VA18O1 • Virginia Nurses 2018

Table of Contents

VA18O1 • Virginia Nurses 2018

How to Receive Credit

NetCE 5 Hour Course #38631 • Venous Disease and Ulcers

38631 • Venous Disease and Ulcers

1. INTRODUCTION

2. AN OVERVIEW OF LOWER EXTREMITY VENOUS ANATOMY

3. PATHOPHYSIOLOGY OF VENOUS INSUFFICIENCY

4. EPIDEMIOLOGY OF VENOUS DISEASE

5. ASSESSMENT AND DIAGNOSIS

6. TREATMENT

7. SKIN CARE

8. PATIENT AND FAMILY EDUCATION

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

NetCE 10 Hour Course #96962 • Opioid Use Disorder

96962 • Opioid Use Disorder

1. INTRODUCTION

2. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

8. CLINICAL EFFECTS

9. SPECIFIC OPIOID DRUGS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

11. PATHOPHYSIOLOGY

12. EFFECTS OF OPIOID USE DISORDER

13. OPIOID OVERDOSE

14. OPIOID WITHDRAWAL

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

16. MANAGEMENT OF OPIOID USE DISORDER

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

18. OPIOID USE DURING PREGNANCY

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

21. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

VA18O1 • Virginia Nurses 2018

Maryam Mamou, BSN, RN, CRRN, CWOCN

www.netce.com

Copyright © 2026 NetCE, All rights reserved.

VA18O1 • Virginia Nurses 2018

Expiration Date: 03/31/2021

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.

38631 • Venous Disease and Ulcers

Maryam Mamou, BSN, RN, CRRN, CWOCN

www.netce.com

Copyright © 2020 NetCE, All rights reserved.

Chronic venous insufficiency is the most prevalent vascular disorder and, if left untreated, can result in the development of a venous ulcer. Nurses who work in acute care, wound clinics, long-term care, and home health care regularly encounter patients with venous disease and venous ulcers. As such, they should be professionally prepared to provide state-of-the-art, evidence-based care to these patients.

Table of Contents

38631 • Venous Disease and Ulcers

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planner

Division Planner Disclosure

Director of Development and Academic Affairs

Director Disclosure Statement

About the Sponsor

Disclosure Statement

Implicit Bias in Health Care

1. INTRODUCTION

2. AN OVERVIEW OF LOWER EXTREMITY VENOUS ANATOMY

THE STRUCTURE OF VEINS

TYPES OF VEINS

BICUSPID VALVES

MUSCLE PUMPS

LOWER EXTREMITY VENOUS CIRCULATION

3. PATHOPHYSIOLOGY OF VENOUS INSUFFICIENCY

4. EPIDEMIOLOGY OF VENOUS DISEASE

SEX/GENDER

AGE

RACE

COSTS

5. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

PHYSICAL EXAMINATION OF THE LOWER EXTREMITIES

NUTRITION ASSESSMENT

DIAGNOSTIC TESTING

CEAP CLASSIFICATION

VENOUS ULCER ASSESSMENT

6. TREATMENT

MANAGING SYMPTOMS OF VENOUS DISEASE

COMPRESSION THERAPY

PENTOXIFYLLINE

HORSE CHESTNUT SEED OIL

BIOENGINEERED THERAPY

ULTRASOUND THERAPY

OPENING CLOSED WOUND EDGES

SURGICAL TREATMENT OF VENOUS INSUFFICIENCY

LOCAL WOUND CARE

7. SKIN CARE

8. PATIENT AND FAMILY EDUCATION

9. CONCLUSION

Works Cited

Evidence-Based Practice Recommendations Citations

38631 • Venous Disease and Ulcers

Education Category. Infection Control / Internal Medicine

Release Date. 03/01/2020

Expiration Date. 02/28/2023

Course Overview

Chronic venous insufficiency is the most prevalent vascular disorder and, if left untreated, can result in the development of a venous ulcer. Nurses who work in acute care, wound clinics, long-term care, and home health care regularly encounter patients with venous disease and venous ulcers. As such, they should be professionally prepared to provide state-of-the-art, evidence-based care to these patients.

Audience

This course is designed for nurses in all care settings who may care for patients with venous disease or ulcers.

Course Objective

The purpose of this course is to enable nurses to accurately assess and treat venous disease and venous ulcers and to provide patient and family education for preventive care and lifestyle changes.

Learning Objectives

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

1. Identify the different components of the venous system, and explain the pathophysiology of venous insufficiency.

2. Discuss the epidemiology of venous disease.

3. Outline the signs and symptoms of venous disease.

4. Cite the various diagnostic tests used to identify and classify venous disease and ulcers.

5. Evaluate the role of compression therapy and surgical interventions in treating venous disease and venous ulcers.

6. Review the importance of patient education in preventing the reoccurrence of venous ulcers.

Faculty

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

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

Faculty Disclosure

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

Division Planner

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

Division Planner Disclosure

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

Director of Development and Academic Affairs

Sarah Campbell

Director Disclosure Statement

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

About the Sponsor

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

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

Disclosure Statement

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

Implicit Bias in Health Care

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

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

1. INTRODUCTION

Venous insufficiency is the most prevalent vascular disorder and can result in significant morbidity, including lower extremity ulcers. Venous leg ulcers, also referred to as venous insufficiency ulcers, stasis ulcers, and varicose ulcers, are a major health problem in the United States. They are a common and disabling condition and often reoccur. The healing time is long—taking several weeks to several months; approximately 60% of venous ulcers remain unhealed after six months [1,2]. As the population ages, the frequency of venous ulcers is also increasing. They are one of the most prevalent forms of chronic wounds, and healthcare professionals should have a clear understanding of their impact on patient care [1].

2. AN OVERVIEW OF LOWER EXTREMITY VENOUS ANATOMY

Veins are part of the circulatory system and are responsible for carrying blood from all parts of the body back to the heart. Whereas blood in the arteries is bright red in color, blood in the veins is dark red due to the high concentration of carbon dioxide it is carrying. In most instances, veins follow the same routes as their companion arteries [3].

The study of the circulatory system dates back to the time of Hippocrates, and it is said that he was one of the first to discover the connection between venous disease and ulceration formation [4]. However, the distinction between arteries and veins was not always clearly understood. During the Middle Ages, it was thought that veins and arteries formed two distinct conduit systems, with veins carrying liquids that provided nutrients to the body and being closely aligned with the liver [4]. This concept of venous circulation continued until the 1600s [4]. Though it was observed that both arteries and veins carried blood, it took years of research to fully understand how they functioned [4].

THE STRUCTURE OF VEINS

Similar to the other vessels in the circulatory system, the vein walls are composed of three layers. The innermost layer of epithelial tissue is the tunica intima, the tunica media is the middle layer, and the outer layer is the tunica externa. The tunica externa is made up of collagen and elastic fibers and is the thickest layer of the vein walls [3].

Vein walls vary in size, with the smallest veins having a diameter of 0.5 cm and the largest (the superior and inferior venae cavae) having a diameter of up to 3 cm [3]. Veins have the ability to distend to accommodate varying degrees of blood volume flowing through them; however, they do not have the capacity to withstand high pressures [3]. The lumen in veins is much larger than that found in the arterial system [3]. This is important because the size of the lumen determines the resistance to blood flow [3].

TYPES OF VEINS

Deep Venous System

Veins in the legs are divided into three major groups based on their relationship to the muscular fascia: deep veins, superficial veins, and perforator veins [5]. The deep venous system consists of the posterior and anterior veins and includes the common iliac veins, the femoral veins, and the popliteal veins [3]. These veins are located under the muscular fascia inside the muscle compartments of the leg, usually in close proximity to their companion arteries [5]. However, there is considerable variability in individual anatomy [6]. The deep veins are responsible for draining blood from the lower extremity muscles.

Superficial Venous System

The greater and lesser saphenous veins form the superficial venous system, also known as the saphenous system [5]. Superficial veins lie above the deep fascia and drain the cutaneous microcirculation [6]. The great saphenous veins are the longest veins in the body; they travel up from the dorsum of the foot to the groin and are located in the subcutaneous tissues [3]. Superficial veins are noticeable in some persons as a blue continuous line passing along the leg beneath the skin [3].

The Perforator Veins

The perforator veins are the branches that cross the muscular fascia to connect the deep veins with the superficial veins in a ladder-like system [5]. There are more than 90 perforator veins in a human leg [5]. The normal path of blood flow in the lower extremities is from the superficial to the deep veins via the perforator veins [7].

BICUSPID VALVES

Veins are equipped with flap-like bicuspid valves, which are made from the inner lining of the veins (i.e., the tunica intima) [3]. Blood is governed by the rule of gravity, and without intervention, it will flow downwards. The venous valves prevent the backward flow of blood in the veins by closing together in the middle of the vein to form a barrier [8]. The bicuspid valves in the veins of the lower extremities are opened when an individual is at rest in the supine position [6]. Valve closure occurs when the pressure gradient is reversed, following a brief period of antegrade flow.

The great saphenous veins are equipped with up to 20 valves along their entire course, the majority of which are found below the knee [3]. The perforator veins are also equipped with numerous valves to ensure one-way flow of blood from the superficial to the deep veins [6].

MUSCLE PUMPS

The leg muscles and the pumping action of the heart play a major role in venous blood flow, but the blood-holding capacity of the lower extremity veins when an individual is standing is regulated by two factors: the venous valves and the calf muscle pump [6]. Around 90% of venous blood return from the lower extremities flows through the deep veins and is facilitated by the action of muscle pumps in the foot, calf, and thigh [6].

Among these three pumps, the calf pump is the most important and is responsible for the greatest pressures [6]. During ambulation, this pump is responsible for propelling 70% of the blood out of the calf [8]. When the calf muscle pump contracts, blood is pushed out of the veins and the resting pressure in the veins decreases. Because blood flows from areas of high pressure to areas of low pressure, this decrease in the pressure gradient in the deep venous system after contraction allows blood to flow from the superficial veins to the deep veins via the perforating veins [6]. As long as the valves of the venous system are functioning correctly, there is little retrograde blood flow [9].

If the calf muscle pump is functioning below capacity or fails completely, high venous pressures will develop, which can ultimately lead to the development of varicose veins, edema, and venous ulcers. Many variables can adversely affect the contraction of the calf muscle pump, including vascular insufficiency, neurologic disease, injury, bone and joint conditions, and limited mobility [9]. Temporary or permanent immobilization resulting in an inability to contract the leg muscles causes sluggish circulation in the venous system and can lead to venous insufficiency [3].

LOWER EXTREMITY VENOUS CIRCULATION

The human heart is responsible for pumping blood throughout the circulatory system. Blood circulates through the capillaries, and then enters the venules, the small veins that carry the deoxygenated blood from the tissues. Venules join together to form the larger veins, which return the blood to the right side of the heart [3]. There is a small but significant pressure difference between the heart and the venous system, and when the left ventricle contracts, this generates sufficient pressure to assist with venous blood flow back to the heart [3].

The function of leg veins is to return blood from the lower extremities to the heart, and this is accomplished in conjunction with the muscles in the legs. The volume of blood that flows through the venous system back to the heart is referred to as venous return [3]. The normal blood pressure in veins is much lower than in arteries, and bleeding from a severed vein will be slow and steady, rather than the quick bursts seen with arterial bleeding [3]. The artery and companion vein(s) often share a vascular sheath, allowing arterial pulses to aid venous return.

Muscle pumps in the foot, calf, and thigh work together to drive blood out of the lower leg (against gravity) and back to the heart. As noted, the calf muscle pump is the most vital component of this process. Bicuspid valves prevent back-flow of blood to the foot and ankle.

3. PATHOPHYSIOLOGY OF VENOUS INSUFFICIENCY

Chronic venous insufficiency encompasses many different venous conditions that result from impaired venous return and resultant venous stasis. Malfunction of the venous valves, referred to as valvular incompetency, is the first step in the development of venous disease [10]. In valvular incompetency, the valves fail to close completely and allow retrograde blood flow, which results in venous hypertension. Chronic venous hypertension, the hallmark of chronic venous insufficiency, leads to the development of lower extremity complications [7].

The end result is pooling of blood (stasis) in the venous system, which can lead to initiation of the inflammatory process and on-going capillary damage [11]. With inflammation, there is activation of the white blood cells and endothelial damage, which are contributing factors to venous ulcer formation and delayed healing [11].

There are several reasons venous valves may not function properly, including congenital absence of the valves, venous thrombosis/phlebitis, and trauma [11]. Ambulation is necessary for contraction of leg muscles and activation of the calf muscle pump, and extended periods of immobility can lead to an increase in venous pressure.

4. EPIDEMIOLOGY OF VENOUS DISEASE

Chronic venous insufficiency is defined as persistent ambulatory venous hypertension of the lower extremities that can cause pain, skin changes, edema, and ulceration [12]. It is the most prevalent vascular disorder and, if left untreated, can result in the development of a venous ulcer. As noted, the most common cause of chronic venous insufficiency is venous reflux, particularly of the superficial deep veins [11]. Manifestations include telangiectasias, reticular veins, and varicose veins, the latter of which affects 25 million adults in the United States [12]. In addition, more than 6 million individuals in the United States have more advanced lower extremity venous disease, including venous ulcers [12]. Studies indicate there are 600,000 new lower extremity leg ulcers in the United States each year, and it is estimated that venous ulcers are responsible for up to 70% of wounds of the lower extremities [5,9]. Up to 2% of adults will develop a venous ulcer at some point in their lives [2,5]. In the long-term care setting, the prevalence of venous ulcers is higher, with an occurrence rate of approximately 2.5% among all new admissions [13].

SEX/GENDER

In the Edinburgh Vein Study, involving 1,566 subjects, the prevalence of chronic venous insufficiency was 9.4% in men and 6.6% in women [14]. However, research indicates that the female-to-male ratio of varicose vein prevalence is 3:1 [12]. Venous ulcers also occur more frequently in women than in men, with an overall occurrence rate for women of 1.42 per 100 person-years and 0.76 per 100 person-years for men [11,13].

AGE

Chronic venous insufficiency becomes more common with advanced age. Data from the Edinburgh Vein Study indicate the prevalence rate doubled in men (21%) and women (12%) older than 50 years of age [14]. The likelihood of developing a venous ulcer also increases with age, possibly as a result of progression of the disease. In one study, nearly half of participants experienced deterioration (including skin changes) after 13 years [15]. Of persons with venous ulcers, approximately 22% develop their first ulcer by 40 years of age and 72% develop an ulcer by 60 years of age [9]. An increasing number of older adults have mixed venous and arterial disease, which presents more challenges for effective treatment [9].

RACE

There is some evidence that chronic venous insufficiency is more common in white individuals than in racial/ethnic minorities [16,17]. However, when present, venous disease in black patients is more likely to present at a more advanced stage at a younger age compared with white patients, resulting in increased ulcer debridement, deep vein thrombosis rates, and hospital charges [17].

COSTS

Due to the chronic nature of venous insufficiency and ulcers, they are costly. Patients may experience a significant socioeconomic impact as a result of direct care-related costs, disability, reduced productivity, and impaired quality of life [12]. In the United States, the approximate cost of venous ulcer care is estimated between $2 billion and $3.5 billion annually [5].

5. ASSESSMENT AND DIAGNOSIS

PATIENT HISTORY

When taking a patient history, it is important to explore risk factors for lower extremity venous disease [9]. Some of the more common prevailing risk factors are [5]:

- A history of deep vein thrombosis or leg ulcer(s)

- A family history of venous disease

- Multiple pregnancies, particularly in a short time span

- Older age

- Obesity

- Leg surgery or trauma

- Sedentary occupation and lack of exercise

- Drug injections into the veins of the lower extremities

There are also certain conditions that can trigger venous ulceration, including dry skin, cellulitis, insect bites, burns, and contact dermatitis [5]. These potentiating conditions are found in more than 70% of patients who present with venous disease and ulcers [5]. It is important to note that leg trauma does not have to be recent or severe to cause venous disease, and many times the patient may not recall the trauma.

It is also important to inquire about any prior instances of thromboembolism and if the patient has a history of venous ulceration [10]. A history of venous ulcers greatly increases the likelihood of future ulcer development. For female patients, it is important to enquire about varicosities close to the vagina [10]. A full review of current medications should be done, as well as ascertaining the patient's allergies, if any [10].

If the patient currently smokes, information should be gathered about the length of time he/she has been a smoker and how many cigarettes are smoked on a daily basis. If the patient previously smoked, establish how many years it has been since he or she quit.

A large number of those with venous disease also have one or several comorbidities, many of which are chronic conditions. Comorbid conditions have a negative impact on venous health and ulcer healing and should be thoroughly reviewed when assessing the patient and monitored throughout the course of treatment.

PHYSICAL EXAMINATION OF THE LOWER EXTREMITIES

Diagnosing lower extremity venous insufficiency relies mainly on clinical findings. A physical examination of both extremities should be done from mid-thigh level to the toes [5]. Patients will sometimes query why it is necessary to examine their "good leg," and the best response is that a comparison between both legs will help to indicate the severity of the venous disease. If feasible, it is better to examine patients while they are standing [10].

Swelling in Lower Extremities

One of the early changes that individuals with venous insufficiency notice is swelling in their legs and a feeling of heaviness. Most patients will report that elevating their legs will reduce the swelling. Edema is an important finding in venous insufficiency, and the patient should be asked when he or she first noticed the swelling and how it has progressed over time. In venous disease, edema is usually first noticed around the ankles, and with time, it gradually progresses up the patient's leg to include the calf area. Edema may be present for a considerable length of time before progressing, for example to a venous ulcer [5].

It is important to examine both extremities for the presence of edema. Chronic venous insufficiency will result in edema on the affected side, which progresses as the disease worsens. The sudden appearance of unilateral edema may be a sign of acute deep vein thrombophlebitis and requires immediate medical attention [7].

There are two forms of edema: pitting and non-pitting. Non-pitting edema presents as a swollen area that is hard to the touch. With pitting edema, pressure in the swollen area results in a persistent indentation. Pitting edema around the ankle that worsens through the day is a typical finding in advanced venous disease.

Serial bilateral ankle and calf measurements are useful to monitor the progress of edema. This consists of first measuring from the sole of the foot to just above the patient's ankle, then measuring the circumference at this point on both ankles. This same process is repeated for the widest area of the patient's calf on both extremities. In patients with edema, these measurements should be repeated at least weekly (with each wound assessment) using the same distance from the sole of the patient's foot each time to accurately determine the progression of the edema.

Skin Changes

Chronic venous insufficiency affects the skin and fat tissue, and some individuals with venous disease have no symptoms other than skin changes accompanied by distended veins [18]. There is often thinning of the epidermis, and with longstanding venous disease, the texture of the skin on the lower legs changes, becoming shiny, indurated, and usually darker than the surrounding skin [10]. If there is no component of arterial disease present, the patient's feet will feel warm to the touch and the dorsalis pedal and popliteal pulses will be palpable [18]. The presence of hair on the legs and feet is an indication of sufficient arterial supply and should be noted during the physical examination. Hemosiderin staining is a brownish or grayish discoloration of the skin caused by blood leaking into the tissues and breakdown of red blood cells [19]. Atrophie blanche is a change in skin texture and color attributed to venous insufficiency and presents as atrophic areas of white or pale skin [20].

Stasis dermatitis, also known as venous dermatitis or venous eczema, is dry, scaling skin of the lower extremities [18]. The first presentation is a reddish-brown skin discoloration, typically of the medial ankle. As the disease progresses, eczematous changes may be present, with weeping patches and plaques. Stasis dermatitis is often the first and most common skin change associated with venous disease. It is extremely pruritic (with insidious onset), which is a source of significant discomfort for patients.

Lipodermatosclerosis

Lipodermatosclerosis is an inflammation and hardening of the subcutaneous fat and dermal tissue found in longstanding venous insufficiency. It is caused by protein accumulation in the tissues, most noticeably in the "gaiter area" of the leg (between the knee and ankle) [18]. Lipodermatosclerosis presents as hard, waxy, hyperpigmented tissue with swelling of the surrounding areas. This has given rise to the description of a "bottle leg" formation [18].

Vein Abnormalities

Ankle flaring, a symptom of venous disease, presents as a cluster of distended small veins around the malleolus [5]. Telangiectasias (e.g., "spider veins") and reticular veins are also common and present as dilated intradermal and subdermal venules. These findings are more common in women than men and can develop in the absence of more serious venous insufficiency [21].

Varicose veins are one of the most common signs of venous insufficiency. They are dilated, elongated, tortuous superficial veins that become progressively larger, typically 3 mm or greater in diameter [21]. In some cases, patients may experience superficial thrombophlebitis in these veins, but they are often asymptomatic aside from the appearance.

Assessing Pulses and Temperature in the Lower Extremities

During the physical examination, the femoral and pedal pulses should be assessed. The pedal pulses include the dorsalis pedal pulses, located between the first (great) toe and the second toe on the dorsum of the foot, and the posterior tibial pulse, located behind the medial malleolus. In younger patients, it may be possible to palpate these pulses; however, in older patients, use of a handheld Doppler is often necessary to detect a pulse beat [22].

It has been documented that individuals with venous disease and those who progress to venous ulceration have higher skin temperatures around the ankle than the general population [5]. A sudden elevation in temperature more than 4 degrees Fahrenheit may be indicative of a developing leg ulcer [5].

Venous Refill Time

Venous refill time should be assessed at presentation and regularly during treatment to get an overall measurement of venous reflux [24]. It is generally recorded as the number of seconds needed for the veins of the foot and lower leg to refill when the leg is in a dependent position.

Trendelenburg Tourniquet Test

In the past, the Trendelenburg tourniquet test (also referred to as the Brodie-Trendelenburg test) was used as a clinical exam technique to assess valve competency in the lower extremities and the severity of varicose veins. However, the results of this test are not considered reliable or accurate, and it has largely been replaced by duplex ultrasound testing [23].

NUTRITION ASSESSMENT

Unfortunately, nutritional status is not often assessed in patients with venous disease, and nutritional deficiencies are underdiagnosed and under-reported in this patient group [5]. A full nutritional assessment should be part of the initial patient evaluation.

Protein deficiency and inadequate calorie intake are common findings in patients with venous ulcers, and there is a correlation between protein deficiency and wound size at the 12-week mark [5]. Vitamin C deficits and low serum albumin levels are also common in persons with venous ulcers [5]. Resolution of these deficiencies should be included in the treatment plan, as venous ulcers will not heal in patients who are nutritionally compromised.

DIAGNOSTIC TESTING

The location and severity of venous reflux will help to determine the choice of treatment. Diagnostic testing used in the assessment of venous disease has been organized into three levels [24]. Level one is the patient work-up, which takes place during the initial intake process and includes the physical examination and continuous-wave, handheld Doppler studies [24]. All individuals who present with venous insufficiency should have a level one assessment. Level two encompasses more complex vascular laboratory studies, such as scanning, plethysmography, and venous pressure [24]. These studies will provide more detailed diagnostic information and further help to determine the course of treatment. Level three studies include phlebography and varicography and are done for more complex cases and as pre-operative preparation [24].

