precede burnout, making it incumbent on physicians to recognize stress early to help prevent burnout before it occurs. Preventing burnout is vital not only for the well-being and professional preservation of physicians but also for ensuring optimal patient outcomes. Several personal and professional lifestyle strategies can help physicians cope with stress, achieve better work-life balance, and become more engaged in their work.

Audience

This course is designed for all physicians in all settings, especially oncology, palliative care, mental health, and critical care.

Course Objective

The prevalence of burnout among physicians is higher than that among the general U.S. population. The purpose of this course is to provide information on personal and professional strategies to cope with stress and avoid burnout.

Learning Objectives

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

1. Define burnout and its relationship to job dissatisfaction and stress.

2. Identify the work environment and personal risk factors for burnout.

3. Recognize the most common physical, psychologic, and interpersonal/social signs and symptoms of stress and burnout and tools to measure burnout.

4. Discuss the prevalence of burnout among physicians.

5. Explain the primary causes of stress and burnout among physicians.

6. Describe the effects of physician burnout on the quality of health care.

7. Select personal and professional lifestyle changes to manage stress and prevent burnout.

Faculty

Lori L. Alexander, MTPW, ELS, MWC, is President of Editorial Rx, Inc., which provides medical writing and editing services on a wide variety of clinical topics and in a range of media. A medical writer and editor for more than 30 years, Ms. Alexander has written for both professional and lay audiences, with a focus on continuing education materials, medical meeting coverage, and educational resources for patients. She is the Editor Emeritus of the American Medical Writers Association (AMWA) Journal, the peer-review journal representing the largest association of medical communicators in the United States. Ms. Alexander earned a Master’s degree in technical and professional writing, with a concentration in medical writing, at Northeastern University, Boston. She has also earned certification as a life sciences editor and as a medical writer.

Faculty Disclosure

Contributing faculty, Lori L. Alexander, MTPW, ELS, MWC, 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

Division Planners Disclosure

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

About the Sponsor

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

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

Disclosure Statement

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

1. INTRODUCTION

Work is a significant source of stress in all occupations. According to a nationwide survey by the American Psychological Association (APA) and the American Institute of Stress, job pressure was the leading cause of stress, and other surveys have shown that approximately one-third of working Americans experience chronic work stress, with only 37% saying they were excellent or very good at managing job work stress [1,2]. Work-related stress that is left unaddressed has the potential to develop into burnout over a period of time. The costs of burnout are even higher than stress and affect not only the well-being of the individual but that of the individual's family, friends, and colleagues. Burnout among physicians and other healthcare professionals carries the additional consequence of negatively affecting the quality of patient care and health outcomes. This consequence is even greater, given the high rates of burnout among physicians, rates that are higher than among the general U.S. population.

This course provides an overview of burnout, addressing its development, characteristics, and measurement. The prevalence of burnout according to several variables is discussed, as are the most common causes of stress and burnout. The effect of burnout on patient outcomes is noted, and strategies to cope with stress and avoid burnout are described.

2. HISTORY AND DEFINITION OF BURNOUT

The term "burnout" originated in the 1940s as a word to describe the point at which a jet or rocket engine stops operating [3]. The word was first applied to humans in the 1970s by the psychiatrist Herbert Freudenberger, who used the term to describe the status of overworked volunteers in free mental health clinics [4]. He compared the loss of idealism in these volunteers to a building—once a vital structure—that had burned out, and he defined burnout as the "progressive loss of idealism, energy, and purpose experienced by people in the helping professions as a result of the condition of their work"[5].

The term burnout is used (perhaps overused) by many, and definitions have varied since the time the word was first applied to humans. The word has been used to describe a mild degree of unhappiness caused by stress, as well as any degree of distress, from fatigue to major depression [6]. In the early 1980s, social psychologist Christina Maslach and her colleagues began to explore the loss of emotional feeling and concern for clients among human services professionals. Since then, she has researched burnout extensively, becoming the leading authority on the topic and the author of the criterion standard tool to assess burnout, the Maslach Burnout Inventory (MBI) [7,8,9].

Maslach emphasizes that burnout is not a problem related to an individual [9]. Instead, her research indicates that burnout is a problem of the social environment in which people work and is a function of how people within that environment interact with one another and perform their jobs [9]. She notes that burnout is more likely when there is a "major mismatch between the nature of the job and the nature of the person who does the job" [9]. These mismatches are at the core of the development of burnout. The term burnout is now usually limited to mean burnout as described by Maslach: a syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment [6].

Burnout can occur in any setting, and it has been studied most extensively in a wide range of occupations within the human services field, from healthcare professionals to teachers, police, and prison workers [6]. High levels of burnout among healthcare professionals have been well documented.

3. DEVELOPMENT OF BURNOUT

In general, when an individual first enters a chosen career, he or she is motivated. If the work environment is not supportive of the individual's efforts and concerns, the reality of the job and the individual's expectations begin to diverge and frustration and disappointment arise [6]. These feelings can lead to job dissatisfaction, resulting in decreased productivity, loss of confidence and enthusiasm, and behavior changes. If the situation is not addressed, stress accumulates and causes typical stress-related symptoms. These physical symptoms, when coupled with emotional emptiness, signify the first stage of burnout: mental and physical exhaustion [8]. Left untreated, burnout will continue through four more stages: indifference, feelings of failure as a professional, feelings of failure as a person, and emotional numbness (being "dead inside") (Figure 1) [8].

Figure 1: FIVE STAGES OF BURNOUT

Source : [20]

CAUSES OF STRESS AND BURNOUT

The specific factors within the work environment that lead to stress and subsequent burnout vary among occupations and among individuals within a single occupation. The root of burnout is in the work environment, but because not all individuals working in a single environment will experience burnout, personal risk factors must have a role in making an individual vulnerable. These personal risk factors include demographic variables and personality traits (Table 1) [6].