Duplex Ultrasound

Venous ultrasound is an important tool to determine the source of venous insufficiency [18]. A duplex ultrasound is used to locate malfunctioning perforator veins that may exist between the superficial and deep veins [10]. The American College of Phlebology has also recommended assessment of the patency and competency of the common femoral and popliteal veins [25]. Duplex ultrasound is regarded as the most reliable noninvasive test for diagnosing venous insufficiency [5].

Photoplethysmography and Air Plethysmography

Photoplethysmography, which assesses the degree of venous reflux and measures venous filling times, may also be helpful. Normal venous refill time is 20 seconds or longer [5]. Shorter refill times are indicative of venous reflux or obstruction.

Air plethysmography testing is used to evaluate the degree of calf muscle pump impairment. A cuff surrounding the calf measures changes in limb volume during specific maneuvers (e.g., leg lift), allowing for assessment of outflow and filling rates. Normal venous filling occurs at a rate of <2 mL per second; rates greater than 4 mL per second indicate venous reflux and correlate with the level of venous insufficiency [12].

Venography

Computed tomographic or magnetic resonance venography is normally done to outline the venous system before surgical intervention is undertaken [5]. It will also give insight regarding obstructions or compression, if present.

Laboratory Studies

Laboratory studies used in the assessment of venous disease and to determine eligibility for treatment approaches include hemoglobin, hematocrit, and prothrombin time [5]. For patients on anticoagulant therapy, it is important to keep in mind that there may be increased bleeding from venous ulcers.

Ankle-Brachial Index Monitoring

Evidence Based Practice Recommendation

The Guideline Subcommittee of the European Dermatology Forum recommends ankle-brachial-pressure index should always been determined before pressure therapy is given.

https://onlinelibrary.wiley.com/doi/10.1111/jdv.13848

Last Accessed: February 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

All patients with venous insufficiency should have ankle-brachial index (ABI) studies done regularly, usually every three months [5]. The ABI is a noninvasive, indirect measurement of arterial blood flow to the lower extremities. Approximately 26% of those with venous problems also have arterial insufficiency, and the ABI value will help determine if the diagnosis is severe arterial disease, mixed arterial and venous pathology, or primarily venous disease [26,27]. An ABI value greater than 0.8 indicates primarily venous disease, while a value of 0.5–0.8 suggests a mixed etiology [24]. An ABI value less than 0.5 points to severe arterial disease, and compression therapy is not recommended for these patients [5].

An ABI reading greater than 1.3 is indicative of incompressible blood vessels, usually found in patients with diabetes. This result is inaccurate and requires further testing (e.g., duplex ultrasound, transcutaneous oxygen measures, photoplethysmography) to obtain a correct reading [25,26].

ABI testing is done by comparing the systolic blood pressures in the ankle to the systolic brachial blood pressures [28]. When obtaining an ABI reading, start by explaining the procedure to the patient and allowing him or her to rest in the supine position. The most accurate results are obtained when the patient is relaxed in a comfortable position with an empty bladder [26]. After about 15 minutes, take brachial blood pressure readings in both arms; the higher of the systolic pressure readings will be used to calculate the ABI value.

Next, place the blood pressure cuff around the ankle just above the malleolus. If there is a wound present, cover it with a dressing before applying the cuff. Apply ultrasound gel below the medial malleolus and move the handheld ultrasound probe slowly in a half circle around the ankle until a pulse is detected. Hold the probe at a 45-degree angle pointing upward to meet the blood flow. Inflate the blood pressure cuff until the audible pulse signal disappears, then slowly release the cuff until the pulse is heard again, indicating the systolic pressure. Complete this process for both ankles, again noting the highest systolic pressure reading.

To calculate the ABI value, divide the highest ankle systolic pressure by the highest brachial systolic pressure. For example, if the ankle systolic pressure is 90 mm Hg and the highest brachial systolic pressure is 100 mm Hg, this will result in an ABI of 0.9.

ABI testing should not be done for patients with severe foot or leg pain or suspected deep vein thrombosis, as there is a possibility of dislodging the clot [26]. In addition, patients who are unable to remain supine for the duration of the test are ineligible.

CEAP CLASSIFICATION

Evidence Based Practice Recommendation

The Guideline Subcommittee of the European Dermatology Forum recommends the use of the full CEAP classification in all cases of venous ulcer. This is done via a combination of physical examination and technical aid (especially duplex ultrasound).

https://onlinelibrary.wiley.com/doi/10.1111/jdv.13848

Last Accessed: February 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

The clinical-etiology-anatomy-pathophysiology (CEAP) classification system is used to determine the severity of venous disease and was originally developed in 1994 by the American Venous Forum. It has since been updated and revised but continues to be the standard for classifying venous disease (Table 1) [11,24,29,47].

Table 1: CEAP CLASSIFICATION FOR VENOUS DISEASE

Clinical

C0

No visible or palpable signs of venous disease

C1

Telangiectasias or reticular veins

C2

Varicose veins

C3

Edema

C4a

Pigmentation and eczema

C4b

Lipodermatosclerosis and atrophie blanche

C5

Healed venous ulcer

C6

Active venous ulcer

S

Symptoms including ache, pain, tightness, skin irritation, heaviness, muscle cramps, and/or other complaints attributable to venous dysfunction

A

Asymptomatic

Etiology

Ec

Congenital

Ep

Primary

Es

Secondary (post-thrombotic)

Anatomy

As

Superficial veins

Ap

Perforator veins

Ad

Deep veins

Pathophysiology

Pr

Reflux

Po

Obstruction

Pr,o

Reflux and obstruction

Pn

No venous pathophysiology identifiable

Source: [29]

As the name implies, the CEAP classification system consists of four dimensions. The clinical dimension is probably the most widely used and encompasses what the veins look like. The etiology dimension describes the nature of the underlying cause of the venous insufficiency, while the anatomy dimension identifies the veins affected. Pathophysiology describes the cause of the condition—whether it is reflux, obstruction, or a combination of both [7,29].

VENOUS ULCER ASSESSMENT

Diagnosing venous ulcers correctly is necessary to ensure that appropriate treatment is implemented [9]. These wounds should be clearly distinguished from other ulcers of the lower extremities, classified, and documented. The first step in this process is to obtain a complete clinical history from the patient, followed by a physical examination and full wound assessment [5].

Venous ulcers normally develop on the medial malleolus, ankle, or posterior calf; over a perforating vein; or along the route of the great or small saphenous veins. They do not occur above the knee or in the area of the forefoot [20,22]. In appearance, the ulcers are usually irregular and shallow, with granulation tissue and fibrin evident in the wound bed [11].

A single ulcer or several wounds may be present. If left untreated, the ulcer can extend completely around the patient's leg. The amount of drainage from a venous ulcer varies from mild to copious, and the periwound area is often macerated; scaling and crusting may also be present [5].

A venous ulcer is described as chronic when it persists for longer than three months. Ulcers that have been present for more than 12 months and are greater than 6 cm in diameter are regarded as having a poor prognosis for healing [11].

Wound Assessment

A complete assessment of the venous ulcer, including photographic documentation, should be done when a patient first presents and at all subsequent visits (ideally weekly). This is helpful in tracking healing progress and can provide positive reinforcement to patients who may find treatment long and arduous.

Wound assessment should take place in a private area that allows the patient to be positioned comfortably and has adequate lighting to provide for proper visualization of the wound, the periwound area, and the entire lower extremity.

A decrease in wound size is predictive of eventual full healing. If there are no changes in the wound dimensions after four weeks, a full review of the treatment plan is warranted [5]. Wounds that do not decrease in size by approximately 30% during the first four weeks of treatment have a 68% likelihood of not being healed within 24 weeks [5]. Leg ulcers that show no signs of improvement after six weeks of treatment should be biopsied to rule out malignancy or other causes that would prevent healing (e.g., collagen-vascular diseases, bacterial or fungal infection) [30].

During the assessment patients should be asked about chronic leg cramps and restless legs syndrome [18]. Chronic pain and insomnia should also be noted [18].

Wound Measurement

Accurate measurement of the wound is probably the most important feature of wound assessment [7]. It provides information on the initial size and progression or non-progression of healing, allowing for valuable feedback on the effectiveness of clinical interventions [31].

Wounds should always be measured in centimeters, using a plastic or paper ruler. Wound length is measured from head to toe; width is measured from hip to hip [32]. The depth of the wound can be obtained by gently inserting a sterile cotton-tipped applicator into the wound bed and marking it at skin level. The applicator is then measured using a metric ruler [32].

Tunneling and Undermining

Sinus tracts and undermining impair healing, and it is important to immediately identify their presence [31]. A sinus tract is a tunnel that extends from any part of the wound and can bore through subcutaneous tissue and muscle [31]. This tunnel creates dead space, which can result in abscess formation and further impede the healing process [31]. A sinus tract can be measured using a sterile cotton swab [31].

Undermining is defined as destruction of the tissue under the skin around the edges of the wound. The easiest way to measure and describe undermining is by using the face of the clock [31]. With the patient's head representing 12 o'clock, sweep the area of undermining or probe the tunneling to ascertain the depth. For example, undermining along the right border would be recorded as extending from 1 o'clock to 5 o'clock with a depth of 4 cm [31]. It is important to check around the entire perimeter of the wound, as undermining can occur in more than one location.

Wound Bed

It is also vital to assess and document the appearance of the wound bed. If the wound bed has a mixture of tissue in it, this should be documented by an approximate percentage (e.g., the wound base is 75% granulation tissue and 25% slough). Granulation results in "beefy" red tissue with a shiny, moist granular appearance, while necrotic tissue is gray, brown, or black. Eschars are typically gray to black and dry or leathery in appearance [33]. Slough tissue is yellow/white to gray in color. It may be stringy or thick and appear as a layer over the wound bed [33]. The presence of thick slough or eschar is an indicator of arterial insufficiency [45]. Epithelial tissue will often begin to grow in from the edges over the wound surface. This tissue is generally pink and shiny. As a quick reference color guide, red is associated with normal healing, yellow indicates slough or dead tissue, and black is necrosis [33].

Surrounding Skin

The condition of the surrounding skin surface up to 4 cm from the edge of the wound circumferentially should also be assessed and documented. Its characteristics should be noted, particularly color and integrity [18]. Maceration from excessive drainage may indicate that the dressing used is not appropriate and a different product is needed. Circumferential redness up to 2 cm from the wound is indicative of cellulitis.

6. TREATMENT

Problems with venous circulation are not new, and reports of venous disease were recorded in the early days of medical practice. The first reported documentation of varicose veins and their treatment can be traced back to ancient Egypt [4]. In the Middle Ages, nuns discovered the benefits of massaging and applying tight wraps to legs with edema.

The earliest treatments for venous disease were vein stripping and ligation [4]. Today, treatment of venous disease is primarily surgical, and surgical intervention for varicose veins is one of the most frequently performed nonemergent surgical procedures in the United States [34].

If a venous ulcer has not yet developed, the primary goal of treatment of chronic venous insufficiency is to reduce venous hypertension and prevent ulceration. The plan of care for these patients will include weight management, compression therapy, leg elevation, setting realistic goals to become more physically active, and patient education. If an ulcer is present, the goal is to achieve complete healing and prevent ulcer reoccurrence.

Complete healing of a venous ulcer takes an average of 24 weeks. Nearly 15% of ulcers do not heal, and the five-year reoccurrence rate is up to 40% [24]. The selection of treatment options for patients with venous ulcers is often influenced by and modified because of the presence of other health issues. Diabetes, lymphedema, obesity, malnutrition, and intravenous drug use can all impact treatment efficacy and can lead to delayed healing [24]. When evaluating the treatment plan for a non-healing venous ulcer, one of the factors to re-assess is the presence of other health conditions and how well they are being managed.

A holistic approach is essential in treating venous disease and venous ulcers. Better healing outcomes are achieved when a multidisciplinary team approach is used along with evidence-based wound care [24]. The team involved in the treatment of venous disease should include physician specialists, podiatrists, surgeons, nurses who have training and/or experience in wound care, social workers, and discharge planners. The role of discharge planners and social workers in the care of these patients is often overlooked. However, the financial burden and lifestyle changes venous disease imposes on patients make assistance beyond physical care crucial to achieve successful outcomes.

There are five major treatment options for patients with venous disease [24]:

- Compression therapy

- Local wound care for venous ulcers

- Surgical interventions

- Medical treatment

- Advanced technology

As noted, conservative management is normally the first treatment option for patients without ulcers, including leg elevation, exercise, and compression therapy [21]. Treatment modalities generally focus on symptom management, such as reducing swelling or edema and eliminating lipodermatosclerosis [11,21].

Leg elevation has been shown to be effective in reducing edema. Ideally, patients with leg edema should elevate their legs above the level of the heart for 30 to 45 minutes three to four times daily, unless there are medical contraindications to doing this [35]. Patients for whom this is not feasible should be encouraged to elevate their legs to a degree that is comfortable and to maintain that position for as long as possible.

MANAGING SYMPTOMS OF VENOUS DISEASE

Pain

Venous insufficiency-related pain does not radiate to other areas of the body and is not adversely affected by joint movement; the pain is localized to the area of venous disease and ulcer location, if present. Pain can reach a level of severity that makes walking difficult and eventually impossible. Numbness and tingling may also be present.

Pain associated with venous ulcers is usually described as moderate-to-severe stabbing, throbbing, or aching pain [9]. Patients state that pain worsens with prolonged standing, especially for long periods of time. Elevating the affected leg usually diminishes pain. It is reported that venous ulcer pain can linger for up to three months after wound healing [9]. Usual pain management techniques and pharmacology should be used to ensure patient comfort.

Pruritus

As discussed, stasis dermatitis, which occurs with longstanding venous disease, can be intensely pruritic, with some patients describing the sensation of itching as worse than the pain. However, scratching can lead to injury of already compromised skin surfaces and venous ulceration, with the possibility of infection, delayed healing, and scarring [36]. In addition, the amount of leg or foot itch is correlated with CEAP classification and degree of pain [36].

Patients with venous disease have identified itching as a factor that negatively impacts their quality of life [36]. Clinicians caring for patients with venous compromise should recognize that pruritus can pose a serious problem, and it should be included in the assessment process and addressed in the treatment plan [36].

Curative treatments are not always possible, but focusing on restoring the natural equilibrium of the skin should be the goal. Antihistamines can be used to decrease the sensation of itching, and emollient products can help to restore the skin's natural barrier [36]. Topical steroid ointment may be used to reduce inflammation and alleviate itching, but in most cases, it should not be used for more than two weeks [5].

Nonpharmacologic interventions for managing pruritus include stress management training and guided imagery [36]. Validating patients' experiences with itching and allowing them time to express their frustrations are also useful coping mechanisms.

COMPRESSION THERAPY

Evidence Based Practice Recommendation

According to the Guideline Subcommittee of the European Dermatology Forum, compression therapy is the treatment of first choice in an uncomplicated venous leg ulcer.

https://onlinelibrary.wiley.com/doi/10.1111/jdv.13848

Last Accessed: February 14, 2020

Level of Evidence: Expert Opinion/Consensus Statement

Compression therapy is still the mainstay of treatment of venous disease. Compression helps to heal venous ulcers more quickly by reducing edema in the affected extremity and increasing venous return toward the heart [9,24]. As swelling in the extremity decreases, circulation to the skin surface provides improved oxygenation to promote healing [10]. Ambulatory patients should be encouraged to walk as much as possible after compression is applied in order to obtain maximum benefit from the therapy [10].

Several options are available for compression therapy, including elastic tubular support bandages, adhesive elastic wraps, hook-and-loop closure wraps, Unna boots, and multilayer compression (composed of two, three, or four layers of bandages) [13]. A multilayer, high-compression approach involving an elastic bandage provides better results for venous ulcer healing compared with non-elastic compression [44].

Since their conception, Unna boots have been the most widely used form of compression for venous ulcers [13]. The device is not actually a boot but a paste bandage impregnated with zinc oxide, glycerin, gelatin, and sometimes calamine [13]. This dressing applies compression via the slow drying and shrinkage of the bandage. Depending on facility protocol, the Unna boot is usually changed three days after the first application and weekly thereafter.

The Unna boot should be applied from just above the patient's toes to approximately 1 inch below the knee. Different application methods may be used. The boot may be pleated as it is applied to avoid wrinkles and creases, or it can be cut through and applied in overlapping strips. With each spiral, there should be a 75% to 80% overlap. The gauge is then covered with an elastic, self-adhesive bandage with 50% overlap and 50% stretch to provide additional compression [18].

The Unna boot provides inelastic compression, meaning that the pressure gradient is high while the patient is walking but low (or lacking) when the patient is resting. As such, multilayer compression bandages may supply more effective compression for non-ambulatory patients than the Unna boot. The Unna boot also does not adapt to changes in the patient's leg size, which can lead to complaints of pain and discomfort [11].

Multilayer bandages are often more effective in maintaining the pressure gradient beneath the compression. Multilayer compression includes an orthopedic wool bandage that is applied spirally around the patient's leg. This helps to absorb drainage and protect boney prominences. The second layer is a cotton crepe bandage that is spirally wrapped around the patient's leg. The third layer is an elastic bandage that conforms to the patient's leg. This bandage may be applied in a spiral fashion (with 50% stretch and 50% overlap) or in a "figure eight" configuration that will increase the amount of compression applied. The fourth and final layer is an elastic cohesive bandage that is wrapped in a spiral fashion and holds the inner layers in place [13]. Short-stretch bandages are usually used for compression; long-stretch bandages are not a good choice, as they stretch when the calf muscle is contracting and provide minimal compression. Two-layer compression systems lead to the same level of venous ulcer healing as the four-layer options, are more comfortable, and provide for a better quality of life for the patient [30,44]. Elastic wraps often come with markings on the surface to indicate appropriate application (e.g., rectangular shapes that will change to squares when the bandage is applied with the correct amount of tension) [13].

The degree of compression therapy can be categorized as light, moderate, or high [5]. Light compression applies 20–30 mm Hg of pressure to the ankle area and is recommended for patients with venous insufficiency who are unable to tolerate higher levels of compression. Approximately 35–40 mm Hg of compression (moderate) is regarded as the most appropriate level for venous ulcer wound healing. A high level of compression is obtained with a pressure gradient of 40–50 mm Hg. As noted, there is strong evidence that approaches that achieve higher levels of compression (i.e., 35 mm Hg or greater), including multilayer elastic systems, achieve the best healing outcomes [9].

The patient's pain level should be taken into consideration when choosing compression therapy. Patients who are experiencing pain may better tolerate an inelastic support system to start, until pain and edema levels are under control [9].

Compression cannot be used for all patients with venous insufficiency; it is contraindicated for individuals with decompensated chronic congestive heart failure and those with mixed arterial and venous disease in which diminished arterial circulation is a significant risk factor [9]. Compression should not be used in any patient with an ABI less than 0.5 (i.e., with arterial disease). Carefully monitored, modified light compression (20–27 mm Hg at the ankle level) can be used in patients with an ABI of 0.6–0.8 [18].

In addition, many patients are unwilling to wear continuous compression. In these cases, intermittent pneumatic compression (IPC) may offer a viable alternative. IPC therapy uses an air pump and a "sleeve" with one or several bladders [24]. The sleeves are wrapped around the patient's leg(s), and the air pump is used to inflate and deflate the bladders at set intervals [24]. Depending on the type of IPC used, there are variations in the compression cycles that can be set to meet the patient's therapeutic needs [24]. IPC should not be used with patients who have edema related to chronic heart failure, active phlebitis, deep vein thrombosis, cellulitis, or wound infection [13].

Applying Compression Bandages

Before applying compression bandages, it is important to explain the procedure to the patient and address any questions or concerns he or she may have. The patient's ankle circumference should also be measured. If the circumference is less than 7.5 inches, extra padding should be added around the ankle area. This can be done using a piece of the first roll of orthopedic padding. As swelling decreases, it is important to recheck the ankle circumference weekly and to adjust the padding as necessary. A very thin extremity and boney prominences should also be protected with extra padding to prevent bruising when compression is applied.

The patient's foot should be maintained in a neutral position (i.e., foot flexed to 90 degrees). The first layer of compression starts just above the patient's toes and is wrapped in two anchor turns. Continue wrapping up and around the patient's ankle, then fold back down to enclose the heel. Using a spiral wrapping technique, proceed up the patient's leg, overlapping 50% with each turn. Continue wrapping to about 1 inch below the patient's knee, then cut away any unused bandage.

The second and third layers of the compression bandages are applied in the same manner. However, the third layer is the light compression bandage, and only one turn should be applied at the top of the leg (just below the knee). If more than one layer of bandage is applied, it can cause too much pressure in this area. Extra bandage should be cut off and discarded.

The fourth layer is the cohesive compression bandage and should be applied with 50% stretch and 50% overlap. Two- and three-layer compression bandaging systems are applied in the same way.

Compression bandages can be left on for up to seven days. However, if wound drainage seeps through, the wrapping should be changed. During changes in bandaging, the wound is assessed and redressed.

Patient Teaching

The greatest risk factor with compression of any type is arterial occlusion, and patients and family/caretakers should be aware of this possible complication. Face-to-face teaching should be done after the compression is applied, and written instructions should be sent home with the patient along with contact information if problems arise. The following points should be included in compression instructions:

- If the patient experiences pain, tingling, or numbness in his/her foot or toes, if swelling develops, or if the toes become a blue/gray color, the compression should be removed immediately. If the tingling, numbness, pain, or discoloration continues after the compression is removed, the patient should return to the wound clinic or go to the emergency room.

- Patients should not stand or sit in the same position for more than 30 minutes without moving.

- Patients should be advised to keep the legs raised above the level of the heart as much as possible to decrease swelling.

- The compression wraps should be kept dry and clean. When showering, compression bandaging should be completely protected in a waterproof covering; baths may be preferred. If a compression wrap or Unna boot does get wet or damaged, it should be removed. If a wound is present, it should be covered with a clean dressing and the patient's physician or clinic should be contacted.

Compression Stockings

Comfortable compression stockings are effective in preventing the reoccurrence of venous ulcers and improving patient quality of life [10]. Patients should be advised to wear gradient elastic compression stockings, which provide more compression in the foot, with reduced levels of pressure moving up the leg [10]. Usually, the physician will recommend the best level of compression for the patient. The patient's legs should be measured at the ankle and calf level by a trained clinician to ensure that the stockings fit correctly.

Compression stockings are available in most large stores or pharmacies or mail ordered from several companies and can be worn with the patient's normal footwear. Patients and caretakers should be advised to buy at least two pairs of stockings to facilitate washing and drying. Manufacturer instructions should be followed for washing, but in most instances, hand-washing and air-drying are preferred. Lower levels of compression are better than no compression at all or stockings that are "left in the drawer" [9]. However, patients should be informed that nonmedical support hosiery and anti-embolism stockings (with a pressure gradient of 8–18 mm Hg) are not suitable for compression therapy and were not made for this purpose [5].

The major drawback is that people may find it difficult to don the stockings independently, especially if they have arthritis or neurologic deficits. There are stockings available with a side zipper that makes them easier to apply and remove, although they may be more expensive. It is also possible to purchase an inner silk lining sleeve to facilitate sliding the compression stocking on and off. Several brands of compression stockings also come with a wide band at the top, which provides a better grip [10]. Some people find that wearing rubber gloves helps to get the stockings on easily, but others do not find this helpful.

Compression stockings have been described as "operator dependent," meaning they must be worn to be effective [10]. It should be emphasized to patients and caregivers that compression therapy is a lifetime commitment. Many patients may mistakenly believe that the stockings are only worn until swelling is abated, but all at-risk patients should continue to use them.

Patients and their families should also be educated about the correct use of compression. Compression stockings should be put on first thing in the morning, before the patient gets out of bed; patients should not wait until swelling is noticed to apply the stockings. It is not advisable to apply moisturizing lotion to the legs just before putting on the stockings, as this makes the skin sticky and can make it more difficult to get the stockings on [10].

Compression stockings should be replaced about every six months to maintain maximal level of compression. It is important to note that Medicare and most private insurances will only cover the cost of compression stockings if a venous ulcer is present; there is no reimbursement for compression therapy to prevent the reoccurrence of venous ulcers.

PENTOXIFYLLINE

Pentoxifylline (Trental), a derivative of xanthine, is an effective adjunct in the treatment of venous disease. It reduces blood viscosity and platelet adhesion and aggregation and increases fibrinolytic activity and microcirculation [11,28]. When pentoxifylline is used in conjunction with compression, the healing rate of venous ulcers is significantly increased [37]. The recommended (off-label) dosage is 400 mg three times daily, and common side effects include nausea, gastrointestinal disturbances, dizziness, and headache [11,28].

HORSE CHESTNUT SEED OIL

Horse chestnut seed oil has also been suggested to manage edema and relieve itching and other symptoms of chronic venous insufficiency, such as leg heaviness and pain [5]. The active ingredient in this herbal preparation is escin, a triterpenic saponin [38,39]. Meta-analyses of horse chestnut seed extract (available as an oral tincture, tablets, or topical gel) have found that it is superior to placebo in reducing leg pain, edema, leg volume, leg circumference, and pruritus, but no differences were found when compared with traditional therapies (e.g., compression) [38,40]. Potential adverse effects are typically mild (nausea, dizziness, headache), making horse chestnut seed extract a potentially attractive option for patients. However, the available evidence is limited, and larger randomized controlled studies are necessary to confirm the efficacy [38].

BIOENGINEERED THERAPY

Bioengineered therapy in conjunction with compression therapy is an option for the treatment of venous ulcers that have not healed after 30 days [30]. Single-layered and bilayered bioengineered skin cellular substitutes do not provide a graft covering to the wound, but rather donate multiple growth factors to the wound bed to stimulate healing [24]. The Wound Healing Society states that bilayered artificial skin in conjunction with compression therapy is better than compression and a simple dressing [41].

ULTRASOUND THERAPY

Low-frequency ultrasound therapy may be considered when wound healing fails to progress after four weeks of standard care [42]. In one clinical trial, this treatment decreased healing times for venous ulcers compared with usual care [30]. However, a systematic review of several studies showed no clear evidence that ultrasound therapy increased healing rates, and researchers indicated that most evidence is rated as low or very low quality due to risk of bias and imprecision [48]. The assumed mechanism of action involves improvements in the microenvironment of the wound [30]. To date, there is no established standard for ultrasound therapy in the treatment of venous leg ulcers, but limited studies indicate that a minimum of two to three sessions per week is necessary in order to see results [42].

OPENING CLOSED WOUND EDGES

In full thickness wounds, the process of re-epithelialization occurs only from the wound edges, and undermining, tunneling, or rolled wound edges can inhibit wound healing. The simplest way to open closed wound edges is the treat them with silver nitrate sticks, known as AgNO3 cauterization. This requires a physician's order and is achieved by rolling the moistened tip of a silver nitrate stick along the wound edge, which causes it to turn a grayish color and to slough off over several days [18]. Subsequent treatments may be necessary to open the complete circumference of the wound edges. A topical anesthetic may be applied 15 minutes prior to beginning the silver nitrate treatment in order to prevent associated pain [18].

SURGICAL TREATMENT OF VENOUS INSUFFICIENCY

The goal of surgical treatment of venous insufficiency is to either remove or permanently close non-working veins. There is some debate of whether venous surgery increases the healing rate of existing venous ulcers, but it has been proven to decrease the rate of ulcer reoccurrence, and it is considered definitive treatment for chronic venous insufficiency. One of the most problematic issues with venous ulcers is the reoccurrence rate, which can be more than 40% [2]. As such, prevention of ulcer occurrence is one of the most important aspects of treating venous insufficiency.

Venous Stripping

In the past, venous stripping was regarded as the "gold standard" for treatment for venous insufficiency. During this procedure, the problematic vein is removed through small incisions in the patient's leg [19]. This results in elimination of venous reflux and stasis and eradication of the bulging vein [43].

Most commonly, venous stripping removes the saphenous vein. The procedure may be done with local or general anesthesia. A small incision is made in the groin, and second incision is made close to the knee. A wire stripper is inserted to disconnect the vein at both locations and remove the vein from its location [43]. Tiny incisions are made along the length of the patient's leg in areas where there are bulging veins to facilitate removal of tributary varicose veins that were not directly attached to the saphenous vein [43]. The patient's leg is then wrapped in compression bandages from the ankle to the thigh to decrease pain and minimize bruising. This compression is maintained in place for several days [43].

Other Approaches

Over the past decade, other procedures, such as venous ablation and foam sclerotherapy, have become popular in the treatment of venous disease, in many cases replacing venous stripping as the treatment of choice. These procedures are minimally invasive and result in less pain for the patient [21].

Venous Ablation

Venous ablation uses laser technology to destroy the inner lining of the saphenous vein and prevent blood flow. The procedure is done under local anesthesia, requires fewer incisions, and allows for a faster return to regular activities. It has a success rate of more than 90% [43].

Another option is adhesive ablation, which uses a cyanoacrylate glue to occlude the vein [46]. This approach minimizes adverse effects, as it is non-thermal and non-tumescent.

Foam Sclerotherapy

Foam sclerotherapy may also be used to treat venous insufficiency. Ultrasound guidance is used to navigate a needle filled with the sclerosant drug and air (microfoam) to the appropriate location, where the mixture is injected directly into the vein [43]. This results in scarring of the inside of the saphenous vein and blocked circulation. It is done as an outpatient procedure and can be repeated, if needed.

Subfascial Endoscopic Perforator Surgery

Subfascial endoscopic perforator surgery (SEPS) is a minimally invasive procedure that alleviates perforator disease, which is characterized by perforator vein incompetence and resultant venous reflux. The procedure involves disconnection of abnormal perforator veins. In addition to improving venous sufficiency, SEPS may increase venous ulcer healing when used along with compression therapy [5,30]. SEPS has low rates of infection and is instrumental in reducing ulcer reoccurrence [30].

LOCAL WOUND CARE

General principles of wound care should be implemented when treating a venous ulcer. Ulcers should be cleaned when first diagnosed and then with every dressing change. The purpose of wound cleaning is to remove nonadherent debris from the wound bed in order to promote healing and make the wound less susceptible to bacterial overgrowth and infection. While cleaning the wound, it is necessary to minimize trauma to the wound bed and healthy tissue.

If debridement is needed, for example, if infection is present, sharp surgical debridement under local anesthesia is in most instances the best option. Depending on the size of the wound this can be done either in the outpatient wound clinic or in the surgical center. Regular (weekly) debridement is routinely done to maintain the wound in a healing state and to prevent the build-up of biofilm on the wound surface.

Wound dressings are a pivotal aspect of wound care. Dressings insulate the wound from the external environment, provide a barrier to prevent infection, maintain a moist environment, wick fluid from areas of tunneling, and absorb drainage [18]. Ideally, a wound dressing should also provide for gaseous exchange, allowing oxygen, carbon dioxide, and water vapor to pass in and out through the dressing [7].

Several wound dressing options are available. Bacterial colonization and infection are frequently found in venous ulcers, and antimicrobial dressings such as cadexomer iodine have showed good results in treating these wounds. Oral antibiotics are only indicated when cellulitis is present.

Silver dressings are a good choice and work well under compression. Foam dressings have been shown to reduce pain and decrease leakage and wound odor. While these dressings can be applied under compression, thicker versions (4–7 mm) may cause indentations at the foam edge [5,42]. Tapering the edges of foam dressings may help ameliorate this problem.

Availability and cost should also be kept in mind when selecting a dressing. Certain dressing types may not be covered by private insurances or Medicare.

7. SKIN CARE

Increased swelling in the affected leg causes small slits and breaks in the skin, often with copious amounts of weeping. Skin care can help prevent breaks in the skin, but it can also introduce additional risks in some patients. Patients with venous ulcers are particularly susceptible to contact reactions, and even topical antibiotics can cause sensitivity reactions in susceptible patients. Other products associated with stasis dermatitis include creams and gels containing lanolin and perfumes [5]. Care should be taken when choosing and applying topical lotions and medications to avoid the possibility of allergic reactions and the development of contact dermatitis, as this significantly increases the risk of venous ulceration [26].

Maintaining skin cleanliness and moisturizing frequently can protect skin integrity. The skin should be cleaned with water and a gentle soap, preferably a pH-balanced cleanser. Alkaline products remove skin lipids, which increases water loss and weakens the barrier function of the skin. Hot water for bathing and scrubbing and using harsh cleaning agents should also be avoided. A soft cloth should be used to pat rather than rub the skin dry. The nurse or physician should be notified of any redness, discoloration, or skin breakdown.

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

8. PATIENT AND FAMILY EDUCATION

It is not uncommon for individuals with venous disease to delay seeking treatment, often due to misconceptions regarding their condition. Many people believe that their symptoms are not serious enough to warrant medical attention. Patient will frequently treat wounds at home for weeks, and sometimes months, before seeking medical care. But this can lead to an increased risk of non-healing and difficult-to-heal venous ulcers. Varicose veins are often regarded as a cosmetic problem—an unsightly consequence of aging, but not a threat to well-being. These myths can be successfully addressed through patient education.

Most people are not aware that without treatment venous insufficiency will progress and can have debilitating consequences. Men are more likely than women to present with advanced stages of venous disease because they are less likely to seek early treatment for lower extremity pain and swelling [18].

Patients with venous ulcers and their caregivers should be taught how to assess the wound with each dressing change done in the home. This should include the signs of wound infection, such as changes in the amount of wound drainage, odor, and the color of the wound bed (e.g., changing from a bright red to a dark ruddy color). Changes in the periwound area, including alterations in appearance, swelling, tenderness, and pain level, are also important to note. The occurrence of any of these symptoms should prompt the patient and/or caregiver to contact his or her physician immediately.

An honest discussion should be held with the patient and significant others about what treatment is going to entail, including the necessity for weekly visits to the wound clinic for debridement and dressings changes. If a patient has difficulty keeping appointments, treatment will not be successful and healing may not be achieved.

It is vital to listen carefully to patients' concerns about treatment. Patients may be worried about missing work, transportation to appointments, wound care at home, and/or the cost of supplies. All members of the team caring for the patient should be aware of the concerns and support the patient to explore solutions. The input of the team social worker and/or case manager is particularly important at this time.

Many individuals with venous disease do not have sufficient knowledge to manage their condition successfully in the long term. The focus should be extended beyond wound healing and to making changes to maintain a healthy lifestyle. If a patient smokes, the benefits of smoking cessation for wound healing should be discussed. Weight management, safe exercise (e.g., walking), and prevention of trauma to the lower extremities should be explored with the patient/family. Concrete suggestions are better than general recommendations. For example, a patient may be instructed to take a brisk walk every day, not to cross his/her legs, and not to stand for more than 30 minutes at a time.

For patients who are unable to walk, an alternative exercise is sitting in a rocking chair and using the feet to push back while rocking steadily. This helps to increase calf muscle pump function and also provides ankle flexion exercise [5]. Non-ambulatory patients should be encouraged to do this several times per day.

More attention is now being paid to the impact that venous disease and especially venous ulcers have on the quality of life for patients. Those with venous disease often have a less favorable perception of their overall health status than those who do not have venous problems, especially if edema and changes in skin texture are present [22]. Patients with venous ulcers report having less vitality, and leg pain may cause isolation and depression. Financial concerns related to treatment and care are a major source of worry and anxiety for many patients. Interestingly, successful healing of a venous ulcer does not always lead to a patient reporting an improvement in perceived quality of life [22].

Questions related to quality of life issues should be included in the initial patient assessment and with all follow-up visits. Inquiries should be specific and directed to what, if any, changes venous disease and venous ulceration (if present) have necessitated in their usual daily activities, including work, recreational activities, and social interactions [22].

9. CONCLUSION

As clinicians and educators, nurses play a vital role in the care of patients with venous disease and venous ulcers. We are ideally placed to build therapeutic relationships with patients that can translate into more positive healing outcomes.

Works Cited

1. Weller CD, Buchbinder R, Johnston RV. Interventions for helping people adhere to compression treatments for venous leg ulceration. Cochrane Database Syst Rev. 2013;(9):CD008378.

2. Van Hecke A, Beeckman D, Grypdonck M, Meuleneire F, Hermie L, Verhaeghe S. Knowledge deficits and information-seeking behavior in leg ulcer patients: an exploratory qualitative study. J Wound Ostomy Continence Nurs. 2013;40(4):381-387.

3. Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 15th ed. New York, NY: John Wiley & Sons Inc.; 2016.

4. Veinscreening.com. History of Veins and Venous Disease. Available at http://www.veinscreening.com/history-veins-venous-disease. Last accessed January 29, 2020.

5. Kelechi TJ, Johnson JJ, WOCN Society. Guideline for the management of wounds in patients with lower-extremity venous disease: an executive summary. J Wound Ostomy Continence Nurs. 2012;39(6):598-606.

6. Meissner MH. Lower extremity venous anatomy. Semin Intervent Radiol. 2005;22(3):147-156.

7. Sussman C, Bates-Jensen B (eds). Wound Care: A Collaborative Practice Manual for Health Professionals. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.

8. Burnand KG, Wadoodi A. Physiology of venous insufficiency. In: Gloviczki P, Dalsing MC, Eklof BG, Moneta GL, Wakefield TW (eds). Handbook of Venous Disorders: Guidelines of the American Venous Forum. London: Hodder Arnold; 2009.

9. Krasner DL (ed). Chronic Wound Care: The Essentials. Malvern, PA: HMP Communications LLC; 2014.

10. Moneta GL, Partsch H. Compression therapy for venous disorders and venous ulceration. In: Gloviczki P, Dalsing MC, Eklof BG, Moneta GL, Wakefield TW (eds). Handbook of Venous Disorders: Guidelines of the American Venous Forum. London: Hodder Arnold; 2009.

11. Collins L, Seraj S. Diagnosis and treatment of venous ulcers. Am Fam Phys. 2010;81(8):989-996.

12. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2014;130(4):333-346.

13. Wipke-Tevis DD, Sae-Sia W. Management of vascular leg ulcers. Adv Skin Wound Care. 2005;18(8):437-445.

14. Ruckley CV, Evans CJ, Allan PL, Lee AJ, Fowkes FG. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg. 2002;36(3):520-525.

15. Lee AJ, Robertson LA, Boghossian SM, et al. Progression of varicose veins and chronic venous insufficiency in the general population in the Edinburgh Vein Study. J Vasc Surg Venous Lymphat Disord. 2015;3(1):18-26.

16. Criqui MH, Jamosmos M, Fronek A, et al. Chronic venous disease in an ethnically diverse population: the San Diego Population Study. Am J Epidemiol. 2003;158(5):448-456.

17. Dua A, Desai SS, Heller JA. The impact of race on advanced chronic venous insufficiency. Ann Vasc Surg. 2016;34:152-156.

18. Doughty D, McNichol L. Wound, Ostomy and Continence Nurses Society Core Curriculum: Wound Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.

19. Asbjornsen C. Medical Overview of Venous Disease. Available at https://www.veinhealthcarecenter.com/physician-information.php?Medical-overview-of-venous-disease-2. Last accessed January 29, 2020.

20. Association for the Advancement of Wound Care. Venous and Pressure Ulcer Guidelines. Available at https://www.o-wm.com/article/association-advancement-wound-care-aawc-venous-and-pressure-ulcer-guidelines. Last accessed January 29, 2020.

21. Scovell S. Overview and Management of Lower Extremity Chronic Venous Disease. Available at https://www.uptodate.com/contents/overview-of-lower-extremity-chronic-venous-disease. Last accessed January 29, 2020.

22. Mathes BM. Clinical Manifestations of Lower Extremity Chronic Venous Disease. Available at https://www.uptodate.com/contents/clinical-manifestations-of-lower-extremity-chronic-venous-disease. Last accessed January 29, 2020.

23. Hoffmann WH, Toonder IM, Wittens CHA. Value of the Trendelenburg tourniquet test in the assessment of primary varicose veins. Phlebotomy. 2004;19(2):77-80.

24. Kimmel HM, Robin AL. An evidence-based algorithm for treating venous leg ulcers utilizing the Cochrane Database of Systematic Reviews. Wounds. 2013;25(9):242-250.

25. American College of Phlebology. Practice Guidelines: Treatment of Superficial Venous Disease of the Lower Leg. Available at https://www.phlebology.org/wp-content/uploads/2014/10/SuperficialVenousDiseaseGuidelines.pdf. Last accessed January 29, 2020.

26. WOCN Wound Committee. Ankle brachial index: quick reference guide for clinicians. J Wound Ostomy Continence Nurs. 2012;39(2S):S21-S29.

27. Hettrick H. The science of compression therapy for chronic venous insufficiency edema. J Am Col Certif Wound Spec. 2009;1(1): 20-24.

28. Parsa H, Zangivand AA, Hajimaghsoudi L. The effect of pentoxifylline on chronic venous ulcers. Wounds. 2012;24(7):190-194.

29. Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg. 2004;40(6):1248-1252.

30. Gibbons GW, Orgill DP, Serena TE, et al. A prospective, randomized, controlled trial comparing the effects of noncontact, low-frequency ultrasound to standard care in healing venous leg ulcers. Ostomy Wound Manage. 2015;61(1):16-29.

31. Baranoski S, Ayello EA. Wound Care Essentials: Practice Principals. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015.

32. Bryant RA, Nix DP. Acute and Chronic Wounds: Current Management Concepts. 5th ed. St. Louis, MO: Mosby Elsevier; 2015.

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

34. van den Bremer J, Moll FL. Historical overview of varicose vein surgery. Ann Vasc Surg. 2010;24(3):426-432.

35. Taradaj J, Franek A, Blaszczak E, et al. Using physical modalities in the treatment of venous leg ulcers: a 14-year comparative clinical study. Wounds. 2012;24(8):215-226.

36. Paul JC, Pieper B, Templin TN. Itch: association with chronic venous disease, pain and quality of life. J Wound Ostomy Continence Nurs. 2011;38(1):46-54.

37. Worley CA. "It hurts when I walk:" venous stasis disease—differential diagnosis and treatment. Dermatol Nurs. 2006;18(6):582-583.

38. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev. 2012;11:CD003230.

39. Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency: a criteria-based systematic review. Arch Dermatol. 1998;134(11):1356-1360.

40. Suter A, Bommer S, Rechner J. Treatment of patients with venous insufficiency with fresh plant horse chestnut seed extract: a review of 5 clinical studies. Adv Ther. 2006;23(1):179-190.

41. The Wound Healing Society. Chronic Wound Care Guidelines. Available at https://woundheal.org/Publications/WHS-Wound-Care-Guidelines.cgi. Last accessed January 29, 2020.

42. Al-Muhairi A, Phillips T. Surgical pearl: a wound dressing tip for venous ulcers. Wounds. 2006;18(6):158-161.

43. Bradbury SW, Lambert AD, McLafferty RB, Ruckley CV. Chronic venous insufficiency presentation. In: Gloviczki P, Dalsing MC, Eklof BG, Moneta GL, Wakefield TW (eds). Handbook of Venous Disorders: Guidelines of the American Venous Forum. London: Hodder Arnold; 2009.

44. O'Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2012;11:CD000265.

45. Vasudevan B. Venous leg ulcers: pathophysiology and classification. Indian Dermatol Online J. 2014;5(3):366-370.

46. Lam YL, De Maeseneer M, Lawson J, De Borst GJ, Boersma D. Expert review on the VenaSeal system for endovenous cyano-acrylate adhesive ablation of incompetent saphenous trunks in patients with varicose veins. Expert Rev Med Devices. 2017;14(10):755-762.

47. Almeida JI, Wakefield T, Kabnick LS, et al. Use of the clinical, etiologic, anatomic, and pathophysiologic classification and Venous Clinical Severity Score to establish a treatment plan for chronic venous disorders. J Vasc Surg Venous Lymphat Disord. 2015;3(4):456-460.

48. Cullum N, Liu Z. Therapeutic ultrasound for venous leg ulcers. Cochrane Database Syst Rev. 2017;(5):CD001180.

Evidence-Based Practice Recommendations Citations

1. Guideline Subcommittee of the European Dermatology Forum. Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers. J Eur Acad Dermatol Venereol. 2016;30(11):1843-1875. Available at https://onlinelibrary.wiley.com/doi/10.1111/jdv.13848. Last accessed February 14, 2020.

96962 • Opioid Use Disorder

Mark Rose, BS, MA, LP

www.netce.com

Copyright © 2018 NetCE, All rights reserved.

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the opioid-addicted patient; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of prescription opioid abuse and dependence (i.e., OxyContin and Vicodin) will be addressed. The actual liability of abuse and dependence of legitimately prescribed prescription opioids will be conveyed.