Table 1: POTENTIAL RISK FACTORS FOR BURNOUT

Dimension

Risk Factor

Work environment

Work overload

Lack of control over one's work

Insufficient reward for one's contributions

Absence of community

Lack of fairness

Conflict in values

Demographic variables

Younger age

Early in career

Lack of life partner or children

Higher level of education

Personality traits

Low self-esteem or confidence

No recognition of personal limits

Need for approval

Overachieving

Need for autonomy

Impatience

Intolerance

Empathy

Extreme conscientiousness

Perfectionism

Self-giving

Type D personality

Source: [6]

Work Environment Factors

Burnout is more likely when an individual's experience (actual or perceived) does not match one or more situational factors in a work environment [9]. Among the mismatches that most commonly lead to burnout in any work environment are [9]:

- Work overload: Limitations in terms of staff, time, and other resources

- Lack of control: Unable to perform job functions the way an individual believes is the "right" way

- Insufficient reward: Absence of acknowledgment of an individual's contributions in the work environment and lack of opportunities to advance

- Absence of community: Poor working relationships, absence of adequate supervisory or peer support, poor leadership style

- Lack of fairness: Inequality in workload, salary, or other signs of professional respect

- Conflict in values: Disagreement between job requirements and an individual's personal principles

Personal Risk Factors

Demographic variables have been studied in relation to burnout, and several have been found to influence the risk of burnout, alone or in combination, including [6]:

- Age

- Sex

- Family status

- Educational status

- Personality traits

Burnout is less prevalent among older individuals because they tend to be more stable and have a more balanced perspective on life [6]. In addition, the increased rate of burnout among younger individuals is a function of a "survival of the fittest" concept. Burnout usually occurs early in one's career (in the first one to five years), and many young, burned-out individuals leave the profession; as a result, the remaining individuals in an occupation are the "survivors" [6].

Across most work settings, levels of burnout have been somewhat consistent among men and women. One meta-analysis demonstrated similar overall rates of burnout among men and women, but there were differences between the sexes with regard to burnout components, with slightly higher levels of emotional exhaustion among women and somewhat higher levels of depersonalization among men [10]. Differences in burnout among male and female physicians will be discussed later in this course.

Family status also seems to play an important role in burnout; rates of burnout are higher among single workers and workers with no children than among married workers and those with children [6]. The emotional resources provided by a family are thought to be the reason for this difference.

In general, educational status seems to have an effect, with higher levels of burnout among workers with higher levels of education [6]. This difference could be the result of the expectations associated with advanced education and job choices [6]. In a study in which burnout was compared among physicians and the general population, an MD or DO degree was associated with a higher risk of burnout, whereas a Bachelor's degree, Master's degree, or doctoral degree (other than MD or DO) was associated with a lower risk [11].

Studies have also been done to explore the relationships between personality traits and the risk of burnout. Maslach noted that characteristics such as low self-esteem or lack of confidence, failure to recognize personal limits, need for approval, drive to overachieve, need for autonomy, impatience, intolerance, and empathy increased susceptibility to burnout [6]. Others have postulated that extreme conscientiousness, perfectionism, and self-giving (selflessness) also increase susceptibility, as does a type D personality (a joint tendency for negative emotions and social inhibition) [12,13,14]. Many of these personality traits are common among physicians; in fact, several are essential for success in this profession, which may explain, in part, the high levels of burnout among physicians.

4. IDENTIFICATION AND MEASUREMENT OF BURNOUT

Identifying the signs of stress and burnout is important to preserve the overall health and well-being of individuals. Burnout is associated with many signs and symptoms. For accurate identification, care should be taken to distinguish burnout from other conditions, such as stress, prolonged fatigue, and depression (Table 2) [6,15,16,17,18].

Table 2: DISTINCTION BETWEEN BURNOUT AND CLINICAL ENTITIES WITH SIMILAR PRESENTATION

Other Clinical Entity

Burnout

Stress

Precipitated by isolated or situational instances

Result of prolonged stress

Prolonged fatigue

Associated with health-related factors

Associated with job-related factors

Depression

Related to factors within every domain

Related to specific factors in the work setting

Source: [6,15,16,17,18]

DISTINGUISHING BURNOUT FROM OTHER ENTITIES

Stress can cause many of the same physical, psychologic, and interpersonal/social symptoms as burnout. However, stress is distinct from burnout in that it is usually precipitated by isolated or situational instances, whereas burnout is the result of prolonged stress [6]. Prolonged fatigue often overlaps with burnout, but the precipitating factor differs for each; fatigue is usually associated with health-related causes, whereas burnout is caused by job-related factors [15,16].

Depression and burnout may have a similar clinical presentation, and signs of depression can be associated with burnout. However, depression is related to factors within every domain of an individual's life and is not limited to specific factors in the work setting [17,18]. Depression is more likely among individuals who have had a recent loss or a personal or family history of depression, but burnout is more likely if symptoms are worse in the work environment and if the individual works long hours and has no time for outside interests.http://www.netce.com/

The most important distinction between burnout and all of these entities is that only burnout is characterized by the collective features of emotional exhaustion, depersonalization, and lack of accomplishment, as measured on the MBI.

SIGNS AND SYMPTOMS OF STRESS AND BURNOUT

The signs and symptoms of stress and burnout are multidimensional, with physical, psychologic/psychiatric, and interpersonal/social manifestations (Table 3) [1,2,8,19,20]. As such, a multidisciplinary approach should be taken not only to confirm the presence of burnout but also to rule out other illnesses or conditions. In addition to the traditional medical history and physical examination, a social and occupational history should be obtained in an effort to identify potential stress factors and possible social consequences [8]. An evaluation of the type, course, and frequency of symptoms can help distinguish them as signs of burnout, and a drug history can help to identify potential substance abuse problems. The signs and symptoms of burnout discussed here are similar across work settings. Burnout among physicians is associated with these characteristics as well as some unique features, which will be described later.