Table of Contents

96962 • Opioid Use Disorder

Course Overview

Audience

Course Objective

Learning Objectives

Faculty

Faculty Disclosure

Division Planners

Division Planners Disclosure

About the Sponsor

Disclosure Statement

1. INTRODUCTION

2. DEFINITIONS

3. BACKGROUND

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

DEMOGRAPHICS OF ILLICIT OPIOID USERS

GEOGRAPHIC PATTERNS OF MISUSE

RISK FACTORS FOR OPIOID USE DISORDER

EPIDEMIOLOGY OF OVERDOSE

5. CLASSIFICATION

6. OPIOID SYNTHESIS

7. PHARMACOLOGY

ENDOGENOUS OPIOID PEPTIDES

OPIOID RECEPTORS

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

8. CLINICAL EFFECTS

ANALGESIA

EFFECT ON MOOD AND REWARD

NEUROENDOCRINE SYSTEM

RESPIRATION

GASTROINTESTINAL TRACT

CARDIOVASCULAR SYSTEM

OTHER EFFECTS

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

MIXED AGONISTS/ANTAGONISTS

OPIOID ANTAGONISTS

10. NATURAL HISTORY OF OPIOID DEPENDENCE

INITIATION

CONTINUATION

DETOXIFICATION AND WITHDRAWAL

RELAPSE FOLLOWING SUSTAINED ABSENCE

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

OPIOID DEPENDENCE

12. EFFECTS OF OPIOID USE DISORDER

INFECTIOUS DISEASE

ENDOCRINE/METABOLIC EFFECTS

NEUROCOGNITIVE EFFECTS

13. OPIOID OVERDOSE

RISK FACTORS

SYMPTOMS

14. OPIOID WITHDRAWAL

ACUTE OPIOID WITHDRAWAL

PROTRACTED WITHDRAWAL

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

DEVELOPMENT OF DEPENDENCE

16. MANAGEMENT OF OPIOID USE DISORDER

CRISIS INTERVENTION

HARM REDUCTION

DETOXIFICATION AND WITHDRAWAL

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

ACUPUNCTURE

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

ASSESSMENT

TREATMENT APPROACH

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

18. OPIOID USE DURING PREGNANCY

HEROIN

METHADONE

BUPRENORPHINE

OXYCODONE

NALTREXONE

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

20. CONCLUSION

21. GLOSSARY

Works Cited

Evidence-Based Practice Recommendations Citations

96962 • Opioid Use Disorder

Education Category. Psychiatric / Mental Health

Release Date. 04/01/2018

Expiration Date. 03/31/2021

Course Overview

Morphine and heroin were first synthesized and used medicinally in the nineteenth century, and recreational and illicit use followed. Historically, heroin dependence has been difficult to treat successfully, with poor outcome being attributed to patient characteristics, environmental factors, and the powerful reinforcing effects of the drug. Agonist-replacement therapy was introduced 40 years ago and represented a breakthrough in the management of heroin addiction. Advances in treatment have included newer pharmacotherapies, psychosocial therapy, and the growth and accessibility of 12-step programs such as Narcotics Anonymous. This course will provide the most pertinent, up-to-date information regarding the characteristics of the opioid-addicted patient; the mechanism of opioid action and the neurobiology of opioid addiction; the epidemiology, diagnosis and risk factors of opioid abuse and dependence; and pharmacologic, psychosocial, 12-step/self-help, and alternative therapies that are effective in treating opioid use disorders. Additionally, the demographics, characteristics, comorbidity and treatment of prescription opioid abuse and dependence (i.e., OxyContin and Vicodin) will be addressed. The actual liability of abuse and dependence of legitimately prescribed prescription opioids will be conveyed.

Audience

This course is designed for medical and mental healthcare providers, including physicians, nurses, psychologists, dentists, and social workers, who may be involved in identifying or treating opioid dependence.

Course Objective

The purpose of this course is to assist healthcare professionals in identifying, treating, and providing appropriate referrals to patients with opioid use disorders. Fear of creating new opioid addicts has influenced prescribing practices for decades, and this course will convey the actual risk of patient addiction to these pain-relieving drugs when used legitimately.

Learning Objectives

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

1. Define key terms associated with opioid abuse and dependence.

2. Outline the background and epidemiology of opioid use and abuse, including risk factors for misuse and dependence.

3. Describe the pharmacology and clinical effects of opioids.

4. Discuss characteristics of specific opioid drugs and opioid antagonists.

5. Review the natural history, pathophysiology, and effects of opioid abuse and dependence.

6. Identify signs and symptoms of opioid overdose and withdrawal.

7. List the issues associated with the abuse of or dependence on legitimately prescribed opioids.

8. Discuss the role of crisis intervention and harm reduction in the management of opioid abuse and dependence.

9. Identify methods of managing the detoxification and withdrawal associated with cessation of opioid abuse or dependence.

10. Discuss therapies used to maintain extended abstinence from opioids, including agonist replacement and abstinence therapies.

11. Identify common psychologic comorbidities present in opioid-dependent patients and implications for treatment.

12. Outline the effects of opioid use on fetuses and neonates and appropriate interventions for opioid-dependent pregnant women.

13. Identify factors associated with favorable/ unfavorable treatment outcome.

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

Alice Yick Flanagan, PhD, MSW

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

The purpose of this course is to provide the reader with a current, evidence-based overview of opioid use disorder and its treatment. Topics covered in this review include the history and demographics of illicit and prescription opioid abuse; risk factors, background characteristics, and comorbid conditions of opioid abusers; the pharmacology of opioid drugs; the biologic and behavioral characteristics of opioid dependence; and management of opioid dependence, including treatment of overdose, detoxification and withdrawal, agonist replacement therapy, and drug-free approaches. Additional areas of the course will be devoted to the abuse liability of prescription opioids and the impact of opioids on the fetus.

2. DEFINITIONS

A confusing aspect of the body of research on opioid abuse and dependence is the inconsistent use of important terminology that describes the nature and severity of involvement with therapeutic and illicit opioids. Misuse and misunderstanding of these concepts and their correct definitions has resulted in misinformation and represents an impediment to proper patient care. The following definitions have been proposed in an effort to encourage more correct usage of this terminology [1,2,3,4,5,6]:

- Misuse, nonmedical use: Patients' use of an opioid that departs from intended prescribing, including use for an unintended purpose, exceeding the prescribed amount, or taking the drug more frequently or for longer than prescribed.

- Abuse: Definition varies widely depending on the context, but generally means a maladaptive pattern of use with the primary intent of achieving euphoria or getting high. The Drug Enforcement Administration (DEA) defines abuse as the use of a schedule II through V drug in a manner or amount inconsistent with the medical or social pattern of a culture. The American Psychiatric Association defines abuse as "a maladaptive pattern of substance use, leading to clinically significant impairment or distress as manifested by one or more behaviorally based criteria."

- Addiction: Defined by the American Society of Addiction Medicine (ASAM) as "a primary chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing the development and manifestations." It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Addiction is also referred to as psychologic dependence.

- Dependence: This term has replaced the term "addiction" in some contexts. Opioid dependence refers to both psychologic dependence (or addiction) and physical dependence. Physical dependence consists of neurobiologic adaptation (development of tolerance) from chronic exposure.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines opioid use disorder as a problematic pattern of opioid use, leading to clinically significant impairment or distress. Opioid use disorder may be diagnosed if a patient exhibits two or more of the following [2,7]:

- Opioids taken in larger amounts or over a longer period than was intended

- A persistent desire or unsuccessful efforts to cut down or control use

- A great deal of time is spent in activities necessary to obtain, use, or recover from use

- Craving, or a strong desire or urge to use

- Recurrent opioid use resulting in failure to fulfill major role obligations at work, school, or home

- Continued use despite having persistent or recurrent social or interpersonal problems caused by or exacerbated by use

- Important social, occupational, or recreational activities are given up or reduced because of use

- Recurrent use in situations in which it is physically hazardous

- Continued use despite knowledge of having a persistent or recurrent physical or psychologic problem that is likely to have been caused by or exacerbated by use

- Tolerance

- A need for markedly increased amounts to achieve intoxication or desired effect

- A markedly diminished effect with continued use of the same amount

- Withdrawal

Note: The criteria for tolerance and withdrawal are not considered to be met for those taking opioids solely under appropriate medical supervision.

In summary, the term dependence is used to describe two separate phenomena. Pharmacologically, drug dependence is characterized by the presence of tolerance and a withdrawal syndrome. Psychiatrically, drug dependence is characterized by compulsive use, inability to reduce use, preoccupation, drug-seeking behaviors, and a heightened vulnerability to relapse after abstinence [8].

Pseudoaddiction describes drug-seeking behaviors iatrogenically produced in pain patients by inadequate pain treatment. This is manifested as preoccupation with and pursuit of opioid medication driven by a desire for pain relief, not the drug's mood-altering effects. Pseudoaddiction develops in three phases. Initially, the patient receives an inadequate level of analgesia, which leads to the patient's escalation of analgesic demands and behavioral changes. This may be exaggerated to convince others of the pain severity and need for more medication, which results in a crisis of mistrust between the patient and the healthcare team. Pseudoaddiction is preventable when the patient's report of pain is accepted as valid [1,3,4,5].

3. BACKGROUND

The first reference to opium is found in the 3rd century BCE. The use of opium was well-understood by Arab physicians, and Arab traders introduced the drug to Asia, where it was utilized primarily for the control of dysentery [9].

The isolation of morphine from opium was achieved in 1806 and was named for Morpheus, the Greek god of dreams [9]. The discovery of other alkaloids in opium followed: codeine in 1832 and papaverine in 1848. By the mid-nineteenth century, pure alkaloids were used in medical practice in place of crude opium preparations [9].

In addition to the highly beneficial therapeutic effects, the toxic side effects and addictive potential of opioids have been known for centuries. These undesired effects have prompted a search for a potent synthetic opioid analgesic free of addictive potential and other complications. However, all synthetic opioids introduced into medical use share the same liabilities of the classical opioids. The search for new opioid therapeutics has resulted in the synthesis of opioid antagonists and compounds with mixed agonist-antagonist properties, such as buprenorphine, which has expanded therapeutic options and provided the basis of expanded knowledge of opioid mechanisms [9].

Nonmedical use of prescription opioids was reported in literature as early as 1880. A report in 1928 documented that injection of opioids contributed to the development of nonmedical use and misuses of prescription opioids. Before 1930, the prevalence of nonmedical opioid injecting in the United States was low. But by the mid-1940s, more than one-half the admissions to the National Institute of Mental Health's Lexington Hospital were for the misuse of prescription opioids [10].

4. EPIDEMIOLOGY OF OPIOID USE DISORDER

As of 2015, the estimated worldwide prevalence of past-year opioid use was 35 million people [11]. In 2015, an estimated 12 million people in the United States had misused prescription opioids in the past year and 6.5 million had done so in the past month [11]. With only 4.5% of the world's population, the United States annually consumes more than 80% of all opioid supplies, including [12]:

- 99% of all hydrocodone

- 78% of all oxycodone

- 57% of all methadone

- 51% of all hydromorphone

- 43% of all meperidine

- 31.5% of all fentanyl

Substantial regional differences in abuse patterns exist. In the majority of Europe, Africa, and Asia, heroin is the most prevalent illegally consumed opioid. In the Americas and Oceania (Australia and New Zealand), illegally diverted or misused prescription opioids (e.g., codeine, hydrocodone, morphine, hydromorphone, oxycodone, meperidine) are the primary opioids of abuse. However, some African and Asian nations have reported a surge in prescription opioid abuse in the last decade, and there is growing evidence of the nonmedical use of opioids, specifically tramadol, in some countries in the Near and Middle East [11,13]. Traditional opium-cultivating countries and their neighbors contain the majority of raw opium users. Although comprising less than 5% of the world population, Americans consume roughly 80% of the global opioid supply [14,15].

The Drug Abuse Warning Network (DAWN) was established in 1972 by the DEA to track and publish data collected from participating states on emergency department (ED) visits resulting from substance misuse or abuse, adverse reactions, drug-related suicide attempts, and substance abuse treatment [16]. By its final year in 2011, DAWN had collected data from metropolitan areas in 37 states, with complete coverage in 13 states. Although their total figures did not capture all 50 states, the population rates were representative and able to be extrapolated to the United States as a whole [16].

Data from the DAWN network indicates that opioid abuse is a growing problem in the United States. In 2011, the overall admission rate for misuse or abuse of opioid analgesics (excluding adverse reactions) was 134.8 per 100,000, an increase of 153% compared with 2004. In the 13 states involved in the DAWN network, the top four opioid analgesics involved in drug-related ED visits for 2011 were various formulations of oxycodone (175,229), hydrocodone (97,183), methadone (75,693), and morphine (38,416). Between 2004 and 2011, ED admissions increased 74% for methadone, 220% for oxycodone, 96% for hydrocodone, and 144% for morphine. Heroin-related emergency department episodes increased from 213,118 in 2009 to 258,482 in 2011 [17]. There was no meaningful change in ED admission rates involving opioid analgesics between 2009 and 2011 [16]. However, from July 2016 to September 2017, across 52 jurisdictions in 45 states, there were more than 140,000 suspected opioid-involved overdose ED visits, a nearly 30% increase during the period. The increases were observed across both sexes (30% in men and 24% in women) and all age groups, with the greatest increase (36%) occurring in those 35 to 54 years of age [18].

Although prescription opioid abuse decreased by approximately 12% between 2010 and 2011, heroin use increased. There were 119,000 total users in 2003, but 281,000 by 2011 and 669,000 by 2012 [19]. In addition, first-time past-year use increased significantly between 2006 (90,000) and 2012 (156,000), with the greatest increases among young adults 18 to 25 years of age [19]. In 2016, an estimated 11.8 million people in the United States 12 years of age or older reported past-year use of heroin and 3.6 million reported past-month use [20]. According to the National Survey on Drug Use and Health, there were 171,000 new heroin users older than 12 years of age in 2016 [20]. Most new users are male and older than 18 years of age. In 2016, an estimated 636,000 persons received treatment for heroin abuse [20]. It is important to note that this survey underestimates heroin use, possibly to a substantial extent, as obtaining accurate statistics on illicit drug use is difficult [20].

According to the Monitoring the Future survey, NIDA's nationwide annual survey of drug use among the nation's 8th-, 10th-, and 12th-graders, heroin use either declined or remained relatively stable from 2014 to 2017 [21]. Lifetime heroin use (at least one use in an individual's lifetime) measured 0.7% among 8th-graders, 0.4% among 10th-graders, and .0.7% among 12th-graders; past-month use measured 0.2% among 8th-graders, 0.1% among 10th-graders, and 0.3% among 12th-graders. The survey also monitors the use of diverted opioids and shows past year oxycodone use rates at .08%, 2.20%, and 2.0%, respectively [21].

Nonmedical use of prescription opioids has caused increasing concern among law enforcement officials and regulatory, pain relief advocacy, and drug abuse organizations [22]. Between 1992 and 2003, the U.S. population increased 14%, while persons abusing opioid analgesics increased 94% and first-time nonmedical opioid analgesic users 12 to 17 years of age increased 542% [12]. The prevalence of lifetime nonmedical oxycodone use increased from 8.9% in 2003 to 10.1% in 2004 [23]. Although 2003 was the last year data was reported for total oxycodone-containing product use, based on other data it is likely that its illicit use has increased. For example, OxyContin (an extended-release formulation of oxycodone) misuse alone doubled in the last half of the 2000s. Lifetime nonmedical users of pain relievers grew from 31.8 million (13.2%) in 2004 to 34.8 million (13.7%) in 2010. During 2015 in the United States, an estimated 12.4 million (4.7%) individuals misused prescription pain relievers; 2.1 million (0.8%) initiated misuse of prescription pain relievers; and 2 million (0.8%) had a substance use disorder involving prescription pain relievers [24]. ED visits involving nonmedical use of narcotic pain relievers increased 117%, from 168,379 visits in 2005 to 366,181 visits in 2011 [25].

Among high school seniors, 2% used hydrocodone/acetaminophen (Vicodin) nonmedically in 2017, while rates were 0.7% and 1.5% among 8th- and 10th-graders, respectively [21]. More than 137 million prescriptions were written for hydrocodone-containing products in 2013, making it the most prescribed drug in the United States [26]. At least 24 million Americans have ever used a hydrocodone product illicitly. In 2014, the DEA reclassified hydrocodone-containing products from Schedule III to Schedule II of the Controlled Substances Act. Following the rescheduling, prescriptions dropped from 120 million in 2014 to 93.5 million in 2015 [27,28].

Some studies estimate that as many as 20% of individuals in the United States have used a prescription opioid for nonmedical purposes at least once during their lifetime [29,30]. In 2015, 2.9 million young adults had used an opioid medication for nonmedical purposes in the past year. This number dropped to 2.5 million in 2016 [20]. The greatest misuse was among individuals 18 to 25 years of age, and the incidence was higher in women than men of all age groups, except among those 12 to 17 years of age where the rates were similar [20]. Among persons 12 years of age or older, treatment admissions for prescribed opioid abuse have more than doubled in the last decade. In 2015, 491,000 people received past-year substance use treatment for prescription opioids. . This number decreased slightly to 453,000 in 2016 [20].

The number of new nonmedical users of the four major classes of prescription-type drugs (pain relievers, tranquilizers, stimulants, and sedatives) increased between 1991 and 2010; the largest increase occurred with pain relievers. In 1990 there were 628,000 initiates compared with 5.1 million in 2016 [20]. As of 2016, it is conservatively estimated that 1.7 million individuals are dependent on prescription pain medication for nonmedical use [20]. The number of primary treatment admissions for pain medication abuse/dependence was 718,000 in 2016 [20].

Between 2002 and 2016, lifetime nonmedical use of pain relievers increased among persons 12 years of age and older, from 29.6 million to 91.8 million [20]. In 2015, 2.1 million individuals reported using prescription pain relievers nonmedically for the first time within the last year—nearly 5,800 per day [24]. Approximately 97.5 million individuals 12 years of age or older were past-year users of prescription pain relievers in 2015 [24].

DEMOGRAPHICS OF ILLICIT OPIOID USERS

Male-to-female ratios for lifetime heroin-only users and lifetime heroin and oxycodone users show that use is higher for men than for women [20]. However, within the 65 or older age group, the proportion of female admissions reporting primary abuse of oxycodone was nearly three times that of men (7.2% vs. 2.8%) [31]. Male opioid users are more likely to also use other illicit drugs; female opioid users are more likely to also abuse other prescription drugs [32]. There is a high incidence of mood/anxiety disorders among opioid users, and this incidence is significantly greater among women than men.

In 2016, the percentages of past-year nonmedical use of pain relievers among the predominant racial and ethnic groups were [20]:

- White: 4.5%

- Hispanic or Latino: 4.3%

- Native Hawaiian or Pacific Islander: 4.2%

- American Indian/Alaska Native: 3.9%

- Black or African American: 3.9%

- Asian: 1.8%

Lifetime oxycodone-only users and lifetime heroin and oxycodone users are similarly distributed racially and ethnically, with both groups being predominantly white (66.9% and 67.8%, respectively) [24]. A small percentage of these users are black or African American, and an even smaller proportion are other minority races/ethnicities.

Past-year heroin-only users and past-year heroin and oxycodone users are predominantly 18 to 34 years of age (7% and 7.3%, respectively) [24]. Past year oxycodone-only users are more likely to be 26 years of age or older (11.2%) [24]. As of 2016, individuals 18 to 34 years of age have the highest percentage of past year (7.25%) and past month (2%) illicit pain medication use [24].

The increase in opioid analgesic abuse is particularly troubling because respiratory depression and death can result from the doses at which these agents are frequently abused, especially when mixed with other central nervous system depressants [33]. The two populations for whom prescription opioid abuse is especially problematic are adolescents, due to the uncertain implication of future dependence, and the elderly, due to the increased vulnerability to toxicity. Early exposure to opioids in adolescent users may cause neurobiologic changes and behavioral consequences that differ from adults [33].

GEOGRAPHIC PATTERNS OF MISUSE

Nonmedical use of opioid analgesics has been observed in both rural and urban areas. Small metro (4.4%), large metro (4.5%), and urbanized nonmetro (4.0%) areas have the highest percentage of past-year illicit pain medication users; however, less urbanized (4.0%) and completely rural areas (3.9%) have significant rates as well [24]. Research data also suggest a rising problem with injecting among rural opioid users, a problem more typically associated with urban drug users [10]. The Mountain (17.9%) and Pacific West (15.7%) areas have the highest percentage of lifetime users, followed by the Eastern Central South (15.5%), Eastern North Midwest (14.0%), and New England (13.9%).

RISK FACTORS FOR OPIOID USE DISORDER

Persons at heightened risk for heroin experimentation include those who abuse alcohol or marijuana, those with first-degree relatives addicted to alcohol or other drugs, and those with friends and associates addicted to heroin or at high risk of heroin experimentation [8]. Of course, not all persons who use drugs regarded as having a high liability of abuse and dependence end up becoming addicted to the drug. Among persons who try heroin, an estimated 23% develop heroin dependence, a rate comparable to cocaine but greater than marijuana [34].

The expected drug effect and the setting of use (context of administration) play important roles in the social learning of drug use. Because opioids, like other drugs that increase dopamine turnover, lead to conditional responses, the use of opioids may become conditioned to the activities of daily living. As a result, environmental stimuli become powerfully associated with opioid use, which can trigger cravings for the drug [33]. The visibility of pharmaceutical marketing and advertising of medications may also play a role by changing the attitudes towards ingestion of these agents [33]. For youth, a social learning aspect to drug use is likely, based on the modeling of drug use by adults in their families and social networks [33].

Individuals who use nonmedical prescription opioids before 13 years of age are more likely to become addicts than those who initiated use at 21 years of age or older. The odds of becoming an addict are reduced 5% each year after 13 years of age [35]. Additionally, it is a commonly held view among adolescents (27%) that prescription drugs are "much safer" than street drugs [36]. This belief is undoubtedly shared with much of the adult population and has led to the extraordinary rise in recreational prescription drug users.

Evidence Based Practice Recommendation

The Institute for Clinical Systems Improvement recommends considering screening patients for substance use disorders when there is an unclear etiology of pain.

https://www.guideline.gov/summaries/summary/50568

Last Accessed: March 21, 2018

Level of Evidence: Expert Opinion/Consensus Statement

Marked increases in prescriptions written for opioids in the United States and Internet access to prescription drugs may explain a portion of the increase in opioid use disorder. However, although Internet access is a major problem and accounts for some of the increase in opioid drug abuse, the same rate of increase has not been observed for other prescription drugs, such as stimulants, suggesting that other factors are involved [33]. Changes in the way medicine is practiced also influence prescription practices. Primary care physicians provide a greater proportion of care for pain patients rather than pain specialists, increasing the potential of diversion and abuse [33].

The increase in emergency department mentions is not solely accounted for by an increase in prescriptions; for example, from 1994–2002, fentanyl mentions increased more than 50-fold while the number of prescriptions increased only 7.2-fold. Similar excessive increases in emergency department mentions relative to prescriptions have been observed with oxycodone but not morphine or hydrocodone [33].

Risk Factors for Prescription Opioid Abuse Among Pain Patients

Long-term use of prescription opioids for chronic pain results in abuse or dependence in 2.8% to 18.9% of patients [33]. Predictors of dependence on opioid medications among pain patients include substance abuse-related diagnoses, positive toxicology for opioids, and other medical diagnoses, including diagnosis of comorbid psychiatric conditions [37]. Other patients at risk include those with idiopathic pain (no clear etiology) or high levels of psychologic distress or disability [7]. Alcoholism and other drug dependence are often viewed as contraindications for opioid medications in chronic noncancer pain.

EPIDEMIOLOGY OF OVERDOSE

Overdose is a major cause of premature death among opioid drug users. Nonfatal overdoses (defined as instances in which loss of consciousness and respiratory depression occur but are not fatal) are highly prevalent among heroin users, occurring in 50% to 70% of this population [38]. According to the ASAM and the Centers for Disease Control and Prevention (CDC), there were 20,101 overdose fatalities attributable to prescription painkillers in 2015 and 12,990 overdose fatalities attributable to heroin. Men 25 to 44 years of age had the highest heroin death rate at 13.2 per 100,000, which was an increase of 22.2% from 2014 [39,40].