Table 3: SYMPTOMS ASSOCIATED WITH STRESS AND BURNOUT

Dimension

Manifestation

Physical

Exhaustion, lack of energy

Musculoskeletal symptoms

Respiratory illness

Gastrointestinal disorders

Cardiovascular conditions

Headache

Insomnia

Changes in appetite

Psychologic

Anger

Depression

Anxiety

Frustration

Guilt

Cynicism

Tension, irritability

Mood swings, outbursts of temper

Sadness

Withdrawn, numb feeling

Emotional detachment

Decreased coping abilities

Inability to concentrate

Lack of drive or initiative

Loss of idealism

Dissatisfaction with personal accomplishments

Addictive behavior

Interpersonal/social

Inability to communicate with family, friends, and colleagues

Cynicism, suspiciousness toward co-workers and others in work environment

Neglect of family and social obligations

Marital dysfunction

Questioning of spiritual beliefs

Source: [1,2,8,19,20]

MEASURING BURNOUT

The criterion standard for measuring burnout is the MBI, a self-assessment tool first published in 1981 by Maslach and Jackson [7]. The MBI was originally developed for the human services industry, and since then, two additional versions have been developed—a general survey and an educator-specific survey [8]. The tool has been shown to be reliable, valid, and easy to administer and has been translated into several languages for use around the world. The MBI is often used in conjunction with other assessments to evaluate the relationship between burnout and organizational policies, productivity, and social support [7].

The MBI addresses the three defining aspects of burnout syndrome with 22 statements in three subscales [6]:

- Emotional exhaustion: Nine statements to measure feelings of being emotionally overextended and exhausted by one's work

- Depersonalization: Five statements to measure an unfeeling and impersonal response to the recipients of one's services, care treatment, or instruction

- Personal accomplishment: Eight statements to measure feelings of competence and successful achievement in one's work

Each statement in the MBI expresses a particular feeling or attitude; for example, one statement in the depersonalization subscale is "I've become more callous toward people since I took this job" [6]. For each statement, the respondent indicates how frequently he or she experiences that feeling by using a fully anchored scale ranging from 0 (never) to 6 (every day). Higher scores on the emotional exhaustion and depersonalization subscales indicate higher degrees of burnout. A lower score on the personal accomplishment subscale corresponds to a lower degree of burnout. A separate score is determined for each subscale, and a scoring key provides threshold scores to indicate a low, average, or high degree of burnout on each subscale.

Because the length of the MBI may limit its use, researchers have explored the use of single-item measures from the instrument. Studies of healthcare professionals have shown that responses to one statement in the emotional exhaustion subscale ("I feel burned out from my work") and one statement in the depersonalization subscale ("I have become more callous toward people since I took this job") correlate well with the results of the full inventory [21,22]. More recently, a nonproprietary single-item measure has been shown to be a reliable substitute for the emotional exhaustion subscale of the MBI [23].

The use of tools to assess well-being or psychologic status in conjunction with the full MBI can help professionals gain a better understanding of the sources of stress for individuals. The Mayo Clinic Physician Well-Being Index is often used in studies of burnout among physicians [24]. In addition, the General Health Questionnaire, developed by Goldberg, is designed to measure common mental health problems (domains of depression, anxiety, somatic symptoms, and social withdrawal) and was developed as a measure to identify individuals who are likely to have or be at risk for the development of psychiatric disorders [25].

5. BURNOUT AMONG PHYSICIANS

Physicians certainly fall into the category of human services professionals and so are especially vulnerable to burnout [6]. In addition to the emotional strain of dealing with people who are sick or dying and who have extreme physical and/or emotional needs, features unique to medical practice and the evolving state of health care have created additional stress for physicians [26]. As noted earlier, stress and job dissatisfaction play a role early in the development of burnout, and studies have confirmed that job or professional dissatisfaction is associated with burnout among physicians [27,28,29]. These findings highlight the need to understand and address causes of stress and job dissatisfaction among physicians in order to prevent burnout.

Burnout has been studied among physicians in general, as well as across the span of their careers (medical students, fellows) and across specialties. The rates of burnout vary among these subgroups, but in general, the rates are higher than among workers in the general population and have increased over the past few years [11,30,31].

PREVALENCE OF BURNOUT

Since the early 2000s, many studies and surveys have been done to assess burnout in physicians, and the rates have ranged from 27% to 60%, with rates of 50% to 78% among medical students and residents [28,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. These rates are somewhat consistent with the findings of more recent surveys of physicians in all specialties. One of these surveys, a 2014 study of nearly 7,000 physicians, showed an overall rate of burnout of 54% [30]. The other survey, reported on in the 2015 Medscape Lifestyle Report, represents the findings from nearly 20,000 physicians; the overall burnout rate was 46% [31]. The rates in both surveys are higher than those previously reported by both authors: from 46% in 2011 to 54% in the first study, and from 40% in 2013 to 46% in the second study [30,31]. These rates reflect a much higher rate of burnout among physicians compared with the general U.S. population, which was reported to be 28% in 2014 [30].

As Maslach noted, the prevalence of burnout among physicians varies according to several factors, including age, sex, marital status, and career stage [6]. In addition, among physicians, the prevalence varies according to specialty area.

Burnout According to Age, Sex, and Marital Status

Age is a factor in burnout among physicians, with the lowest rate (22%) among physicians 66 years of age and older [47]. The highest rates of burnout are found for physicians who are middle-age: 53% for physicians 46 to 55 years of age and 51% for physicians 36 to 45 years of age [47].

Specialty has an effect on the prevalence according to age. For example, in the Medscape survey, the overall burnout rate was 44% for physicians 35 years or younger, but rates were much higher among physicians of this age-group in small specialties such as urology (63%), HIV/infectious diseases (61%), and nephrology and obstetrics/gynecology (53% each) [31]. The rate was also higher for physicians 35 years and younger in internal medicine (53%) and was similar for family medicine (43%). For the so-called high-stress specialties, the burnout rates for younger physicians were lower than the overall rates; the rates were 42% for critical care, 38% for emergency medicine, and 30% for oncology [31].

In a survey of family physicians and general internists, female physicians were nearly twice as likely as male physicians to report burnout (36% vs. 19%) [29]. Other studies have found differences in burnout according to sex, but not at the same magnitude. For example, Dyrbye et al. found burnout rates of 43% for female surgeons and 39% for male surgeons, and in the Medscape survey, the rates were 51% and 43% for female and male physicians, respectively [31,48]. As with physicians overall, the burnout rates among women have varied substantially according to specialty, with the highest rates for female physicians found in urology (67%), orthopedics (61%), critical care (61%), cardiology (60%), general surgery (59%), and emergency medicine (58%) [31]. Among residents, women are more likely than men to have burnout according to scores on the emotional exhaustion and personal achievement subscales [29].