Regional differences have been found in fatal drug overdose involving opioids. In 2016, the five states with the highest rates of death per 100,000 population due to overdose were West Virginia (52.0), Ohio (39.1), New Hampshire (39.0), Pennsylvania (37.9), and Kentucky (33.5) [41]. Significant increases from 2015 to 2016 were seen in the Northeast, Midwest, and South Census Regions. Twenty-six states reported statistically significant increases in drug overdose death rates from 2015 to 2016 [41].

The opioid overdose rate among women has increased faster than it has in men. From 1999 to 2015, overdose fatality increased 471% in women, compared with 218% for men. There has been an alarming increase in the rates of synthetic opioid-related deaths, which increased 850% in women between 1999 and 2015 [42]. In aggregate, women tend to possess background characteristics and opioid analgesic use patterns that may contribute to overdose vulnerability. Women are more likely to experience chronic pain, receive prescriptions for opioid analgesics, receive higher doses of opioids, and use opioids for longer periods than men. Substance use disorders involving opioid analgesics are thought to develop more rapidly in women, and women may be more likely to obtain opioid prescriptions from multiple prescribers than men [39].

Risk Factors for Heroin/Opioid Overdose

Identified risk factors for fatal heroin overdose include male gender, single status, unemployment, history of heroin dependence, no current treatment for heroin dependence, intravenous (IV) use, and concomitant use of alcohol or benzodiazepines. An unexplained and consistent finding is that victims of fatal heroin overdose are generally older, experienced users. Also, at autopsy, a large proportion of overdose fatalities have relatively low blood morphine concentrations [38]. (Heroin is rapidly metabolized into morphine once administered.) Demographic patterns among overdose fatalities suggest that polydrug use and loss of tolerance are key factors, which partially explains low blood opioid concentrations. However, this does not explain the strong association of fatal overdose with age [38].

Risk factors for prescription opioid overdose are similar to those for heroin overdose, but also include obtaining overlapping prescriptions from multiple providers/pharmacies, taking high daily doses of prescription pain relievers, self-medication, polypharmacy, living in a rural area, and mental illness [43]. Most people who abuse prescription opioids get them free from a friend or relative. However, those at highest risk of overdose (i.e., those who use the drugs nonmedically 200 or more days per year) obtain them differently. Twenty-seven percent of those at highest risk of overdose obtain opioids using their own prescriptions; 26% obtain them from friends or relatives for free; 23% purchase the drugs from friends or relatives; and 15% purchase them from a drug dealer. Individuals at highest risk of overdose are four times more likely than the average user to buy the drugs from a dealer or other stranger [44].

Risk Factors for Methadone Overdose

Historically, methadone was used primarily as pharmacotherapy for heroin addiction. During the 1990s, however, methadone gained increased acceptance for use as an analgesic, and methadone began to be prescribed to outpatients with moderate-to-severe noncancer pain. Prescribing rates soared over the next decade; comparison of methadone sales quantity between 1997 and 2007 shows an increase of 1293% [45,46]. This rising use of methadone occurred simultaneously with concerns over the abuse potential of other opioids and the search for a relatively inexpensive long-acting opioid analgesic alternative [47,48].

Since the mid-2000s, methadone has become disproportionately represented in cases of opioid analgesic fatality. Based on data showing that 70% of fatalities among those prescribed methadone occurred in the first seven days of treatment, the FDA changed the methadone labeling in 2006 to lengthen dosing intervals from every 3 to 4 hours to every 8 to 12 hours; the initial recommended dose of 2.5–10 mg was unchanged [49]. In 2008, use of the highest oral dose preparations, 40 mg, was prohibited from use in pain treatment and restricted to addiction therapy [50].

In addition to the general risk factors for opioid overdose, specific factors that contribute to methadone fatality include [50]:

- Payer policies that encourage or mandate methadone as first-line therapy

- Methadone prescribing in opioid-naïve patients

- Lack of prescriber knowledge of methadone pharmacology

5. CLASSIFICATION

Opioid broadly refers to all compounds related to opium. The term opium is derived from opos, the Greek word for "juice," as the drug is derived from the latex sap of the opium poppy Papaver somniferum. Drugs derived from opium, including the natural products morphine, codeine, and thebaine, may be referred to as opiates [9]. However, for the purposes of simplification, all compounds will be referred to as opioids throughout this course.

The narcotic analgesics can be categorized into three groups. The first group includes the natural opium derivatives (heroin, morphine, and codeine) and the semisynthetic derivatives from this group, including hydromorphone, oxymorphone, hydrocodone, oxycodone, dihydrocodeine, and buprenorphine. The two other groups are synthetic chemicals: the phenylpiperidines, including meperidine and fentanyl, and the pseudo-piperidines, including methadone and propoxyphene [51].

6. OPIOID SYNTHESIS

As noted, opium is obtained from the unripe seed capsules of the poppy plant P. somniferum. The sides of the unripe seed pod are slit, and the milky sap that emerges is dried to make powdered opium. Although raw opium contains numerous alkaloids, only a few, such as morphine, codeine, thebaine, and papaverine, have clinical utility. Because morphine synthesis is difficult, the drug is still primarily obtained from opium or extracted from poppy straw [9].

Heroin, or diacetylmorphine, is synthesized by collecting and converting powdered opium to heroin hydrochloride in clandestine laboratories [8]. Impurities in the processing, particularly in heroin from Mexico, result in some street heroin being brown in color. This type of heroin, often referred to as "black tar," is the predominant type available in the western United States. The purity of Colombian and Mexican heroin powder averages 40% to 60% [8]. From the point of entry in the United States to the consumer, heroin hydrochloride is adulterated by the addition of quinine, lactose, mannitol, dextrose, or talc at each level of distribution, to the point that bags costing $10 ("dime bags") may contain only 6% heroin hydrochloride [8].

The numerous synthetic derivatives of morphine and thebaine are made by relatively simple modifications of the molecule. Examples of this include the transformation of morphine to diacetylmorphine by acetylation at the 3 and 6 positions. The main goals of opioid structural modification are to increase the affinity for various species of opioid receptors, alter the activity of the drug from agonist to antagonist, change the lipid solubility, and alter the resistance to metabolic breakdown [9].

7. PHARMACOLOGY

Opioids have been the mainstay of pain treatment for thousands of years, exerting their effects by mimicking naturally occurring endogenous opioid peptides or endorphins [9]. Although many new opioids have been developed with pharmacologic properties similar to morphine, morphine remains the standard against which new analgesics are measured [9].

ENDOGENOUS OPIOID PEPTIDES

The endogenous opioid system is complex and subtle, with diverse functions. The system plays a sensory role, which is prominent in inhibiting response to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role evidenced by the powerful rewarding and addicting properties of opioids; and a cognitive role involving modulation of learning and memory [9].

There are three distinct families of classical opioid peptides: enkephalins, endorphins, and dynorphins. Each of these families is derived from a distinct precursor protein and has a characteristic anatomical distribution. The precursor proteins, preproenkephalin, prepro-opiomelanocortin (POMC), and preprodynorphin are encoded by three corresponding genes. The primary opioid peptide derived from POMC is beta-endorphin. The POMC precursor is also processed into the non-opioid peptides adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone (alpha-MSH), and beta-lipotropin (beta-LPH), suggesting a common precursor for the stress hormone ACTH and the opioid peptide beta-endorphin. This association indicates a shared physiologic linkage between the stress axis and opioid systems, which has been validated by the observation of stress-induced analgesia [9].

OPIOID RECEPTORS

Opioids produce their effects through activity at three major receptor subtypes: mu, kappa, and delta. These G-protein-coupled receptors are linked to adenylate cyclase. The endogenous ligands for these receptors, beta-endorphin, enkephalin, and dynorphin, are expressed heterogeneously throughout the central and peripheral nervous systems, with a distribution pattern parallel with that of opioid receptors. Opioid receptors are also found in the central respiratory centers. Functional studies have revealed substantial parallels between mu and delta receptors and dramatic contrasts between mu/delta and kappa receptors [52].

Most opioid therapeutics, and all opioids with abuse potential, are selective for mu receptors, reflecting their similarity to morphine. However, drugs that are relatively selective at standard doses can interact with additional receptor subtypes at higher doses, resulting in divergent pharmacologic profiles [9]. A large number of endogenous ligands activate a small number of opioid receptors, a pattern strikingly different from most other neurotransmitter systems, in which a single ligand interacts with a large number of receptors that have different structures and second messengers [9].

ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION

Typically, opioids are readily absorbed from the gastrointestinal tract. The more lipophilic opioids are easily absorbed through the nasal or buccal mucosa. The most lipophilic opioids can be absorbed transdermally [9]. Most opioids, including morphine, undergo variable but significant hepatic first-pass metabolism, limiting oral bioavailability relative to parenteral administration. Most opioids act quickly when given intravenously. Compared with more lipid-soluble opioids, such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate [9].

8. CLINICAL EFFECTS

Morphine and most other opioid agonists share in common the following physiologic effects [9]:

- Analgesia

- Changes in mood and reward behavior

- Disruption of neuroendocrine function

- Alteration of respiration

- Changes in gastrointestinal and cardiovascular function

ANALGESIA

Morphine-like drugs produce analgesia, drowsiness, changes in mood, and mental clouding, all without loss of consciousness. Patients in pain report that the pain is less intense, less discomforting, or entirely gone when given therapeutic doses of these drugs. The pain relief is fairly selective, and other sensory modalities are not affected. Some patients experience euphoria. When morphine in the same dose is given to a pain-free individual, the experience may be unpleasant. Nausea and vomiting is common, and drowsiness, difficulty in mentation, apathy, and decreased physical activity may occur. The subjective analgesic and toxic effects, including respiratory depression, become more pronounced as the dose is increased. Morphine-class drugs seldom cause slurred speech, emotional lability, or significant motor incoordination [9].

EFFECT ON MOOD AND REWARD

Although the mechanisms by which opioids induce euphoria, tranquility, and other alterations of mood (including rewarding properties) have not been entirely determined, the neural systems mediating opioid reinforcement are distinct from those involved in physical dependence and analgesia [53]. Behavioral and pharmacologic data point to the probable role of dopaminergic pathways, with interactions between opioids and dopamine mediating the opioid-induced reinforcement [9].

NEUROENDOCRINE SYSTEM

Morphine acts in the hypothalamus to inhibit the release of gonadotropin-releasing hormone and corticotropin-releasing hormone (CRH), which decrease circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and beta-endorphin. This in turn reduces the plasma concentrations of testosterone and cortisol [9].

RESPIRATION

Morphine-like opioids depress respiration in part through a direct effect on the brainstem respiratory centers. Therapeutic doses of morphine depress all phases of respiratory activity and possibly induce irregular and periodic breathing. Clinically significant respiratory depression seldom occurs at standard therapeutic doses. The primary mechanism of respiratory depression involves a diminished responsiveness of the brainstem respiratory centers to carbon dioxide [9].

GASTROINTESTINAL TRACT

Morphine-like drugs directly stimulate the chemoreceptor trigger zone for emesis in the area postrema of the medulla, resulting in the nausea and vomiting experienced by some patients [9]. Morphine also decreases gastric motility; diminishes biliary, pancreatic, and intestinal secretions; and delays digestion of food in the small intestine. In the colon, peristaltic waves are diminished or abolished and tone is increased to the point of spasm, delaying the passage of bowel contents [9].

CARDIOVASCULAR SYSTEM

There are no opioid receptors on the heart, so morphine does not act directly on the heart muscle. However, opioid agonists indirectly affect cardiovascular processes through suppression of reflex vasoconstriction, which may result in bradycardia and hypotension [54]. In cases of injecting use, bacterial endocarditis can develop [54].

OTHER EFFECTS

Opioid agonists may also affect reflexes, particularly swallow/cough reflexes and pupillary dilation. Morphine and related opioids depress the cough reflex by direct action on the cough center in the medulla [9]. Morphine and most mu and kappa agonists also constrict the pupils through excitation of the parasympathetic nerve stimulating the pupil [9].

9. SPECIFIC OPIOID DRUGS

FULL AGONISTS

Heroin

Heroin, or diacetylmorphine, is a highly potent, semisynthetic analgesic produced by the anhydrous acetylation of morphine. Heroin is generally believed to have no significant opioid receptor activity; however, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and then to morphine. While diacetylmorphine and 6-monoacetylmorphine readily cross the blood-brain barrier, morphine itself is much slower to do so; thus, heroin can be considered a prodrug that facilitates the brain entry of morphine [52]. The drug rapidly enters the brain after IV administration, where it binds to mu, kappa, and other stereospecific opioid-receptor binding sites in the locus coeruleus [8]. The onset of euphorigenic action is approximately 30 minutes after intranasal ingestion, 15 minutes after subcutaneous injection, and almost instantaneously after IV injection, with a duration of about three to four hours [8]. As with many other opioids, heroin reduces the anticipatory anxiety associated with emotional or physical pain and alters the perception of pain [8].

Heroin is rapidly deacetylated in the microsomes of the endoplasmic reticulum in the liver to 6-MAM, which is further deacetylated to morphine. It is excreted in the urine over a 30- to 40-hour period as free morphine and morphine 3-glucuronide [8]. Other drugs, including tricyclic antidepressants (TCAs), can inhibit the metabolism of heroin. Genetic variation in the expression of the enzymes involved in opioid metabolism and the potential for drug interactions at these sites may contribute to variation in response to heroin administration both among various individuals and within one individual [52].

The sought-after effects of heroin include intense tranquility, euphoria, analgesia, and a clouding of the sensorium, with the state of ecstasy and contentment immediately following IV injection being the most desired. Many novice heroin users experience adverse effects, such as mild nausea and vomiting. However, tolerance to these effects is soon achieved [8].

The lifestyle of the heroin addict seriously decreases life expectancy. Age-adjusted mortality rates have been found to be least seven times greater than that of the general population, adjusting for age, with death usually attributable to violence or drug effects. Also, the desire to replicate the most intense rush may compel the heroin addict to escalate the dose, resulting in acute heroin overdoses [8].

Codeine

Codeine is approximately 60% as effective orally versus parenterally as an analgesic and respiratory depressant. Several codeine analogs, such as levorphanol, oxycodone, and methadone, have a high ratio of oral-to-parenteral potency, with the greater oral bioavailability reflecting lower hepatic first-pass metabolism [9].

Approximately 10% of ingested codeine is O-demethylated to morphine. Free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, the antitussive effects of this drug may involve distinct receptors that bind codeine itself. The plasma half-life of codeine is two to four hours [9].

Codeine and promethazine syrup is the active component of the recreational drug "purple drank;" other common names include "syrup" and "lean" [55]. The combination of the purple antitussive, soft drinks, and in some cases candy has been mentioned in hip-hop music since the late 1990s and has been particularly popular in the South [55]. All opioid/soft drink concoctions may colloquially be referred to as "sizzurp."

Tramadol

Tramadol is a synthetic codeine analog and a weak mu-opioid receptor agonist. Tramadol is unusual among opioids in that a portion of its analgesic effect is produced by norepinephrine and serotonin uptake inhibition [9]. Tramadol is as effective as morphine or meperidine in the treatment of mild-to-moderate pain. It is 68% bioavailable following a single oral dose and 100% available following intramuscular administration. The affinity of tramadol for the mu-opioid receptor is only 1/6000th that of morphine. However, the primary O-demethylated metabolite of tramadol is two to four times as potent as the parent drug and may partially explain the analgesic effect. Physical dependence with tramadol has been reported [9].

Levorphanol

Levorphanol (brand name Levo-Dromoran) is the only commercially available opioid agonist of the morphinan series, and it possesses pharmacologic effects very similar to those of morphine. Levorphanol is metabolized less rapidly than morphine and has a half-life of 12 to 16 hours [9,56].

Meperidine

Meperidine is predominantly a mu-receptor agonist. This agent, available under the brand name Demerol, is no longer recommended for treatment of chronic pain due to concerns of metabolic toxicity. Meperidine should not be used for longer than 48 hours or in doses greater than 600 mg/day [56]. The central nervous system effects are similar but not identical to that of morphine. In equianalgesic doses, meperidine produces comparable sedation, respiratory depression, and euphoria as morphine. Some patients may experience dysphoria. Meperidine can cause central nervous system excitation, characterized by tremors, muscle twitches, and seizures, primarily due to accumulation of the metabolite normeperidine [1]. Large doses repeated at short intervals by addicts who have developed a tolerance to the sedative effects can produce an excitatory syndrome characterized by hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions [9]. Meperidine is primarily abused by healthcare professionals [9].

Diphenoxylate and Loperamide

Diphenoxylate (in combination with atropine as Lomotil) and loperamide (Imodium) are meperidine congeners that are approved by the U.S. Food and Drug Administration (FDA) for the treatment of diarrhea [56]. These drugs slow gastrointestinal motility by affecting the circular and longitudinal muscles of the intestine, presumably through interaction with opioid receptors in the intestine [9].

Fentanyl and Congeners

Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners (sufentanil, remifentanil, and alfentanil) are similar to those of other mu-receptor agonists. Fentanyl is a popular drug in anesthesia practice because of its relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and relative cardiovascular stability. Fentanyl is approximately 100 times more potent than morphine, and sufentanil is approximately 10 times more potent than fentanyl. These drugs are usually administered intravenously and are substantially more lipophilic than morphine. Time to peak analgesia is rapid, usually within five minutes. Respiratory depression potential is similar to other mu-receptor agonists with a more rapid onset. Fentanyl and sufentanil treatment of chronic pain has become more widespread, and transdermal patches that provide sustained release for 48 hours or more are available [9].

Fentanyl is delivered via the transdermal route for up to 72 hours, with patches containing 2.5, 5, 7.5, or 10 mg of fentanyl. Abuse of both the injectable formulation of fentanyl (Sublimaze) and the transdermal patch is primarily, but not exclusively, a problem among healthcare professionals due to availability and proximity. Fentanyl may be extracted from the patch and injected, or the patch contents may be chewed, ingested, or inhaled. Even a patch that has been used for three days contains sufficient fentanyl to be abused [1].

Methadone

Methadone was first synthesized as an analgesic in Germany during World War II as a response to the difficulty in obtaining raw opium [57]. Methadone is a long-acting mu-receptor agonist with pharmacologic properties quantitatively similar to those of morphine [9]. Methadone is well-absorbed from the gastrointestinal tract and can be detected in plasma within 30 minutes of oral ingestion. Peak concentrations occur in the brain within one or two hours of subcutaneous or intramuscular administration [9]. Oral bioavailability approaches 90% [56,57].

In contrast to heroin, the activity of methadone is due almost exclusively to the parent drug rather than its metabolites. The drug is characterized by a long, but highly variable, half-life. One of the primary elimination pathways of methadone is N-demethylation, with cytochrome P450 3A4 (CYP 3A4) the major enzyme involved [56]. Inhibition of CYP 3A4 with drugs such as ketoconazole and erythromycin may enhance and prolong the effect of methadone. Its induction with drugs such as rifampin, carbamazepine, and phenytoin will have the opposite effect [52,56]. Liver disease can increase the half-life of methadone, but renal failure will not [57]. Additionally, CYP 2D6 may be involved in the metabolism of the active enantiomer of methadone; less than 7% of white persons and more than 25% of Ethiopian persons are ultrarapid metabolizers at CYP 2D6. Individuals with this polymorphism may be more likely to experience methadone overdose [52,58].

Following absorption, methadone is distributed to the brain, liver, kidneys, muscles, and lungs. Tissue binding predominates over binding to plasma proteins, and accumulation of the drug occurs in these tissues with repeated dosing. Plasma concentrations are maintained by this peripheral reservoir. Methadone reabsorption from the tissues may continue for weeks after administration has ceased. It has an elimination half-life of about 22 hours, but metabolism varies in each person [59].

One of the most significant advantages of methadone is that it alleviates cravings for opioids (a primary reason for relapse) and blocks many of the pleasurable effects of heroin, which helps reinforce abstinence [57]. Some of the characteristic properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its ability to demonstrate persistent effects with repeated administration [9]. Accidental overdose fatalities can occur when pain patients re-administer methadone when the analgesia wears off and pain returns, potentially elevating plasma concentrations to life-threatening levels. These same pharmacologic properties also imperil those who use it illicitly. Opioid abusers often co-administer benzodiazepines, which greatly elevates lethality risk with methadone. Concurrent use of alcohol poses the same risk [47,48].

In methadone clinics, methadone is usually dispensed in prepared individual doses mixed with fruit juice to discourage IV use. Methadone is also prescribed for pain. Until recently, there had been little evidence that diversion of methadone from pain management was occurring on any substantial scale. The majority of diverted methadone is used by heroin addicts to self-medicate symptoms of opioid withdrawal. To date, there is no evidence that diversion of methadone from methadone clinics has resulted in significant numbers of new opioid addicts [1].

More frequent adverse effects associated with methadone use include sweating, decreased libido, weight gain, constipation, and irregular menstrual periods, all occurring primarily during the initial stabilization process. Uncommon side effects include facial flushing, pruritus, euphoria or dysphoria, insomnia, urinary retention, and bradycardia [56]. Rarely observed side effects include biliary spasm, urticaria, syncope, overdose death, and torsades de pointes [57]. These effects are more common at higher doses and when methadone is combined with certain other drugs [60]. Risk of QTc prolongation and arrhythmia led to a 2006 black box warning [56].

Tolerance to the opioid properties of methadone develops within four weeks. The minimal effective dose is regarded as 40 mg, but some patients require much greater doses [56,57]. Subcutaneous administration of 10-20 mg methadone to former opioid addicts unambiguously produces euphoria similar in duration and magnitude to that of morphine. Methadone's overall abuse potential is comparable to that of morphine [9].

Hydrocodone

Hydrocodone is a semi-synthetic codeine derivative first used clinically as an antitussive and analgesic in the 1920s. Following a 10-mg oral dose, maximum serum level is observed in 1.3 hours [61]. Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxymetabolites. The 2D6 enzyme demethylates hydrocodone at the 3-carbon position into hydromorphone, which has much stronger mu binding than hydrocodone. Similar to codeine, it has been proposed that hydrocodone is a prodrug. Its analgesic properties are generally considered equipotent to codeine [62,63].

Oxycodone

Oxycodone is similar in structure to hydrocodone, with the addition of a hydroxyl group at the 14-carbon. Oxycodone, as a hydrochloride salt, is a pure agonist opioid that has been in clinical use since 1917. Unlike codeine and hydrocodone, oxycodone is a potent analgesic in its own right and not a prodrug, although 2D6 activity creates the active opioid analgesic metabolite oxymorphone (synthesized and marketed as the analgesic Opana). Oxycodone is suitable for oral administration due to high bioavailability (60%) but may also be taken intramuscularly, intravenously, subcutaneously, or rectally; however, oxycodone is only commercially available in oral preparations [56]. In terms of analgesic potency and lipophilicity, oxycodone is comparable to morphine, and both drugs possess similar abuse potential. With the exception of hallucinations, which occur more rarely with oxycodone than with morphine, the side effects of these drugs are highly similar [64].

Oxycodone is metabolized by demethylation to noroxycodone and oxymorphone followed by glucuronidation [56]. A urine screen may reveal oxycodone alone, oxycodone and oxymorphone, or oxymorphone alone [65].