Maslach noted that having a family may provide support that helps to prevent burnout, and this seems to be true for physicians. Among physicians in the Medscape survey who had never married and lived alone, the burnout rate was 57% [47]. In contrast, the rate was approximately 45% among physicians who were living with a partner.

Burnout According to Career Stage

In keeping with Maslach's theory that burnout usually occurs with the first five years of an individual's career, burnout rates are higher among medical students and residents than among physicians. In one study, the odds of burnout were higher for residents and fellows than for medical students and early-career physicians, and all three of these groups were significantly more likely to be burned out than college graduates of similar ages in other careers [49]. Similarly, a systematic review showed that residents in surgical specialties were more likely to be burned out than attending surgeons [50]. At the other end of the spectrum, the burnout rate is low among internal medicine residency program directors, with a rate of overall burnout of approximately 29% in one study [38]. In a comparison of burnout among physicians in early, middle, or late career (10 years or less, 11 to 20 years, and 21 years or more, respectively), the rate for depersonalization was highest among middle-career physicians [51]. The high rates of burnout among physicians in training are of concern because when burnout develops early during training, it tends to persist throughout residency [35].

Burnout According to Specialty Area

Over the years, the rate of burnout among physicians has varied across specialties, with the highest rates reported among so-called high-stress specialties, such as critical care, emergency medicine, and oncology, as well as among physicians on the frontline of care, such as family practice and internal medicine [11]. The rates found in the Medscape report are somewhat consistent with this trend, with critical care, emergency medicine, family medicine, and internal medicine (along with general surgery and HIV/infectious diseases) being the specialties with the highest rates of burnout (Table 4) [31]. In the 2014 study of 7,000 physicians, emergency medicine, family medicine, and internal medicine were among the 10 specialties with the highest rates of burnout [30].

Table 4: BURNOUT RATE ACCORDING TO PHYSICIAN SPECIALTY

Physician Specialty

Burnout Rate

Critical care

53%

Emergency medicine

52%

Family medicine

50%

Internal medicine

50%

General surgery

50%

HIV/infectious diseases

50%

Radiology

49%

Obstetrics/gynecology (women's health)

49%

Neurology

49%

Urology

48%

Pulmonary medicine

47%

Cardiology

46%

Diabetes and endocrinology

45%

Orthopedics

45%

Nephrology

45%

Plastic surgery

45%

Pediatrics

44%

Oncology

44%

Anesthesiology

44%

Rheumatology

43%

Allergy and clinical immunology

43%

Ophthalmology

41%

Gastroenterology

41%

Pathology

39%

Psychiatry and mental health

38%

Dermatology

37%

Source: [31]

Shanafelt et al. noted that between 2011 and 2014, the burnout rate increased more than 10% in nine specialties [30]:

- Family medicine (51% vs. 63%)

- Pediatrics (general) (35% vs. 46%)

- Urology (41% vs. 64%)

- Orthopedic surgery (48% vs. 60%)

- Dermatology (32% vs. 56%)

- Physical medicine and rehabilitation (47% vs. 63%)

- Pathology (38% vs. 52%)

- Radiology (48% vs. 61%)

- General surgery subspecialties (42% vs. 53%)

The Medscape report also includes information on the degree of burnout, noting the percentage of respondents who reported severe burnout (scores of 6 and 7 on a scale of 1 to 7, with 7 defined as "so severe that I'm thinking of leaving medicine"). The rates of severe burnout ranged from 5% to 12% across specialties. The results showed that the specialties with the highest rates of burnout are not necessarily those with the most severe burnout. Among the five specialties with the highest rates of burnout, only two are among the five specialties with the highest rates of severe burnout: family medicine (11%) and internal medicine (10%) [31]. The other three specialties with the highest rate of severe burnout, urology (12%), plastic surgery (12%), and allergy and clinical immunology (10%), ranked 10th, 16th, and 21st, respectively, of the 26 specialties in terms of the burnout rate.

MOST COMMON CAUSES OF BURNOUT

The job-related factors contributing to burnout among physicians are similar to those in non-healthcare settings. The most commonly reported causes of stress, job dissatisfaction, and burnout—across career stages and specialties—are work overload, inadequate work-life balance, and lack of control over one's work, causes that are in line with the work environment factors described by Maslach [6,11,29,38,40,45,52]. In addition, physicians are challenged by many stressors unique to the practice of medicine, such as practice demands, evolving health policy, difficult or complex patients, and an inability to keep up with research (Table 5) [26,31,53]. Information technology has changed physicians' work environments, and this, too, is a factor contributing to burnout. Again, the importance of these causative factors varies across specialties.

Table 5: MOST COMMON CAUSES OF BURNOUT AMONG PHYSICIANS

Work overload

Spending too many hours at work

Too many patient appointments in a day

Income not high enough

Increasing computerization of practice

Impact of the Affordable Care Act

Lack of control over one's work

Too many difficult or complex patients

Inability to provide patients with the preferred quality of care

Inability to keep up with research

Lack of professional fulfillment

Source: Compiled by Author

Work-Life Balance

Nearly half of physicians report that their job is "extremely stressful," and 81% say they feel "overextended," "overworked," or "at full capacity" [37,53]. Physicians also note that they have "too many patient appointments," leading to increased time pressure during visits, which has been strongly associated with lower rates of satisfaction and higher rates of burnout [29,54]. Long hours, many of which are spent on nonclinical tasks, and unsatisfactory work-life balance are the key factors in feeling stressed or overextended. Physicians work an average of 53 to 63 hours per week, or 13 to 23 more hours a week than the mean for the general population [30,34,44,48,53,55].