Since 1995, oxycodone has been marketed in the United States as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5–10 mg of oxycodone [56]. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts' interest in OxyContin [1].

In 2014, the FDA approved an extended-release version of oxycodone that is formulated to include naloxone in order to deter misuse [66]. If crushed and snorted or crushed, dissolved, and injected, the naloxone will block the euphoric effects of oxycodone, potentially deterring this type of abuse. This combination drug is intended for patients for whom alternative treatment options for chronic pain are ineffective or not tolerated [66]. The drug is no longer available in the United States [56].

Hydromorphone

Hydromorphone is a semi-synthetic hydrogenated ketone of morphine and shares the pharmacologic properties typical of mu-opioid agonists. Hydromorphone is a more potent analgesic than morphine; on a milligram basis, hydromorphone is 5 times as potent orally and 8.5 times as potent intravenously. Hydromorphone can be administered by infusion, intramuscularly, orally, or rectally [67].

Following oral administration of conventional-release hydromorphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours. The primary mode of elimination is by urinary excretion as hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromorphone itself but are unlikely to contribute to the pharmacologic activity. Side effects are comparable to morphine [67].

MIXED AGONISTS/ANTAGONISTS

Discovery of an opioid analgesic with the efficacy but not the side effects or abuse potential of mu-agonists has been the ultimate goal of analgesic research for the past 60 years [29]. Mixed agonist-antagonist compounds have been developed with the hope that they would have less addictive potential and create less respiratory depression than morphine and related drugs. However, achieving the same degree of analgesia produces a similar magnitude of side effects, and a "ceiling effect," limiting the amount of analgesia attainable, is often seen with these drugs. Also, mixed agonist-antagonist drugs (e.g., pentazocine) can produce side effects not often seen with pure agonists, including severe, irreversible psychotomimetic effects [9].

Drugs such as nalbuphine and butorphanol are competitive mu-receptor antagonists, with their kappa receptor agonist action mediating the analgesic effect. Pentazocine qualitatively resembles these drugs but is a weaker mu-receptor antagonist or partial agonist while retaining its kappa-agonist activity. Buprenorphine is a partial mu-receptor agonist [9].

Pentazocine

Pentazocine was developed in an effort to synthesize an effective analgesic with little or no abuse potential. With agonistic actions and weak opioid antagonistic activity, the pattern of central nervous system effects is similar to that of morphine-like opioids, including analgesia, sedation, and respiratory depression. Dysphoric and psychotomimetic effects can be precipitated by higher doses (60 to 90 mg) [9].

In the 1970s and early 1980s, pentazocine (Talwin) was combined with the crushed, blue-colored antihistamine tablet tripelennamine and used intravenously, known as "Ts and Blues." Factors contributing to its widespread abuse included placement outside Schedule II and the erroneous belief that the drug was not abusable. Pentazocine was also widely abused by physicians because it could be prescribed in large quantities outside the stringent Schedule II monitoring system. At one point, pentazocine abuse became so prevalent that the manufacturer contemplated removing the drug from the market. Pentazocine was ultimately reformulated by the inclusion of the opioid antagonist naloxone. Similar to buprenorphine formulations containing naltrexone, when this formulation is taken as directed, the user experiences only the pentazocine effect because of poor oral naloxone absorption. However, if the tablet is dissolved and injected, the naloxone blocks the opioid effects of the pentazocine and precipitates acute opioid withdrawal [1].

Nalbuphine

Nalbuphine is an agonist-antagonist opioid related to naloxone and oxymorphone, with a spectrum of effects that qualitatively resembles that of pentazocine but with a lower potential to produce dysphoric side effects. Although doses of 10 mg or less produce few side effects, much higher doses (70 mg) can produce psychotomimetic side effects such as dysphoria, racing thoughts, and distorted body image. Prolonged administration of nalbuphine can produce physical dependence and withdrawal [9].

Butorphanol

Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine. It is generally more suitable for the relief of acute pain than chronic pain. Major side effects include drowsiness, weakness, sweating, feelings of floating, and nausea. Although the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar. Physical dependence to butorphanol can develop from regular use [9,56].

Buprenorphine

Buprenorphine was initially suggested in 1978 as an alternative oral opioid substitution therapy for opioid addicts. Buprenorphine and methadone are the two most widely used and effective pharmacotherapies for opioid use disorder, and both have regulatory approval in the United States for this indication [68]. Buprenorphine is a semi-synthetic opioid derivative made from thebaine, one of the naturally-occurring alkaloids in opium [69]. Buprenorphine, sold as Buprenex, Subutex, Belbuca, or Sublocade, is a long-acting partial opioid agonist that is classified as a Schedule III narcotic, in contrast to methadone and LAAM, which are Schedule II [56,57,70].

Buprenorphine has a very low oral bioavailability due to substantial intestinal and hepatic metabolism. The sublingual formulation used to treat opioid dependence is well-absorbed and produces opioid agonistic effects comparable to subcutaneous administration. Maximum plasma level is achieved 70 to 90 minutes after sublingual administration, and absolute bioavailability is 35% to 50% [69]. Following absorption, buprenorphine initially accumulates in the liver, kidneys, muscular tissue, and fatty tissue. It is released from fatty tissue when the plasma level drops and is then available at the opioid receptor. The slow dissociation kinetics explains the prolonged period of effectiveness. Buprenorphine is metabolized through the hepatic cytochrome P450 pathway. Approximately 80% is eliminated through binary excretion of the glucuronidated metabolites and 20% via the urinary route [69].

The minimum daily dose needed to suppress opioid use is about 4 mg. Larger doses of buprenorphine (32 mg) result less in an increase in therapeutic effect but more in an extension of the effect, which can last for up to 48 hours [69].

In 2014, the FDA approved a buccal film containing both buprenorphine and naloxone [71]. This combination therapy is applied once daily to suppress signs and symptoms of opioid withdrawal [56]. In 2016, the FDA approved the first buprenorphine implant (Probuphine) for opioid dependence [72]. The implant provides a constant, low-level dose of buprenorphine for six months. It is designed for use in patients who are already stable on a low dose of other forms of buprenorphine, as part of a complete treatment program. Because Probuphine must be inserted and removed surgically, healthcare providers are required to complete training and certification through the Probuphine Risk Evaluation and Mitigation Strategy (REMS) program [72]. In 2017, the FDA approved a once-monthly subcutaneous injection (Sublocade) for opioid use disorder [73]. Sublocade is intended for use in adult patients with moderate-to-severe opioid use disorder who have been on a stable dose of buprenorphine treatment for a minimum of seven days. The drug must be administered in a healthcare setting to avoid inadvertent IV administration that could result in death [73].Buprenorphine use is contraindicated for patients with alcohol intoxication, delirium tremens, and treatment with monoamine oxidase inhibitors. Cases of lethal buprenorphine intoxication almost always involve polyintoxication [69]. Buprenorphine contains a black box warning regarding the potential for serious, life-threatening, or fatal respiratory depression, especially during initiation or dose escalation [56]. Upon discontinuation, a withdrawal syndrome develops, with a delayed emergence in two days to two weeks. Signs and symptoms of buprenorphine withdrawal are typical of a milder morphine-type withdrawal and last roughly one to two weeks [9]. The more benign withdrawal syndrome is due to its partial agonist property at the mu receptor and weak antagonist property at the kappa receptor [57].

OPIOID ANTAGONISTS

Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include naloxone, naltrexone, and nalmefene. Nalmefene is not approved in the United States [56]. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. Naltrexone and naloxone have little or no potential for abuse [9].

10. NATURAL HISTORY OF OPIOID DEPENDENCE

Although the time from initiation to daily use and serious physiologic and psychologic dependence is highly variable, the different stages of opioid dependence are clearly delineated [8]. These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these different processes is crucial to develop an understanding of the therapeutic strategies [13].

INITIATION

During the initiation phase, acute reinforcement of the initial drug effect is mediated by mu-opioid receptors and dopamine that inhabit the ventral tegmental area and nucleus accumbens. This results in conditioned responses and drug craving [13].

CONTINUATION

The second phase of continued drug use is characterized by diverse neurotransmitter involvement, including dopamine in the nucleus accumbens, corticotrophin-releasing hormone in the amygdala, and glutamate in the frontal-cingulate circuit. As tolerance develops, the dose and route of administration often change, with progression to IV use a frequent outcome [8].

DETOXIFICATION AND WITHDRAWAL

During detoxification and withdrawal from opioids and other central nervous system depressants, glutamate and norepinephrine in the locus coeruleus are primarily involved in causing the associated symptoms [13].

RELAPSE FOLLOWING SUSTAINED ABSENCE

Brain regions implicated in relapse to opioid use include the orbitofrontal cortex, anterior cingulate gyrus, and amygdala. Norepinephrine and corticotrophin-releasing hormones are involved in stress-induced relapse. Gamma-aminobutyric acid (GABA) and glutamate mediate brain systems that are involved in compulsive and habitual behavior and mediate cue-induced relapse [13].

11. PATHOPHYSIOLOGY

OPIOID TOLERANCE

Tolerance refers to a decrease in effectiveness of a drug with repeated administration. Tolerance to opioid effects is encountered in both the clinical use of opioids for pain relief and in recreational use of heroin [52]. Tolerance (as well as withdrawal and physiologic dependence) are expected responses to opioids and other controlled substances when given in sufficient doses over time and are not, by themselves, indicative of addiction [74,75]. Acute tolerance stems from transient administration of opioids; sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensitization may underlie the development of tolerance, probably involving phosphorylation of the mu and delta receptors by protein kinase C, protein kinase A, and beta-adrenergic receptor kinase (beta ARK). Long-term tolerance is believed to be associated with increases in adenylyl cyclase activity, a counter-regulation to the decrease in cyclic adenosine monophosphate levels [9].

The degree of tolerance can be influenced by changes in the environment in which drug use occurs. In the presence of cues previously associated with drug ingestion, tolerance is markedly enhanced, compared to the tolerance observed in a novel environment. Thus, administration of an opioid in an environment not previously associated with administration of the drug will be associated with lower tolerance and therefore a higher risk of overdose [52].

OPIOID DEPENDENCE

Opioid dependence is best described as a central nervous system disorder characterized by neurobiologic changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opioids cease to function and degenerate, causing the user to become physically dependent on exogenous opioids [76].

According to the classical theory of addiction, opioid dependence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are independent of the intensity and pattern of the physical symptoms of withdrawal [77].

Alternative hypotheses focus on the role of the mesocorticolimbic dopamine system, an anatomical pathway that originates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex [77]. Dependence on most drugs of abuse is characterized by an altered physiologic state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence [78].

Molecular Basis

The diverse biologic effects of opioids are manifested through specific opioid receptors distributed throughout the central and peripheral nervous system. Opioid receptors, upon the binding of opioid drugs (or endogenous opioid peptides), regulate a multitude of intracellular signaling pathways. Involvement of opioid receptors in opioid dependence is unequivocal. This is reliably demonstrated by the rapid precipitation of withdrawal syndromes in opioid addicts by opioid receptor antagonists such as naloxone [79].

Repeated exposure to short-acting opioids can result in durable alterations in opioid receptor kinetics, transmembrane signaling, and postreceptor signal transduction [80]. Opioid dependence requires sustained activation of opioid receptors, and this chronic signaling process ultimately leads to changes in protein functions of gene transcription [79].

Opioid receptors are members of the G-protein receptor family, and each opioid receptor uses inhibitory G-proteins for signal transduction. Opioid receptors have the capacity to interact with five different forms of G-proteins, regulating a diverse spectrum of effectors ranging from adenylyl cyclases and ion channels to mitogen-activated protein kinases. These isoform-specific and differential regulations of various classes of effectors are combined into a sophisticated signaling network that mediates opioid actions. The enormous diversity in opioid signaling stems from the array of effectors and signaling molecules that functionally interact with the G-protein beta gamma complex [79].

Prolonged administration of opioids causes molecular and cellular adaptations that rapidly develop into tolerance and dependence. An upregulation of adenylyl cyclase responsiveness, referred to as adenylyl cyclases superactivation, is a classic sign of this tissue adaptation [79].

G-protein signals lead to changes in gene expression, and opioid-induced, long-term functional alterations of the nervous system involve changes in gene expression. Many opioid-induced signals converge at the level of transcription factors, although little is known about the exact mechanisms of gene transcription in the development of opioid tolerance and dependence [79].

Mechanism of Reinforcement

Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical messengers in the brain [81]. The mesolimbic dopamine system is the likely substrate upon which opioids act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opioid mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system [77].

Opioids produce reinforcement by inhibition of the GABA neurons that normally inhibit dopaminergic neurons in the ventral tegmental area. This results in a surge of dopamine in the nucleus accumbens and other mesolimbic-mesocortical brain regions [82]. The neurochemical cascade begins with activation of mu- or kappa-opioid receptors differentially distributed on GABAergic cells in the ventral tegmental area and nucleus accumbens and dopamine terminals in the nucleus accumbens. This activation produces rewarding and aversive effects by increasing or decreasing dopamine release in the nucleus accumbens. Inhibition of medium spiny GABAergic neurons in the nucleus accumbens by dopamine and opioids can synergistically facilitate opioid reinforcement. Increases in glutamatergic afferents into the ventral tegmental area may facilitate opioid reinforcement by activating dopamine neurons. An increase in glutamate activity in the nucleus accumbens may decrease opioid action by activating nucleus accumbens GABAergic cells. Also, an increase in nucleus accumbens 5-HT by opioids modulates opioid reinforcement by activation of 5-HT1 and/or 5-HT3 receptors [77].

12. EFFECTS OF OPIOID USE DISORDER

The misuse of opioids results in several acute and long-term effects. Signs and symptoms of acute opioid intoxication include drowsiness, decreased respiration, euphoria, and impaired judgment (Table 1).

Table 1: SIGNS AND SYMPTOMS OF ACUTE OPIOID INTOXICATION

Constricted pupils (or dilated pupils with meperidine)

Euphoria

Apathy

Dysphoria

Drowsiness

Loss of consciousness

Coma

Psychomotor agitation or retardation

Decreased respiration

Decreased heart rate

Pulmonary edema

Impaired social judgment

Slurred speech

Impaired attention and memory

Impaired occupational functioning

Source: [83]

INFECTIOUS DISEASE

Infectious complications from opioid use generally stem from injection use, primarily of heroin, in which bloodborne pathogens are transmitted via contaminated needles. An estimated 60% to 90% of injection users have hepatitis C virus infection [84,85]. Other common infectious diseases include human immunodeficiency virus (HIV) and hepatitis B [8]. Common bacterial infections include Staphylococcus aureus, cellulitis and abscesses around the injection site, pneumonia, bacteremia, and endocarditis. Of HIV-positive persons in the United States, more than 33% have injected opioids and more than 25% report sharing needles with other users [10]. Injection drug users represented 4.2% of new HIV infections in 2016 and 17% of those living with HIV in 2016 [86].

ENDOCRINE/METABOLIC EFFECTS

Opioid use affects multiple endocrine functions and is associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth hormone abnormalities [87].

Hypothalamic-Pituitary-Gonadal (HPG) Axis

Opioid use has been implicated in gonadal dysfunction [88]. Central hypogonadism can result from opioid receptor activation in the vicinity of the hypothalamus. Resultant diminished secretion of gonadotropin-releasing hormone can lead to decreases in gonadotropin and testosterone levels. This effect may decrease over time secondary to the development of tolerance [87].

Metabolic Effects

Heroin use has been associated with abnormalities in glucose metabolism by multiple mechanisms. Fasting insulin levels can be substantially higher in heroin addicts than in control subjects, and insulin resistance stemming from opioid use may be coupled with beta cell dysfunction [89]. Heroin addicts often have lower acute insulin response than control patients evaluated by oral glucose tests and response to a standard meal. This blunted glucose response suggests an association between opioid use and abnormal glucose metabolism [87]. The use of highly active anti-retroviral therapy (HAART) for the treatment of HIV infection is also associated with a number of metabolic problems, including increased prevalence of insulin resistance, dyslipidemia, and changes in fat distribution. Because opioid use can also result in metabolic abnormalities, the presentation of patients who are both HIV-positive and opioid dependent may be complicated.

Chronic heroin use may also complicate dyslipidemia, evidenced by elevated total cholesterol levels, hypertriglyceridemia, decreased total cholesterol and high-density lipoprotein, and elevated triglyceride levels relative to controls [87].

Hypothalamic-Pituitary-Adrenal (HPA) Axis

Opioid addicts may also have impaired adrenal function, documented by a high prevalence of adrenal insufficiency and abnormal response to the cosyntropin test [88]. The action of heroin on neurotransmitters that regulate the secretion of corticotrophin-releasing factor, leading to disturbances in cortisol levels, has been hypothesized as the underlying pathophysiology. This is supported by the observation of lower plasma cortisol levels concurrent with depressed ACTH levels in heroin addicts [87].

In addition, chronic opioid use may contribute to low bone mineral density through reduction in lumbar bone mineral density. Growth hormone axis abnormalities are also seen in heroin addicts [87].

NEUROCOGNITIVE EFFECTS

Cognitive impairment resulting from chronic drug use may contribute to abuse and dependence in at least two ways. The first involves increasing the likelihood of drug-seeking behavior through various induced cognitive deficits, such as failure of impulse control mechanisms. The second involves the interference with users' ability to assimilate and participate in rehabilitation programs that have an educative and cognitive emphasis [90,91].

The chronic use of illicit drugs is often associated with a generalized profile of neuropsychologic deficit. However, it is thought that important differences in the patterns of interaction associated with various neurotransmitter systems, coupled with corresponding differences in the distributions of receptor subtypes, are responsible for the distinct neurocognitive effects of specific drugs of abuse [90].

Compared with marijuana and stimulants, there has been substantially less research into neuropsychologic deficits in chronic opioid abusers. Early studies found relatively little impairment in tasks involving abstraction and reasoning, leading investigators to conclude that chronic opioid use was not associated with deficient frontal lobe functioning. However, newer studies, utilizing more sensitive measures, have demonstrated that opioid abusers do possess marked deficits in frontal lobe functioning relative to healthy control subjects. These deficits may include problems with altered attentional control, altered decision making, or problems with choices involving motivationally significant outcomes [90]. Additional research is needed to establish whether this pattern reflects increased impulsivity. It should be noted that determining causation in studies involving drug users is difficult due to comorbid psychiatric disorders and polysubstance abuse [90].

Cognitive-Motor Effects of Methadone Maintenance

While under the influence of acute opioid ingestion, the ability to work safely or drive a car can be impaired. This does not appear to be the case with methadone patients who have adapted to the effects of opioids for months or even years, a reflection of the substantial tolerance to the central depressing effect when opioids are taken regularly on a long-term basis [92].

A review of the cognitive functioning of methadone patients found that [92]:

- On measures of concentration and attention, methadone patients tended to perform less well than controls.

- Methadone patients performed equally or slightly faster in speed of information processing and equally or slightly worse in motor reaction on measures of simple reactions and simple-choice reactions.

- Performance was inconsistent on complex-choice reactions under reactive stress.

- No evidence for inferior performance of methadone patients in vigilance tasks has been found.

- Methadone patients have performed worse than control groups in visual orientation.

- In tests combining tracking with a reaction task, slower reaction to peripheral signals have been observed in methadone patients together with equal accuracy and greater tracking deviation or smaller number of correct responses and equal tracking deviation.

Researchers concluded that among methadone-maintained patients without complicating comorbidity, visual structuring and reaction are not impaired [92]. Performance of attention, visual orientation, and eye-hand coordination are worsened. In general, performance of methadone patients and comparable healthy subjects overlap to a substantial degree. The study results may be better explained by sociodemographic factors than by the grouping factor; age, gender, and educational attainment showed a greater influence than methadone use. The authors concluded that being a methadone patient does not necessarily mean that impairment of cognitive-motor skills performance is inevitable [92]. Authors of more recent studies have reported similar findings [93,94].

The practical application of these findings suggests that methadone-maintained patients may be as capable as healthy persons in job performance. If job demands encompass skills with no differences found between healthy subjects and methadone patients, if minimum prerequisites are not extraordinarily high, or if patients exhibit favorable features exclusive of their methadone dependence, job performance is unlikely to be affected [92].

13. OPIOID OVERDOSE

In 2016, there were 63,600 drug-overdose deaths in the United States. This was 21% higher than the rate in 2015, including 20,032 deaths that involved synthetic opioid analgesics (other than methadone) and 15,831 that involved heroin. The 2016 overdose death rates were highest for persons 35 to 44 years of age (35.0 per 100,000), whereas the greatest increase in death rates occurred among adults 25 to 34 years of age [95]. Between 1999 and 2016, the age-adjusted death rate from drug overdose more than tripled (from 6.1 per 100,000 in 1999 to 19.8 in 2016). Overdose death rates from synthetic opioids other than methadone (e.g., fentanyl/fentanyl analogs, tramadol) increased from 0.3 per 100,000 in 1999 to 6.2 in 2016. The rate increased on average by 18% each year from 1999 to 2006, did not statistically change from 2006 to 2013, then increased by 88% per year from 2013 to 2016 [95]. The heroin overdose death rate increased from 0.7 per 100,000 in 1999 to 4.9 per 100,000 in 2016. The rate was steady from 1999 to 2005, then increased on average by 10% per year from 2005 to 2010, by 33% per year from 2010 to 2014, and by 19% per year from 2014 to 2016 [95].

Overdose death rates involving natural and semisynthetic opioids (e.g., oxycodone, hydrocodone) increased from 1.0 per 100,000 in 1999 to 4.4 per 100,000 in 2016. This was an average increase per year of 13% from 1999 to 2009 and 3% per year from 2009 to 2016 [95]. Overdose deaths involving methadone increased from 0.3 per 100,000 in 1999 to 1.8 in 2006, then declined to 1.0 in 2016 [95]. Methadone was involved in 3,231overdose deaths in 2016 [95]. Most methadone fatalities occur when the drug is prescribed for pain rather than for addiction treatment [60].

RISK FACTORS

Heroin purity has only a moderate relationship to heroin-related fatalities, and despite the increasing incidence of heroin ingestion by smoking, almost all overdose deaths remain the result of injection. In fatal overdoses, instantaneous death is uncommon, indicating that there is time to intervene in the majority of cases. However, public responsiveness to overdoses is often poor, with the most common reason for delayed response being fear of police involvement [96]. The time following release from prison has also been identified as a very high-risk period for both fatal and nonfatal overdose [96].

Methadone overdose decedents are more likely than other pharmaceutical opioid abusers to not have had a prescription for the overdose drug. They are also significantly more likely to be male [97,98].

Tolerance in Overdose

Variation has been found in the acquisition of tolerance to different opioid effects, including respiratory depression [38]. The role of tolerance in heroin overdose is suggested by the rigors of the heroin lifestyle, which often results in a reduction in use after a decade or more of use. Often, heroin addicts increase the use of other drugs, such as alcohol, to compensate for reduced heroin use. Both of these factors increase the risk for overdose.