Approximately 60% of physicians have also noted time pressure associated with electronic documentation [56]. Physicians have reported that they spend an average of 9 to 11 hours per week on administrative (nonclinical) duties, with approximately 38% saying they work 11 hours or more each week on such duties [53,57]. Thus, tasks such as billing, obtaining insurance approvals, financial and personnel management, and negotiating contracts take up 14% to 20% of their work time [53,57]. An excess of "bureaucratic" tasks was the highest ranked cause of burnout in the Medscape Lifestyle Report, and long hours at work was the second leading cause [31]. The time spent on administrative tasks takes away from time forming relationships with patients, the most satisfying factor about medical practice according to approximately 79% of physicians [53].

Long hours at work create conflicts between responsibilities at work and at home, and rates of work-life conflicts among physicians have been reported to range from 41% to 62%, and only 33% to 48% of physicians are satisfied with their work-life balance [11,34,40,47,48,58]. Both long hours and work-life conflicts have been found to be significantly associated with burnout [34,46,48,50,51]. Physicians' satisfaction with work-life balance has decreased since 2011 and is significantly lower than the rate among the general population (61% vs. 36%) [30]. Pooled multivariate analysis with adjustments for age, sex, relationship status, and hours worked per week showed that, compared with the general population, physicians had an increased risk of burnout and a decreased likelihood of being satisfied with work-life balance [30].

Electronic Environment

The era of information technology in medical practice, most notably electronic health records (EHRs) and computerized physician order entry (CPOE), began in the 1990s, and the technologies have been slow in becoming embraced by the medical community because they are challenging and time-consuming to learn [37]. Approximately 85% of physicians currently use these technologies, and about 60% think that EHRs have improved the quality of care [37,53]. However, the technology has been slow to improve efficiency of care. Surveys have shown that approximately 43% to 75% of physicians think that EHRs decrease efficiency and 47% to 61% of physicians think that using EHRs detracts from patient interaction [37,53,59]. One study showed that physicians who used EHRs spent slightly more time on administrative tasks than physicians who used paper records (17% of work time vs. 15% of work time) [57]. In another study, emergency department physicians spent a mean of 43% of their time on data entry, a significant difference from the time they spent on direct patient care (28%) [60]. In general, physicians are dissatisfied with the amount of time they spend using electronic documentation systems, and stress levels increase and satisfaction levels decrease with increasing use of EHRs [56,61,62]. Physicians who use EHRs and CPOE are also at higher risk for burnout, and "increased computerization of practice" was the fourth most common cause of burnout in the Medscape Lifestyle Report [31,61]. As more physicians become comfortable with using electronic systems, their satisfaction may improve.

Loss of Control or Autonomy

Physicians' autonomy is defined as the ability to determine how they work and decide how much time to spend with patients, what kinds of tests to perform, and what treatments to plan [63]. Autonomy has been reported to be the most important determinant of career satisfaction, yet it appears to be slowly eroding [64,65]. Approximately 50% to 69% of physicians say their clinical autonomy is sometimes or often limited and their decisions are sometimes or often compromised [53,56]. Physicians report being frustrated with decision-making by third parties (insurance companies and government agencies) and restrictions imposed by formularies or guidelines [66]. This loss of physician autonomy has been found to be significantly associated with burnout; lack of clinical and administrative autonomy were both significantly correlated with burnout in emergency physicians, and low control over work was strongly associated with dissatisfaction and burnout among primary care physicians [29,54,66,67,68]. Subjective factors, such as a perception of lack of autonomy, have had a stronger correlation with burnout than objective factors [39].

Other Causes

Many other factors have been noted to be risk factors for physician burnout. According to Maslach, insufficient reward for one's contributions is a risk factor for burnout, and this factor has been shown in studies of physicians. Insufficient income was the third most commonly selected cause of burnout in the Medscape Lifestyle Report, and feeling unappreciated was a substantial contributor to burnout in a study of residents [31,45]. Poor working relationships with colleagues, analogous to Maslach's absence of community, has been reported to be a risk factor for burnout among critical care physicians and nurses [19]. In contrast, good working relationships with other physicians and staff have been associated with a greater likelihood of job satisfaction [54,69].

A factor unique to physicians was found in a 2010 study of U.S. surgeons, in which being sued for malpractice in the last 24 months was strongly associated with burnout [70]. Also unique to physicians is health policy; the impact of the Affordable Care Act was the fifth most common cause of burnout in the Medscape Lifestyle Report [31]. As many as half of physicians say their work environment is chaotic, and this factor has also been significantly associated with burnout [29,37,54].

6. FACTORS ASSOCIATED WITH BURNOUT

Several studies have focused on the relationship between burnout and a variety of factors. The psychologic factors of most concern for physicians are alcohol abuse/dependence, depression, and suicidal ideation (Table 6) [43,71,72,73,74]. Patient care is also a primary concern, as the symptoms of burnout have been linked to suboptimal patient outcomes.

Table 6: PREVALENCE OF MENTAL HEALTH FACTORS IN PHYSICIANS AND MEDICAL STUDENTS/RESIDENTS VS. THE GENERAL POPULATION

Factors

Physicians

Medical Students (MS) or Residents/Fellows (R/F)

General Population

Alcohol abuse/dependence

13% to 26%

32% (MS)

6%

Depression

18% to 40%

58% (MS)

17% to 48% (R/F)

6.6%

Suicidal ideation

5% to 9%

10% (MS)

3.7%

Source: [30,36,43,49,71,72,73,74,75,76]

ALCOHOL ABUSE/DEPENDENCE

Among physicians, alcohol abuse/dependence has been significantly associated with the number of hours worked—a key cause of burnout—as well as with burnout itself [41,43,71,72,73]. Alcohol abuse/dependence is a substantial concern for physicians, as the rate reported in most studies has been much higher than that within the general population and is even higher among medical students [43,71,72,73,74]. In one study, burned out surgeons had a 25% increased risk of alcohol abuse or dependence [72]. However, in the Medscape survey, alcohol abuse was not prevalent, with approximately 50% of respondents reporting that they had less than one drink per day [47]. There was no difference in that study between physicians who were and were not burned out with regard to alcohol use [47].