Polysubstance Use

Polysubstance use in cases of fatal heroin overdose is so frequent that polydrug toxicity is often a better description of the cause of death. The primary drugs associated with fatal and nonfatal overdose are alcohol, benzodiazepines, and TCAs. The risk of nonfatal heroin overdose is increased significantly by TCA use but not by selective serotonin reuptake inhibitor (SSRI) use [17].

Alcohol and benzodiazepines are relatively weak respiratory depressants but can act synergistically with opioid agonists to produce substantial respiratory depression. Stimulants act as functional or physiologic opioid antagonists and may therefore minimize the respiratory depressant effects of opioids [52].

SYMPTOMS

In the case of opioid overdose, symptoms include mental clouding, stupor or coma, miotic pupils, bradypnea, diminished response to painful stimuli, and mottled, cooled skin. Respiratory depression is the most feared acute adverse effect. Direct suppression of the brain stem respiratory center leads to bradypnea, shallow respirations, and a significant overall reduction of tidal volume. Death from opioid overdose is almost always caused by respiratory depression [8,99].

Sequelae of nonfatal overdose include [38]:

- Pulmonary conditions, most frequently edema

- Pneumonia

- Cardiac complications such as arrhythmia, acute cardiomyopathy, and hemoglobinemia

- Rhabdomyolysis (disintegration or dissolution of muscle cells leading to myoglobinuria)

- Neurologic damage through prolonged hypoxia

14. OPIOID WITHDRAWAL

A withdrawal syndrome can be precipitated in humans after even a single dose of morphine. Physical dependence to opioids is assessed by observing the emergence of a withdrawal syndrome following discontinuation of opioid administration or through the administration of a competitive opioid antagonist, such as naloxone [100]. Signs and symptoms of opioid withdrawal include [83,101]:

- Dilated pupils

- Rhinorrhea

- Epiphora/lacrimation

- Piloerection

- Nausea

- Vomiting

- Diarrhea

- Yawning

- Muscle cramps

- Restlessness

- Elevated vital signs

Although the neurophysiology underlying opioid withdrawal is incompletely understood, several neurotransmitter systems are believed to play a role, including dopaminergic, cholinergic, noradrenergic, and glutamatergic systems [100]. The extended amygdala is robustly implicated in affective signs of withdrawal from chronic exposure to opioids. Less is known about the cellular mechanisms underlying acute dependence [78]. The progressive escalation of withdrawal severity that occurs across repeated acute opioid exposure separated by prolonged intervals suggests the involvement of long-term cellular plasticity in acute dependence [78]. The involvement of central mechanisms of the endothelin system in opioid withdrawal is also being investigated [102,103].

There are a number of useful opioid withdrawal scales that can assist the clinician's evaluation of patients by identifying and quantitating the severity of opioid withdrawal symptoms. These include the Objective Opioid Withdrawal Scale (OOWS), the Subjective Opioid Withdrawal Scale (SOWS), and the Clinical Opioid Withdrawal Scale (COWS). The OOWS is useful for measuring and documenting measurable symptoms of opioid withdrawal. The SOWS records the patient's rating of withdrawal on a 16-item scale. The COWS includes 11 items and contains signs and symptoms (both objective and subjective) of withdrawal [104].

In 2014, the FDA cleared the Bridge Neurostimulation System (an electroauricular device) for use in acupuncture. In 2017, the FDA approved a new indication for the device for use in helping to reduce the symptoms of opioid withdrawal [105]. The NSS-2 Bridge is placed behind the patient's ear and emits electrical pulses to stimulate branches of certain cranial nerves. It can be used for up to five days during the acute phase of withdrawal. In one study, within 30 minutes of using the device, all patients showed a reduction in COWS score of nearly 31% [105].

In 2018, the FDA approved lofexidine for the management of opioid withdrawal symptoms [205]. This agent may be incorporated into the treatment of adults with opioid withdarawl symptoms for up to 14 days.

ACUTE OPIOID WITHDRAWAL

Most research regarding acute withdrawal from an opioid has been conducted with heroin users. Withdrawal symptoms are the result of mu-agonist withdrawal in the case of heroin and begin approximately eight hours after the last dose. The symptoms begin slowly, peak at 48 to 72 hours, and then gradually taper during the next four to seven days [101]. As noted, typical symptoms of withdrawal include agitation, anxiety, piloerection, tachycardia, mild hypertension, and pupillary mydriasis. Approximately 8 to 12 hours after the last dose, increases in vital signs, pulse, blood pressure, and respiratory vital rate are observed. At the peak, pronounced anxiety, tremors, shakes, smooth and skeletal muscle cramps, and joint and deep bone pain begin to manifest [8].

PROTRACTED WITHDRAWAL

Withdrawal symptoms may persist long after elimination of the opioid agent. Such persistent behavioral change suggests plastic alternation within the nervous system, some of which may be mediated by the regulation of gene expression [100]. Chronic exposure to opioids may be associated with changes to the mu receptor, resulting in the propagation of signal transduction in the absence of an agonist. The withdrawal phase can be extended due to the cellular changes that occur after long-term opioid exposure [76].

PERSISTENT NEUROADAPTATION AND RELAPSE VULNERABILITY

Opioid dependence is a chronic relapsing disorder characterized by compulsive drug seeking and use. More than 80% of addicts relapse to drug seeking and use after a period of abstinence during the protracted withdrawal phase, underscoring the long-standing nature of the compulsion and high rates of recidivism [106]. Two important brain alterations occur following dependence and withdrawal that are believed to underlie the heightened vulnerability to relapse: conditioned responses of norepinephrine A1/A2 neuron release in the extended amygdala and changes in the mesocorticolimbic dopamine system and its afferents that alter hedonic processing. At the same time, motivation or learning for drug reward and drug-associated cues is increased [106].

Abstinence from chronic drug use unmasks neuroadaptation in brain function that contributes to an ill-defined feeling of dysphoria, anxiety, or malaise that can only be alleviated by renewed administration of the drug. Continued drug use is rewarding because it stimulates the natural reward circuitry and also because the action offsetting the anti-reward response (stress hypersensitivity and anxiety) produces an additional reinforcing effect that increases the sum of positive reinforcement. The protracted withdrawal period is often characterized by elevated anxiety involving alterations in the noradrenergic input to the bed nucleus of the stria terminalis or amygdala. Drug-associated stimuli activate noradrenergic A1/A2 neurons during protracted withdrawal, leading to elevated anxiety through the ensuing release of noradrenergic neurons in the extended amygdala. In turn, additional reinforcing properties are produced via the alleviation of anxiety when these noradrenergic neurons are inhibited, reflecting negative reinforcement [106,107].

Additionally, chronic drug exposure results in a generalized hedonic deficit for natural rewards and an incentive value for drugs. This deficit in the capacity for obtaining reinforcement from non-drug sources generates symptoms such as anhedonia and depression [107]. The sensitized hedonic drug value is also believed to increase motivation for drug use. Furthermore, the changes that occur in hedonic processing mechanisms following chronic opioid exposure may involve multiple systems that recover at different rates. Changes in the afferents to the ventral tegmental area or in plasticity within the ventral tegmental area itself could play a vital role in altered hedonic processing during protracted withdrawal [106,107].

Taken together, these findings suggest that elevated drug seeking during protracted withdrawal may involve two processes: prolonged and elevated anxiety leading to a negative reinforcement mechanism for opioids and increased incentive motivation for drug reward through a sensitization mechanism [106,107].

15. LIABILITY OF ABUSE/DEPENDENCE OF LEGITIMATELY PRESCRIBED OPIOID DRUGS

There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major barrier to prescribing opioids [108]. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [109]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [110]:

- 35% admitted knowing little about opioid addiction.

- 66% and 57% viewed low levels of education and income, respectively, as causal or highly contributory to opioid addiction.

- 30% believed opioid addiction "is more of a psychologic problem," akin to poor lifestyle choices rather than a chronic illness or disease.

- 92% associated prescription analgesics with opioid addiction, but only 69% associated heroin with opioid addiction.

- 43% regarded opioid dependence and addiction as synonymous.

These statistics reflect knowledge and attitude gaps among physicians that lead to undertreatment of pain and unnecessary suffering among patients experiencing pain [108]. In response to this, the Joint Commission and other organizations have enacted accreditation standards that consider pain to be the fifth vital sign, assessed whenever other vital signs are measured [1].

However, with the growing concern about the undertreatment of pain and the underuse of opioids in pain treatment, there is also a renewed concern about prescription opioid dependence and overdose deaths [1]. The disparate concerns regarding undertreatment of pain and facilitation of dependence is underscored by the fact that, until recently, pain management and addiction specialists rarely communicated. Pain management physicians rightly concern themselves with alleviation of pain and have traditionally underestimated dependence among their patients, with such patients often simply dismissed from further care. Addiction specialists, on the other hand, seldom encounter pain patients whose quality of life is vastly improved by opioids, but instead see failed patients from pain treatment programs [1]. Additionally, there is a shortage of pain specialist physicians in the United States that is expected to worsen. This has resulted in most of the medical care for patients with chronic pain being delivered by primary care physicians, despite, as stated, significant and widespread knowledge deficits among these practitioners in the medical skills necessary for providing optimal pain management, managing drug abuse and addiction, and utilizing risk evaluation and mitigation strategies when prescribing opioids [111]. Until the 1990s, Schedule II opioid analgesics were primarily used in operating rooms and inpatient settings because they required intravenous or intramuscular administration. In response to the increasingly permissive climate and by genuine unmet patient need, several nonparenteral Schedule II opioids have been approved by the FDA for use in the treatment of moderate-to-severe pain. Many of these newer agents are high-dose, extended-release formulations of pre-existing opioids, including OxyContin (a controlled-release oral formulation of oxycodone), MS Contin (a formulation of morphine sulfate), and Exalgo (a formulation of hydromorphone hydrochloride), all of which have fulfilled a genuine clinical need by providing an elevated, constant plasma level for extended periods without the fluctuations seen with the short-acting versions. These long-acting formulations may both reduce euphoric effects of the drug and reduce pain more effectively by treating pain before it becomes established (pre-emptive effect) rather than after, when higher doses may be required. However, these formulations can be abused by crushing the tablet or capsule and ingesting the powder intranasally, sublingually, or orally or dissolving the powder in water and injecting the substance. These approaches to ingestion alter the pharmacokinetics by disabling the slow-release mechanism and make a very high dose of the substance available, which substantially increases the reinforcing effects compared with oral consumption of the drug in its unaltered form [29].

Abuse liability is related to the ease of extraction and modification to produce the desired psychologic effect. Medication tends to be more readily abusable if it has a rapid onset and short duration of action, is highly potent, and is smokable or easily ingested. Examples of opioids with high abuse liability include hydromorphone (Dilaudid) tablets, which can be easily dissolved in water and injected, and OxyContin tablets, which can be crushed to disable the controlled-release properties and then snorted or dissolved in solution and injected. A specific black box warning on the labeling of a medication can alert potential substance abusers of the abuse liability. Also, brand name drugs, which carry a higher street value, are more likely to be abused and diverted than generic equivalents [1].

In studies of trends in medical use and abuse of opioid analgesics, a corresponding increase in the rate of abuse with prescription rates has been apparent [15,112,113]. Thus, the increased medical use of opioid analgesics for the treatment of pain has contributed to an increase in opioid analgesic abuse and overdose fatalities. The abuse of hydrocodone and oxycodone products, which has increased disproportionately to their availability since 2000, is an extreme example of this trend [1]. Results of epidemiologic studies indicate a high prevalence of lifetime abuse of other substances and of substance-related disorders in patients with OxyContin dependence, suggesting that substance abuse predated the use of OxyContin [114].

Legitimate pain clinics offer large amounts of drugs with a high potential for abuse, often with little evaluation and follow-up [112]. In some states (e.g., Florida, Texas), increasingly liberal prescribing practices have been linked to rising overdose death rates. A study evaluating opioid overdose in a sample of more than 5.7 million patients found that, irrespective of medical or nonmedical use, the rate of fatal overdose increased in proportion to the amount of prescriptions filled [113]. Furthermore, the risk of fatal overdose increased with prescription strength (morphine dose equivalent), particularly with equivalent doses greater than 50 mg/day. According to the CDC, 40% of all opioid overdose deaths involved a prescription opioid in 2016 [115].

DEVELOPMENT OF DEPENDENCE

The dependence of a patient to a drug initially prescribed for a medical condition is referred to as iatrogenic dependence. Opioid prescriptions fall into two major subgroups: treatment of acute pain with short-term opioids and treatment of chronic pain with long-term opioids. In contrast to the rare association of dependence with short-term use, long-term administration of opioids is estimated to result in opioid abuse or dependence in 2.8% to 18.9% of patients, which typically parallels the rate of abuse or dependence among opioid users in the general population [33].

There is no adequately validated instrument to differentiate pain patients who are at risk of dependence from those who are not. Research suggests that patients, even alcoholics, with no history of opioid dependence are not at heightened risk of becoming addicted with short-term opioid exposure. However, those with a positive history of dependence would benefit from active recovery efforts while receiving such medications [1].

One way to gauge the adequacy of pain control is to consider whether the use of added opioids has resulted in improvements in the functional restoration, physical capacity, psychologic well-being, family/social interactions, and healthcare resource use, which are weighed against unwanted effects, such as daytime sedation, mental confusion, constipation, and other side effects.

Despite the rise in the prescribing and abuse of opioid analgesics, definitive data on the rate of dependence among patients administered opioids for acute pain does not yet exist. There is, however, agreement on how to minimize the risk of iatrogenic dependence. These steps include screening for dependence risk potential based on a family history of substance abuse and the exploration of different delivery systems that adequately treat pain but minimize abuse potential [34]. Although a pattern of aberrant behavior may be grounds for caution, a history of opioid abuse does not necessarily preclude a patient from successful treatment with an opioid [1]. Screening for psychologic disorders is also advisable, including psychosomatic causes of pain.

The final word on the dilemma of balancing the desire for patient pain relief with the desire to minimize the chance of iatrogenic abuse or dependence comes from the authoritative pharmacology textbook The Pharmacological Basis of Therapeutics, which states, "neither the presence of tolerance and dependence nor the fear that they may develop should ever interfere with the appropriate use of opioids for pain relief" [9].

16. MANAGEMENT OF OPIOID USE DISORDER

In 1914, the Harrison Act was passed, which had the effect of criminalizing addiction and led to significant apprehension among physicians in treating narcotic addicts. Treatment for opioid dependence was basically non-existent until 1935, when U.S. Public Health Services opened a hospital in Lexington, Kentucky, devoted to the treatment of opioid dependence. However, treatment was entirely detoxification-based at that time. In 1963, the New York Academy of Sciences recommended that clinics be established to dispense narcotics to opioid-dependent patients. During this time, research identified methadone as a possibly efficacious agent because of its long half-life, which allowed once-daily dosing. In 1972, the FDA created stringent regulations governing methadone, reducing the flexibility of practitioners caring for opioid-dependent patients. The Office of National Drug Control Policy subsequently made changes in the 1995 Federal Regulations of Methadone Treatment to encourage the development of a less restrictive approach and to give physicians more latitude in prescribing methadone [57].

Today, management of opioid dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include [13]:

- Crisis intervention: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opioid antagonist.

- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose.

- Detoxification/withdrawal: Aims to remove the opioid of abuse from the patient's body, either through gradual taper and substitution of a long-acting opioid or through ultra-rapid opioid detoxification.

- Maintenance treatment or opioid (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opioids and introduced to a long-acting opioid agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs.

- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opioids during the detoxification/withdrawal process and may be placed on an opioid antagonist with the goal of minimizing relapse.

All treatment approaches share the common goal of improving health outcomes and reducing drug-related criminality and public nuisance [13].

CRISIS INTERVENTION

Evidence Based Practice Recommendation

According to the World Health Organization, people likely to witness an opioid overdose should have access to naloxone and be instructed in its administration to enable them to use it for the emergency management of suspected opioid overdose.

https://www.guideline.gov/summaries/summary/48893

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/very low

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [116]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [116]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or CNS depression. It is available in a ready-to-use 4-mg single-dose sprayer [117,118].

HARM REDUCTION

Harm reduction measures are primarily employed to minimize the morbidity and mortality from opioid abuse and to reduce public nuisance [96]. As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opioid use [96].

Education

Reducing the risk for harm involves education on polydrug use and needle-exchange programs [96]. The authors of one review noted that there was positive evidence, though limited, to support education regarding noninjecting routes of administration, brief interventions, and supervised injecting facilities [119]. Given that a harm-reduction approach can address risk behaviors that may occur alongside drug use, the authors of one paper suggest that risk-reduction education be based on harm reduction philosophy as a whole rather than on the specific harms of drug use and harm reduction strategies (e.g., needle-exchange programs) [120]. The authors defined six principles—humanism, pragmatism, individualism, autonomy, incrementalism, and accountability without termination—and generalized them for use in healthcare settings with patients beyond those who use illicit substances. Each principle was defined and providers were given descriptions of how to deliver interventions informed by the principles as well as examples of how to apply each principle in the healthcare setting [120].

To improve response to overdoses, opioid abusers and their friends and families should be taught simple cardiopulmonary resuscitation skills to keep comatose users alive until emergency medical personnel arrive. Associates of users should be encouraged to call an ambulance when overdose occurs. The provision of naloxone to opioid users should be tested and evaluated; naloxone could be distributed through existing outlets, such as needle and syringe exchanges, pharmacies, urgent care facilities, or treatment agencies. Heroin users should also be encouraged to switch to noninjecting routes of administration to reduce related morbidity and mortality [96].

Needle-Exchange Programs

Needle-exchange programs, also referred to as syringe services programs, have been shown to be effective in reducing drug-related health problems, reducing injection frequency, and increasing entry and retention in drug treatment [13]. According to one review, there is sufficient evidence of efficacy, effectiveness, and financial benefit to recommend needle-exchange and outreach programs [119]. It is important to note that information regarding infection prevention strategies be provided to all participants in needle-exchange programs, as increased incidences of HIV and other bloodborne pathogens have been noted in this population [121]. The Consolidated Appropriations Act of 2016 gives states and local communities, under limited circumstances, the opportunity to use federal funds to support certain components of needle-exchange programs. Although federal funds cannot be used to purchase sterile needles or syringes for illegal drug injection, these funds can be used to support a comprehensive set of services as part of a needle-exchange program [122].

Injection Rooms

Medically supervised injecting rooms are officially designated areas where injecting opioid users, often persons who use heroin, can inject without fear of arrest and with knowledge that medical assistance is available if overdose occurs. Such facilities have existed in Switzerland since 1986, in Germany since 1994, and in the Netherlands since 1996. The goal of user rooms is to promote health and reduce risk behaviors and public nuisance, with a specific focus on overdose reduction and hygiene [123]. Several descriptive studies have shown significant effects on harm reduction and reduction of public nuisance [13].

Heroin Maintenance

Heroin maintenance, also referred to as heroin-assisted treatment, is the implementation of heroin prescriptions under medical supervision. This option may improve health and reduce heroin overdoses, illicit opioid use, and crime. However, formidable barriers to heroin maintenance exist in the United States [96].

One systematic review compared heroin maintenance to methadone or other substitution treatments of opioid dependence for efficacy and acceptability; retaining patients in treatment; reducing the use of illicit substances; and improving health and social functioning [124]. Eight studies involving 2,007 patients met the inclusion criteria. Five studies compared supervised injected heroin plus flexible dosages of methadone to oral methadone alone. Results suggest an added value of heroin prescribed alongside flexible doses of methadone for long-term, treatment-refractory, opioid users to reduce use of illicit substances and sustain treatment [124].

DETOXIFICATION AND WITHDRAWAL

The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification, or more accurately, medically supervised withdrawal [57,125]. Its purpose is to eliminate physical dependence on opioid medications. It can be considered the medically supported transition to a medication-free state or to antagonist therapy. A careful and thorough review of the risks and benefits of detoxification should be provided and informed consent obtained from patients prior to choosing this option [125,126]. Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program [13,125].

Discontinuation of opioid use must be implemented slowly and cautiously to avoid a marked abstinence syndrome. Withdrawal symptoms may not begin for days after abrupt discontinuation of methadone or buprenorphine given their longer half-lives. Protracted abstinence, or post-acute withdrawal, may last for several months and is characterized by asthenia, depression, and hypotension. Post-acute withdrawal is more likely to occur with methadone than other opioids [57].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [57]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [76]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [57]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [76].

Many opioid withdrawal symptoms, such as restlessness, rhinorrhea, lacrimation, diaphoresis, myosis, piloerection, and cardiovascular changes, are mediated through increased sympathetic activation, the result of increased neuron activity in the locus coeruleus. Non-opioid agents (such as clonidine), which inhibit hyperactivation of noradrenergic pathways stemming from the locus coeruleus nucleus, have been used to manage acute withdrawal [76,104]. The first non-opioid treatment approved for the management of opioid withdarawl symptoms is lofexidine [205]. In studies, patients treated with lofexidine reported less severe withdrawal symptoms and were more likely to complete treatment.

However, some withdrawal symptoms, including anxiety and myalgias, are resistant to clonidine; benzodiazepines and nonsteroidal anti-inflammatory agents may be necessary to treat these symptoms. To mitigate withdrawal symptoms and assist in detoxification, alpha2-agonists, opioid agonist-antagonists, benzodiazepines, and antidepressants have been used [76].

Following detoxification, patients may feel exhausted and weak. Other complications, such as slight variations in hemodynamic status and gastrointestinal tract symptoms, follow quickly and may take several days to resolve. Muscle cramps and low back pain can be treated with nonsteroidal anti-inflammatory drugs. However, the newer cyclooxygenase-2 (COX-2) inhibitors may be advantageous because they produce fewer gastrointestinal side effects [76]. Insomnia is a frequent aspect of acute and protracted withdrawal, as opioids disrupt the normal sleep-wake cycle and many addicts require narcotics to sleep. Although long-term disruption of the normal sleep-wake cycle cannot be corrected rapidly, melatonin (3 mg), benzodiazepines, or antihistamines can be used with beneficial effects. Hypnosis and relaxation techniques are nonpharmacologic methods that may also be used [76]. Psychosocial treatments offered in addition to pharmacologic detoxification treatments positively impact treatment retention and completion, results at follow-up, and compliance [127,128].

Ultra-Rapid Opioid Detoxification

Ultra-rapid opioid detoxification (UROD) has been developed as a means of avoiding the physical symptoms of withdrawal from opioids through the use of general anesthesia. UROD consists of naltrexone-assisted detoxification under heavy sedation or full anesthesia. Chemical sedation has been used since the early 1940s in the management of drug withdrawal. The major breakthrough in the management of opioid withdrawal occurred with the addition of an opioid antagonist during chemical sedation [129]. UROD was introduced in 1990 primarily by private practitioners in a for-profit setting [130].

Traditional withdrawal management utilizes the substitution of the short-acting opioid with a long-acting opioid and subsequent tapering or use of non-opioids. This may involve substantial discomfort to patients, who often terminate the detoxification process and return to opioid use. Some may not even attempt to quit due to fears of the discomfort of the withdrawal process. Thus, attempts have been made to induce and shorten opioid withdrawal through the use of UROD [130].