DEPRESSION AND SUICIDAL IDEATION

As with alcohol abuse, the rates of depression and suicidal ideation are substantially higher in physicians than within the general population [30,36,49,75,76]. Few studies have been done to evaluate the relationship between burnout and depression or suicidal ideation. In one study of attending and resident emergency medicine physicians, burnout was significantly associated with a positive screen for depression [28]. In another study, persistent burnout during residency was associated with screening positively for depression as an intern [35]. Burnout has also been independently associated with suicidal ideation among surgeons and medical students [33,77]. However, the authors of most studies have gathered information on depression and burnout but have not analyzed the relationship. In most of these studies, rates of both depression and burnout have been high (Table 7) [34,40,43,49]. In another study, the rates of suicidal ideation and burnout were high among general internists (9% and 52%, respectively) [40].

Table 7: RATES OF DEPRESSION AND BURNOUT BY SPECIALTY AREA OR STAGE OF CAREER

Subjects

Rate of Depression

Rate of Burnout

Gynecologic oncologists

33%

32%

General internists

40%

53%

Surgeons

30%

40%

Early-career physicians

40%

51%

Residents/fellows

51%

60%

Medical students

58%

56%

Source: [34,40,43,49]

REDUCING HOURS/LEAVING PRACTICE

Burnout and dissatisfaction with work-life balance have been reported to be the strongest predictors of intent to reduce clinical work hours or leave the current position [58]. A systematic review provided evidence that burnout is associated with decreased productivity, defined as inability to work, increased number of sick days, and intent to leave practice or to change jobs [78]. Similarly, a review of physicians' administrative/payroll records showed that burnout scores correlated with reductions in professional effort (measured in full-time equivalent units) over the subsequent two years [79]. Specifically, the authors found that for each 1-point increase on the emotional exhaustion scale of the MBI, the likelihood of reducing work effort increased [79]. In one study, burned out physicians were significantly more likely than nonburned-out physicians to say that they intended to leave their practice within two years [29].

The authors of one study evaluated the number of years hospitalists intended to remain in practice in relation to risk of burnout; the percentage of hospitalists who intended to leave practice in less than four years ranged from 6.4% of those with no risk of burnout to 16.5% for those at risk for burnout to 44% for those who were burned out [80]. Another study was designed to evaluate burnout according to career stage; the physicians most likely to leave practice were those in middle-career, for whom rates of burnout were higher than for early- or late-career physicians. Approximately 12% of middle-career physicians said they planned to leave practice, compared with 5% of early- and late-career physicians [51]. The findings of all of these studies have implications for the supply of physicians, which is projected to fall short of the demand by 61,700 to 94,700 by the year 2025 [81].

PATIENT SAFETY, QUALITY OF CARE, AND PATIENT SATISFACTION

Studies have also addressed the effect of physician burnout on medical errors, quality of care, and patient satisfaction [118]. One of the first of these studies involved internal medicine residents who were surveyed with the MBI and asked to respond to five statements regarding suboptimal care (e.g., "I did not fully discuss treatment options or answer a patient's questions" or "I made…errors that were not due to a lack of knowledge or inexperience") [32]. Approximately 53% of burned out residents self-reported suboptimal care compared with 21% of nonburned-out residents. In multivariate analyses, burnout was strongly associated with self-report of suboptimal care at least monthly. The authors also evaluated each domain of burnout and found that only a high score on the depersonalization domain was associated with suboptimal care. An association between high burnout scores and self-reports of suboptimal care and of medical errors was also found in later studies involving residents [41,82]. In one of these studies, self-reported medical errors and scores for best practices (following principles identified as best practices in anesthesiology) were significantly associated with high risk of burnout among anesthesiology residents [41]. The median best practice score was significantly lower for residents at high risk of burnout than for residents at low risk. In addition, significantly more residents at high risk for both burnout and depression reported multiple medical errors within the previous year compared with residents at low risk (33% vs. 0.7%) [41].

Burnout was also associated with self-reports of suboptimal care in a study of emergency medicine physicians and residents. The authors completed a burnout evaluation and asked six questions to assess suboptimal care; physicians who had high burnout scores were more likely to report all six acts of suboptimal care [28]. In another study, reporting a major medical error during the last three months was significantly associated with burnout among surgeons [83]. The depersonalization domain had the most effect; for each 1-point increase in the score in this domain, there was an 11% increase in the likelihood of reporting an error, and for each 1-point increase in the score on the emotional exhaustion scale, there was a 5% increase in likelihood. In multivariate analysis that controlled for other personal and professional factors, burnout was an independent predictor of reporting a major medical error. In contrast to these findings, studies of family physicians and general internists have shown no consistent relationships between burnout, medical errors, and quality of care [29,54].

With regard to patient satisfaction, a preliminary study involved a survey of 178 matched pairs of physicians and patients who had been hospitalized in the previous year. The authors found that a high score on the depersonalization domain was associated with lower rate of patient satisfaction and longer recovery after hospital discharge (after controlling for factors such as severity of illness) [84].

7. STRATEGIES TO PREVENT AND COPE WITH STRESS AND BURNOUT

There are two primary approaches to preventing and/or coping with stress and burnout. Given that the most significant factors in burnout are related to the work environment, modifying the environment to eliminate these factors has the potential for the most success. However, it is often difficult to change organizational structure, which means individuals must make changes themselves. When implemented appropriately, prevention of burnout is easier and more cost-effective than resolving it once it has occurred; burnout that is addressed in later stages may take months or years to resolve fully [6,9]. Thus, the primary goal is to stop the burnout cycle early by preventing the accumulation of stress. Early recognition of stress is key to prevention [85]. However, several issues create challenges for physicians to prevent stress and burnout: misinterpretation of their own well-being, reluctance to seek help, and disinclination to care for themselves as a priority.

Although recognition of stress is important, physicians have been shown to inaccurately define their own well-being. Shanafelt et al. evaluated surgeons with the Mayo Clinic Physician Well-Being Index and then asked the surgeons to subjectively assess their well-being relative to other physicians [86]. Approximately 89% of the surgeons said that their well-being was at or above average, but 71% of the surgeons who scored in the bottom 30% on the Index relative to national physician norms had said their well-being was at or above average.

Many physicians do not seek help for stress or burnout because of the belief that these conditions are normal for the profession, an attitude that begins in medical school, with students being advised to push through stress [20,86]. This attitude leads physicians to believe that if they just work longer hours, the situation will resolve, but working longer hours only exacerbates stress and accelerates the burnout process. In addition, not dealing with stress appropriately may lead to factors associated with stress, such as alcohol abuse, depression, and suicide ideation. Despite the high rates of these conditions, studies have shown that 33% to 60% of medical students and physicians are reluctant to seek help [27,43,77]. The reasons for the reluctance are concerns about their medical license, discrimination in hospital privileges and professional advancement, perceived stigma, and an inability to take time off from work [27,43,45,87]. To help overcome these barriers, the Joint Commission issued guidelines mandating that medical staff "implement a process to identify and manage matters of individual health for licensed independent practitioners that is separate from actions taken for disciplinary purposes" [88].

The concept of self-care is emphasized in every book or article on preventing job stress and burnout across occupations. Self-care warrants particular emphasis for physicians, as they have been trained to put the care of others ahead of themselves and are not typically good at caring for themselves [89]. Self-care is essential for energizing, restoring, and maintaining the physical and emotional stamina to manage stress and helps increase job satisfaction [6,44,90].

The following strategies to prevent stress and burnout are recommended on the basis of studies of interventions as well as guidance from burnout experts and physicians who have successfully prevented stress and burnout. The strategies address changes in personal and professional lifestyle habits.

PERSONAL AND PROFESSIONAL LIFESTYLE STRATEGIES

Enhance Well-Being

The most important first step in preventing stress and burnout is to enhance well-being. Self-care, improving work-life balance, and mindfulness training and other structured interventions are key elements for maintaining physical and emotional well-being (Table 8) [19,65,90,91,92,93,94]. Enhancing physicians' well-being is vital not only to address the consequences of stress and burnout but also to improve patient outcomes. The relationship between physician well-being and patient outcomes is understudied, but a systematic review (18 studies) showed that well-being was associated positively with patient satisfaction, patient adherence to treatment, and interpersonal aspects of patient care [95]. The authors of the review noted that most of the studies were observational and of average quality.

Table 8: STRATEGIES FOR MANAGING STRESS AND AVOIDING BURNOUT

Strategy Classification

Specific Strategies

Personal lifestyle

Obtain adequate sleep

Ensure proper nutrition

Participate in regular physical activity

Identify and maintain priorities

Schedule adequate vacation time

Participate in hobbies and/or volunteer activities

Maintain sense of humor

Recognize limitations

Seek emotional support and practical assistance from family

Maintain network of friends

Professional lifestyle

Eliminate chaos in the office or practice

Review and redesign workflow

Make documentation a team effort

Take time away (short breaks)

Seek support from colleagues

Promote a healthy work environment

Become an advocate

Organizational level

Create a healthy work environment

Encourage and maintain strong leadership style

Engage in participatory decision making, especially with respect to direct patient care

Foster good interpersonal relationships among all healthcare professionals

Encourage and provide access to training targeted to physician well-being

Source: Compiled by Author

Make Self-Care a Priority

Self-care involves several universal lifestyle measures, such as healthy eating habits, exercise, sleep, and regular health care. The results of studies and surveys have shown that physicians who maintain a healthy diet and follow the Centers for Disease Control and Prevention guidelines for exercise are less likely to be burned out [31,92,96]. Physicians who have successfully avoided burnout recommend self-care as a strategy, with physical well-being ranked as the most common strategy (60%) in a small study of hospice and palliative care physicians [93,94].

Attention to self-care should begin in medical training, and one program was developed to help second-year medical students focus better on personal behaviors, such as exercise, eating habits, sleep, and emotional health. The students were asked to target a specific area for change, set a goal, track their progress toward the goal, and assess their success [97]. Although approximately 50% of the students had not reached their goal by the end of the program, 80% said they were healthier because of the program and 82% said they would use the program again. Such programs during medical training can help foster self-care as a priority.

Improve Work-Life Balance

As noted, work-life balance and work-life conflicts are significantly associated with job satisfaction and burnout. One challenge in achieving an appropriate work-life balance is that physicians often search for a single solution to solve the problem. Drummond, who coaches physicians on how to avoid burnout, notes that burnout is more of a dilemma and so requires ongoing strategies to ensure finding and maintaining an appropriate balance [98].

Physicians who participate regularly in hobbies, personal interests, and meaningful volunteerism are at lower risk of burnout and are more likely to have higher quality of life [92,96]. Experts recommend scheduling time each week to pursue hobbies and participate in activities of interest [92,99,100]. Participating in hobbies was reported by 40% of physicians as a way they avoid burnout [94].

Other strategies include setting strict boundaries between work and home, making time for friends and family, taking regular vacations, and remaining clear about priorities [65,93,94,99]. Personal relationships and personal boundaries were reported by 37% (each) of physicians as a way to avoid burnout. As practical advice, Drummond suggests that physicians work with their families to develop a master "life calendar" that includes not only social events such as having coffee with a friend, reading, and exercise, but also all family members' schedules and special events [100]. Physicians should keep an electronic calendar or take a picture of the calendar with their cell phone, check the calendar when a potential work commitment arises, and learn to say no to colleagues' requests when necessary.

Engage in Mindfulness Training

Mindfulness is defined as purposeful and nonjudgmental attention to one's own experience, thoughts, and feelings [101]. Interventions to enhance mindfulness in primary care physicians have led to short-term and sustained improvements in well-being, reductions in indicators of stress and depression, and lower scores on the emotional exhaustion and depersonalization scales of the MBI [102,103]. A nine-month intervention that involved facilitated physician discussion groups that integrated elements of mindfulness with reflection, shared experience, and small-group learning significantly decreased scores on the depersonalization subscale that was sustained 12 months after the end of the program [104]. Scores on the emotional exhaustion subscale and overall burnout scores also decreased substantially. The intervention improved physicians' sense of meaning in their work but did not lead to significant differences in stress, symptoms of depression, or job satisfaction [104]. Mindfulness has also been associated with more patient-centered communication and an increase in the number of satisfied patients [101].

Explore Other Interventions

Cognitive-behavioral training, physical relaxation (e.g., massage), and mental relaxation (e.g., mediation) may have limited benefit, according to a meta-analysis of interventions to reduce work-related stress in healthcare workers. The study demonstrated low-quality evidence that cognitive-behavioral training, with or without relaxation, reduced stress compared with no intervention, but only after the more than one month of follow-up [105]. Similarly, physical relaxation was most effective one to six months after the intervention. Little evidence supported mental relaxation as a way to reduce work-related stress after up to six months [105].

Develop Efficient Practice Habits

As discussed, use of EHRs is a leading source of physicians' stress and dissatisfaction, and approximately 61% of physicians have reported that other staff could perform functions in EHRs [37]. Thus, making documentation a team effort can help alleviate physicians' electronic burden. In addition, experts recommend that physicians ask colleagues for help in using EHRs more efficiently and that they create templates as a way to semiautomate documentation [98,106].

Given that a chaotic work environment is associated with high rates of stress, job dissatisfaction, and burnout, eliminating chaos can help prevent stress and burnout [65]. Redesigning work flow can also help; this strategy was associated with significant reductions in the burnout rate in a study of primary care clinicians working at 34 clinics [107].

Physicians can work more efficiently by standardizing workflows and processes whenever possible, minimizing interruptions by batching nonurgent tasks, and creating patient resources or delegating patient education [98]. Taking mini-breaks during the day gives physicians time to recharge and refocus [108].

Promote a Healthy Work Environment

Physicians can take steps in their practice to promote a healthy work environment, and physicians in hospitals or managed care settings should work with leaders to ensure that all physicians and staff have a healthy work environment [19]. Flexible scheduling is an important element of a healthy work environment, as it gives physicians better control over their time and helps them achieve greater satisfaction with work-life balance [52,108].

Participate in Support Groups

Support from colleagues can help to increase job satisfaction and reduce the likelihood of burnout [44,80,109]. In one study, professional relationships were the second most common strategy for preventing burnout, reported by 57% of physicians [94]. Physicians are often hesitant to seek help, but such support groups are not designed to be solely for physicians with mental health or substance abuse issues. Instead, support groups offer an opportunity for healthy but stressed physicians to discuss professional and personal problems [90]. Two randomized trials have demonstrated that programs offering physicians an opportunity to meet with colleagues in a structured format substantially reduced the rate of burnout and enhanced physician engagement [104,110].

Support groups can also focus on a theme. For example, residents rotating through a medical intensive care unit developed "grief rounds" as a way to discuss their feelings and other issues related to the deaths of patients they cared for [111]. When asked to assess the program, 77% of respondents agreed or strongly agreed that the rounds enhanced their intensive care unit experience. Further study is planned to determine if the grief rounds are associated with a decrease in burnout.

Pursue Professional Passions

Administrative burden and heavy patient loads often reduce the amount of time physicians have to pursue their professional passions, but time to participate in specific clinical or research interests is essential to having meaningful work, which in turn is paramount to physicians' satisfaction [20,92,112]. In the Medscape survey, lack of professional fulfillment was a leading cause of burnout [31]. Surgeons who focus on finding greater meaning in work have been less likely to become burned out, and other physicians have noted that maintaining passion for one's work is helpful in avoiding burnout [94,96].

Encourage Organizational Change

Physicians should work with leaders to effect organizational change that addresses issues associated with job dissatisfaction and burnout, such as excessive hours or workload, inefficiency, electronic burden, lack of physician autonomy, and inadequate resources for high-quality care and patient safety [20,112,113,114]. Physicians can become advocates for making these changes as well as other strategies, such as promoting part-time careers for physicians, providing protected time for physicians to pursue meaningful professional activities, offering programs that enhance physicians' resiliency (such as mindfulness programs) and provide opportunities for physicians to interact with their colleagues, making physician satisfaction and well-being quality indicators, and emphasizing the importance of self-care [20,114,115]. It is vital that physicians are true partners with leaders in collaborating for such changes [112].

Physicians can become champions of a healthy work environment by developing or participating in a wellness committee. This committee should be composed of physicians, other healthcare professionals, and staff and should collaborate with the organization's leaders [108]. Some potential initiatives are opportunities for physicians to openly and honestly discuss medical errors, how to achieve well-being, and how to avoid stress [65]. A wellness committee can also work to ensure that tools are available to assess physician well-being and burnout and that the results generate resources to address physicians' needs.

CALLS FOR ACTION

The substantial effect of stress, dissatisfaction, and burnout has led some professional organizations to publish position papers or calls for action. For example, the American Academy of Family Physicians published a position paper to note its commitment to helping find personal and system-wide solutions to physician burnout [116]. The Critical Care Societies Collaborative issued a call for action to enhance awareness of burnout in the critical care specialty and to encourage members of the specialty to work to create a healthy work environment [19]. The American Academy of Pediatrics issued a call to prevent burnout by promoting physician health and wellness, and the American Medical Association developed the program STEPS Forward as a resource to help physicians address practice-related issues that have been associated with burnout [85,117].

8. CONCLUSION

Burnout is a syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment. Levels of burnout are high among physicians, ranging from 27% to 60%, with even higher rates among physicians in training. At the root of burnout is job dissatisfaction. If left unaddressed, this dissatisfaction can lead to prolonged stress and subsequent burnout. Several causes of burnout among physicians have been identified, including work overload; long hours; inadequate work-life balance; excessive time for administrative tasks, especially electronic documentation; loss of autonomy; and evolving health policy. These sources of dissatisfaction can be correlated with mismatches identified by Maslach, the foremost authority on burnout.

High degrees of job dissatisfaction and stress precede burnout, making it incumbent on physicians to recognize stress early to help prevent burnout before it occurs. Preventing burnout is vital not only for the well-being and professional preservation of physicians but also for ensuring optimal patient outcomes. Several personal and professional lifestyle strategies can help physicians cope with stress, achieve better work-life balance, and become more engaged in their work. Practices and institutions should focus on creating a healthy work environment in which physicians feel supported by their peers, have control over their schedules as well as decision-making regarding their patients, and are offered resources to help them develop resiliency and enhance their well-being.

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