UROD is also referred to as rapid or anesthesia-assisted detoxification. One reason for the proliferation of terms is that the anesthesia-assisted procedure was commercially used and was submitted as a registered trademark or patent. Therefore, other researchers had to devise novel names for the process. Suggested classification is [130]:

- Ultra-rapid opioid detoxification (UROD): General anesthesia; duration <6 hours

- Rapid opioid detoxification (ROD): Deep sedation; duration 6 to 72 hours

- Compressed opioid detoxification (COD) and naltrexone-compressed opioid detoxification (NCOD): Duration three to six days; preceded by a period of abstinence from opioids under sedation prior to introduction of naltrexone

The common underlying themes in all UROD techniques are a desire to condense the detoxification process into a shorter period to blunt the awareness of physical discomfort and to shorten the time lag between a patient's last dose of opioid and transfer to naltrexone maintenance [130]. This is accomplished by precipitating withdrawal following the administration of opioid antagonists under deep sedation or anesthesia.

A highly specific subgroup of patients may benefit more from UROD. This includes patients unable to abstain with methadone substitution despite adequate motivation, patients unable to stop methadone, and patients who are socially and occupationally active and cannot go through a lengthy detoxification. Patient preference is also an important variable [130].

Absolute contraindications include pregnancy; a history or clinical suspicion of cardiac disease; chronic renal impairment; liver disease; current dependence on benzodiazepines, alcohol, or stimulants; and history of psychotic illness [130]. Relative contraindications include a history of treatment for depression and unstable social circumstances. A comprehensive plan to stabilize such patients should be undertaken before the procedure [130]. Patients with chronic pain syndromes requiring opioid medication are not good candidates unless their pain can be controlled by alternative methods [76].

UROD is best performed in an intensive care unit with full resuscitative equipment and monitoring available [76]. Initiation of opioid withdrawal is precipitated by IV injection of a high-dose antagonist, usually naloxone. Antagonists are chosen that have high binding coefficients relative to agonists (naltrexone binds at the mu receptor 34 times more than morphine) [76]. Parameters that indicate adequacy of withdrawal include a 20% decrease of ventilation below the maximum minute ventilation, an electrocardiogram (ECG) detection of decreased QQ variability, and electroencephalogram (EEG) normalization [76].

Detoxification and withdrawal are rarely complete following UROD, and residual withdrawal symptoms can include drug craving, sympathetic hyperactivity, muscle pain, bone pain, nausea, vomiting, diarrhea, and insomnia. UROD does little to prevent protracted abstinence syndrome, which can last 3 to 10 weeks. Naltrexone may reduce opioid craving during the post-UROD period, with 50 mg per day recommended for relapse prevention [76]. However, patients undergoing long-term naltrexone therapy can become sensitized to opioid drugs, heightening the risk of fatal overdose if opioid use is resumed. Patients with a history of pre-existing liver dysfunction should undergo naltrexone maintenance therapy only under careful supervision. Clonidine may diminish sympathetic hyperactivity and should be continued through the protracted abstinence syndrome [76].

The withdrawal syndrome observed in many of the published studies on UROD was protracted, as reflected in the duration of inpatient stay, which varied from 24 hours to eight days, with a mean duration of three to four days. Therefore, alternatives to UROD are considered to be more cost-effective [130]. Krabbe et al. compared abstinence rates and withdrawal effects of UROD with standard methadone tapering in a prospective three-month trial [131]. They found significantly higher abstinence rates and fewer withdrawal symptoms in UROD patients versus methadone patients at one and two months, with no differences at three months.

A major shortcoming of UROD is the lack of evidence that an opioid antagonist can accelerate the restoration of neurobiologic homeostasis following opioid withdrawal [130]. Although significant drawbacks and questionable long-term efficacy exist with UROD, popular demand has proven difficult to restrain, in part due to the marketing of the procedure as a painless cure for opioid dependence. Marketing and the media have also blurred the fact that the original purpose of the procedure was to induce patients as rapidly as possible onto naltrexone and not to magically and permanently terminate years of opioid dependence [129].

There are a number of drawbacks to UROD relative to other detoxification methods. For example, one study found that, when used alone, naloxone has a high relapse rate in the long term [132]. The study included 64 opioid-dependent men 18 years of age and older (mean age: 31.1 years) at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 patients (25%) reported abstinence. There was no significant difference between the two groups regarding marital status, level of education, and family history of opioid dependence. Four patients from the nonrelapsed group reported on episode of opiate use [132]. Another study was conducted to assess UROD efficacy with naltrexone and estimate the relapse rate in a two-year follow-up period [133]. A total of 424 opioid-addicted self-reporting patients were enrolled in the study and entered the UROD program; 400 patients completed the program. Of the total patients, 303 (75.75%) were successful and 97 (24.25%) relapsed. No patients in the relapse group continued naltrexone maintenance at six-month follow-up. The relapse rate was 14% at the first month visit and 24% at the six-month visit and thereafter. All relapsed patients had discontinued use of naltrexone before relapse occurred [133].

Serious adverse events related to the anesthetic procedure also have been reported. A randomized, controlled trial directly comparing naltrexone-assisted detoxification with and without full anesthesia clearly stated that heavy sedation or full anesthesia should not be used because it does not confer any advantages in withdrawal symptom severity or increased rates of initiation or maintenance and it increases the potential for life-threatening adverse events [13]. A trial comparing naltrexone-induced, anesthesia-assisted detoxification with buprenorphine- or clonidine-assisted detoxification found no difference in withdrawal severity and rates of completion. However, potentially life-threatening adverse events associated with the UROD anesthesia were observed. The authors concluded that the data do not support use of anesthesia for detoxification [134]. Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of initiation and retention on naltrexone maintenance treatment. The risk for adverse events, the high monetary cost, and use of scarce intensive care resources suggest that this form of treatment should not be pursued [135,136]. Additionally, UROD has not undergone the processes of therapeutic protocols, which are recognized as essential in scientific medicine, and no animal studies have been conducted with the procedure [129].

AGONIST REPLACEMENT OR ABSTINENCE THERAPY

Two principle treatment modalities are offered for opioid-dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention [137]. A reasonable approach is initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention [138].

At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems [34]. Instead, the management of opioid dependence often consists of pharmacotherapy with methadone and buprenorphine, which do not eliminate physical dependence on opioids. These medications instead reduce the use of illicit opioids and produce very strong positive health outcomes as measured by decreased mortality, improved mental and physical health, and reduced risk of disease transmission [34]. Considering the high rate of relapse after detoxification, maintenance therapy with methadone or buprenorphine is currently considered to be the first-line treatment for opioid-dependent patients [13].

Any treatment for opioid dependence must take into consideration the chronic relapsing nature of opioid dependence, characterized by a variable course of relapse and remission in many patients. Treatments should emphasize patient motivation, psychoeducation, continuity of care, integration of pharmacotherapy and psychosocial support, and improved liaison between the treatment staff and the judicial system. Pharmacotherapy must be offered in a comprehensive healthcare context that also addresses the psychosocial aspects of dependence [13]. Opioid-dependent patients frequently suffer from physical and psychiatric disorders, and targeted interventions of psychiatric comorbidity are essential in improving treatment outcome for these patients [13]. Polysubstance abuse is the rule rather than the exception in opioid dependence, and concurrent use of other substances should be carefully monitored and treated when necessary [13]. Incarceration should never automatically result in discontinuation of an existing treatment; imprisonment offers a window of opportunity to initiate or restart treatment with a necessary continuation after release [13].

Agonist Replacement Therapy

The goal of opioid replacement therapy is to reduce illicit drug use and associated health risks, with secondary goals of reducing unsafe sexual practices, improving vocational and psychosocial functioning, and enhancing quality of life [57]. The theoretical basis of opioid replacement stems from the finding that chronic opioid use results in an endogenous opioid deficiency as a result of the down-regulation of opioid production. This creates overwhelming cravings and necessitates interventions that shift the dependent patient's attention and drive from obsessive preoccupation with the next use of opioids to more adaptive areas of focus, such as work, relationships, and non-drug leisure activities [57].

The neurobiologic changes resulting from prolonged opioid exposure provide a rationale for specific pharmacotherapies, such as long-acting opioid agonists, that are aimed at stabilizing these complex systems [80]. Opioid agonist maintenance treatment stabilizes brain neurochemistry by replacing short-acting opioids, which can create rapid changes in opioid levels in the serum and brain, with a long-acting opioid that has relative steady-state pharmacokinetics. Opioid agonist maintenance treatment is designed to have minimal euphoric effect, block the euphoria associated with administration of exogenous opioids (competitive antagonism), eliminate the risk of infectious disease and health consequences associated with injection drug use, and prevent opioid withdrawal [80].

Successful maintenance treatment entails stabilization of opioid dependence through opioid receptor occupation. Positron emission tomography studies have revealed that only 25% to 35% of brain opioid receptors are occupied during steady-state methadone maintenance, suggesting that unoccupied opioid receptors disrupted during cycles of opioid abuse could normalize during methadone maintenance [57]. Additionally, opioid replacement therapy blocks much of the euphoria from illicit heroin use. Long-term opioid agonist treatment also has a positive impact on public health, through significantly reducing overdose deaths, criminal activity, and the spread of infectious disease [57].

As of 2016, 417,057 patients in the United States were enrolled in opioid replacement therapy in 1,308 opioid treatment programs [139]. However, this represents only an estimated 19% of all opioid-dependent patients. Although some have criticized the practice of methadone and buprenorphine therapy on the grounds that one opioid is merely being substituted for another, the clinical benefits strongly support this treatment modality [57]. When compared to active street heroin users, these benefits include a four-times lower HIV seroprevalence rates, 70% fewer crime-days per year, and a one-year mortality rate of 1% (versus 8%) [60].

Methadone

The first demonstrated efficacy of methadone treatment for opioid dependence was published in 1965. Methadone is now the most inexpensive and empirically validated agent available for use in opioid replacement therapy. Studies have shown one-year treatment retention rates of 80%, with significant reductions in illicit opioid use [57]. Individual and group counseling are the main ancillary therapies and consist primarily of cognitive-behavioral and supportive-expressive approaches. There is some evidence that augmentation of methadone with intensive psychosocial therapy significantly improves outcomes [57]. Efforts to provide methadone in an office-based setting have been successful, although federal regulation has limited the flexibility of providers [80,104].

Evidence Based Practice Recommendation

When considering initiation of methadone, the American Pain Society recommends that clinicians perform an individualized medical and behavioral risk evaluation to assess risks and benefits of methadone, given methadone's specific pharmacologic properties and adverse effect profile.

https://www.guideline.gov/summaries/summary/49245

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/low

As noted, methadone maintenance treatment offers substantial benefits over no treatment, including reduced risk of death and disease, reduced heroin use, reduced criminal involvement, and improved well-being. However, the benefits are less with poor-quality or under-funded programs. The quality of the staff-patient interaction, attitudes of staff, good management of clinics, and good record-keeping characterize higher-quality programs [140].

Methadone maintenance is also cost-effective [57]. A 1997 study of Veterans' Affairs patients showed that the estimated six-month costs are about $21,000 for an untreated drug abuser, $20,000 for an incarcerated drug abuser, and $1750 for a patient enrolled in a methadone maintenance program [141]. A 2010 study using data from one healthcare plan reached a similar conclusion regarding cost-effectiveness (albeit with differing cost estimates) [142]. The annual costs (in 2004 dollars) were $18,694 for patients receiving no methadone with 0 or 1 outpatient addiction treatment visits; $14,157 for patients receiving no methadone with 2 or more visits; and $7,163 for patients receiving methadone.

There is an unrealistic expectation that opioid users should be able to stop using all drugs. Although some do successfully stop, dependence is a chronic problem for most patients, associated with frequent relapses, serious health risks, and psychosocial impairment [140]. Unfortunately, a serious stigma surrounds methadone treatment, which is experienced most acutely by patients but also by professionals. This may pose a barrier to treatment support [140].

Treatment is initiated with a dose of 25–30 mg and is gradually titrated in 5- to 10-mg increments per day to a desired range of 60–120 mg. Low-dose treatment is associated with less positive outcomes than doses of 60–120 mg/day or greater [57,60]. One published review of efficacy literature concluded that high doses of methadone (>50 mg daily) are more effective than low doses (<50 mg daily) in reducing illicit opioid use. This may be due to the increased availability of highly pure heroin [60]. Additionally, high doses of methadone are more effective than low doses of buprenorphine (<8 mg daily). High dosages of methadone are comparable to high dosages of buprenorphine (>8 mg daily) on measures of treatment retention and reduction of illicit opioid use [13]. Methadone is contraindicated for the following patients [104]:

- Those with known hypersensitivity to methadone hydrochloride

- Those experiencing respiratory depression

- Those with acute bronchial asthma or hypercapnia

- Those with known or suspected paralytic ileus

Buprenorphine

Buprenorphine offers several advantages over methadone, including lower cost, milder withdrawal symptoms following abrupt cessation, lower risk of overdose, and longer duration of action, allowing alternate-day dosing [57,143]. Identifying subpopulations of opioid addicts who differentially respond to buprenorphine versus methadone has not been clearly established. However, patients with less chronic and less severe heroin dependence benefit more fully from buprenorphine than from a pure opioid agonist like methadone [57].

Studies support buprenorphine as a viable alternative for opioid maintenance therapy. However, its mixed agonist/antagonist action entails special considerations. Buprenorphine may precipitate opioid withdrawal, and patients being switched from short-acting opioids must abstain from illicit opioid use for at least 24 hours before initiating buprenorphine therapy [57,104]. Another drawback is associated with the sublingual route of administration. This administration presents some difficulties because the tablet is relatively large and slow to dissolve under the tongue and swallowing diminishes its effectiveness. Also, the transition to buprenorphine from long-acting opioids is difficult [34]. The ASAM warns that diversion and misuse are possible with buprenorphine, as is physical dependence. Respiratory depression may occur if buprenorphine is used with CNS depressants including alcohol, other opioids, and illicit drugs. Neonatal withdrawal has also been reported after use of buprenorphine during pregnancy. Buprenorphine is not recommended for patients with severe hepatic impairment [104].

Higher doses of buprenorphine (12 mg or greater) are more effective than lower doses in reducing illicit opioid use, with some studies reporting similar efficacy to methadone on major treatment-outcome measures. One systematic review was conducted to evaluate buprenorphine maintenance compared to placebo and methadone maintenance in the management of opioid dependence [144]. Outcomes considered were treatment retention, suppression of illicit drug use, and reduction in criminal activity and mortality. A total of 31 trials involving 5,430 participants with moderate- to high-quality evidence were included in the review. According to the data reviewed, buprenorphine retained participants better than placebo at low doses (2–6 mg), at medium doses (7–15 mg), and at high doses (≥16 mg). Only high-dose (≥16 mg) buprenorphine was more effective than placebo at suppressing illicit opioid use (as measured by urinanalysis). Buprenorphine in flexible doses (i.e., adjusted to participant need) was less effective than methadone in retaining participants, and for those retained in treatment, no difference was observed in suppression of illicit opioid use. In low fixed-dose studies, methadone (≤40 mg) was more likely to retain participants than low-dose (2–6 mg) buprenorphine. However, there was no difference between medium-dose (7–15 mg) buprenorphine and medium-dose (40–85 mg) methadone in retention or in suppression of illicit opioid use. Similarly, there was no difference between high-dose (≥16 mg) buprenorphine and high-dose (≥85 mg) methadone in retention or suppression of self-reported heroin use [144]. In a 2011 study of 34,000 Massachusetts Medicaid beneficiaries, the incidence of relapse was greater with buprenorphine than with methadone [143]. The primary advantage of buprenorphine over methadone is its superior safety profile [34].

Slow-Release Oral Morphine

Slow-release formulations of morphine that are effective with once-daily dosing are a viable alternative in the treatment of opioid dependence. These formulations considerably delay time to peak concentration after oral administration, resulting in delayed onset of action and making the reinforcing effects very weak when it is administered orally. Several trials have suggested that slow-release morphine has approximately equal efficacy with methadone; however, there is no definitive evidence of this effect [34,145,146]. Slow-release oral morphine may be a viable alternative for patients who are intolerant to methadone [147].

Diacetylmorphine (Heroin)

The pharmacokinetic properties of heroin make it less than ideal for use as a maintenance drug, and the main rationale for heroin maintenance has been the treatment of patients who simply do not respond to any other treatment modality. Although preliminary results seem to be positive, before suggesting that heroin treatment may have a place with a subpopulation of patients, further studies using standardized protocols are needed. Significantly, studies so far clearly indicate that heroin maintenance, with or without methadone, can be implemented safely. The relatively high cost of heroin maintenance compared with standard methadone or buprenorphine treatment is a drawback of this approach. However, at least one study suggests that heroin combined with methadone may be more cost-effective than methadone alone [34].

The results of medically prescribed heroin administration to chronic, treatment-refractory, heroin-dependent patients have been detailed in two reports. One report from Switzerland concluded that supervised medical prescription of heroin was associated with favorable treatment retention, reduced illicit drug use, reduced criminality, and improved health outcomes and social functioning. These findings were also reported in a controlled trial from Spain and Germany [13]. Research projects were also performed in the Netherlands, Canada, and England, and others are planned in Belgium and Denmark. Based on the positive outcomes thus far, heroin maintenance has become routine treatment for otherwise untreatable heroin addicts in Switzerland, the Netherlands, Germany, and England and is being recommended in Canada [148,149].

Agonist Replacement and Psychosocial Therapy

The addition of any psychosocial support modality to agonist replacement therapy significantly reduces illicit use during treatment, and treatment retention and results at follow-up are also improved [127,128]. There are two general types of psychosocial therapy used for treating addictive disorders. The first includes therapies developed for treating depression and anxiety that were later adapted for treating persons with addictive disorders, examples of which include cognitive behavioral therapy, supportive expressive therapy, and interpersonal therapy. The second type includes therapies developed specifically for persons with addictive disorders, such as the closely-related motivational interviewing and motivational enhancement therapy [150].

Drug counseling, another approach specific to addictive disorders, emphasizes abstinence, involvement in 12-step programs, and assistance with social, family, and legal problems. Drug counseling is not considered psychotherapy because it focuses on behaviors and external events rather than the intrapsychic processes [150].

Most studies of psychotherapy with opioid-dependent patients have been conducted in methadone programs and are actually pharmacotherapy/psychotherapy studies. In addition to pharmacologic intervention, methadone programs typically use behavioral contingencies that are based on cessation of illicit drug use and other improvements [150].

A review of the literature on psychosocial therapy outcomes with opioid-dependent patients receiving methadone has found evidence of an interaction between measures of psychiatric symptoms, therapy assignment, and outcomes [150]. Patients with minimal psychiatric symptoms did equally well with drug counseling alone or with drug counseling plus supportive expressive therapy or cognitive-behavioral therapy. Patients with moderate-level symptoms did somewhat better if they received additional psychotherapy, and patients with more severe psychiatric symptoms had substantially better outcomes with additional psychotherapy than with drug counseling alone. Improvements were observed in employment, legal, psychiatric, and drug use indices. Patients with opioid dependence and antisocial personality disorder did not benefit from additional psychosocial therapy beyond drug use reduction, but patients with opioid dependence, antisocial personality, and depression exhibited improvement in multiple areas [150].

Therapist variables played an important role in outcome, with better results associated with therapists who formed a positive, helping relationship with the patient. There is also some evidence that the best patient outcomes come from methadone programs with a higher level of services that include counseling, medical, and psychiatric services [150].

Abstinence-Oriented Therapies

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [13].

The primary goal of pharmacotherapy during detoxification is to alleviate opioid withdrawal severity and associated distress/medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacologic treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine's advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables [13].

Opioid Antagonist Therapy

Relapse-prevention programs have traditionally involved long-term residential placement of nine months or more, often using the therapeutic community format. More recently, pharmacotherapeutic agents, such as naltrexone, have been added to reduce relapse risk. A drawback with opioid antagonist therapy is the high dropout rate during detoxification, which results in highly selective patient samples in most of the naltrexone maintenance studies. Naltrexone maintenance or relapse-prevention treatment should be reserved only for those patients who are highly motivated for long-term total abstinence and who are otherwise psychosocially stable [104]. Relapse prevention with naltrexone may also be suitable for pregnant women who are unable to stabilize on methadone or buprenorphine. Patients should be warned that reduced tolerance following naltrexone treatment may increase the risk of overdose [13].

The primary problem with naltrexone treatment is low compliance, with retention in treatment ranging from 6% to 45% [34,104]. Strategies to improve treatment compliance include combining naltrexone maintenance with contingency management, involving the provision of vouchers redeemable for goods and services contingent on naltrexone intake and drug-free urines [82]. The authors of one investigation evaluated prescribing patterns for opioid use disorder medications among a commercially insured population in the United States from 2010 to 2014. The evaluation revealed consistently low treatment completion rates for two forms (e.g., injectable, oral) of naltrexone. At 30 days post-initiation, 52% of individuals treated with injectable naltrexone had discontinued treatment, and 70% of individuals treated with oral naltrexone had discontinued treatment. The proportion of patients treated with either form of naltrexone grew over time, but the discontinuation rates were significantly higher compared with individuals treated with sublingual or oral-mucosal buprenorphine/naloxone [151]. Although the focus of this investigation was not on the reasons for treatment discontinuation, it did highlight the poor treatment compliance with naltrexone. The extended-release injectable naltrexone formulation may help overcome the compliance issues associated with the oral formulation [104].

Naltrexone is contraindicated in patients with hypersensitivity reactions to the agent, in patients with current physical and physiologic dependence on opioids, and in patients in acute opioid withdrawal [104]. At present, reviewers conclude "there is no sufficient evidence of efficacy of naltrexone to justify its use in the maintenance treatment of opioid dependence" [152].

Psychosocial Monotherapy

Evidence Based Practice Recommendation

In opioid treatment program settings, the Department of Veterans Affairs Work Group suggests offering individual counseling and/or contingency management, with consideration of patient preferences and provider training/competence.

https://www.guideline.gov/summaries/summary/49968

Last Accessed: March 21, 2018

Strength of Recommendation: Weak for

There is no data to support psychosocial interventions as a sole intervention for opioid dependence [127,128]. Psychosocial treatments alone are not adequately proven treatment modalities, nor are they superior to any other type of treatment for opioid dependence [153]. However, psychosocial treatments offered in addition to pharmacologic detoxification treatments are effective in terms of treatment completion, opioid use, and participant abstinence at follow-up [128].

12-Step/Self-Help Programs

Twelve-step programs for opioid abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety [154]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [154]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [155].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [155].

Part of the effectiveness of NA and MA is related to their ability to provide a competing and alternative reinforcer to drug use. Involvement in 12-step programs can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect the person stands to forfeit if they resume drug using. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [156]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Emphasis and facilitation of early engagement in a 12-step program involvement are key [157].

Narcotics Anonymous

Relative to the more established AA, there are few studies published on NA. However, some research has revealed important information about how NA functions to help both new and long-term members abstain from opioids and other drugs. Being active as an NA sponsor over a one-year period was found to be strongly associated with substantial improvements in sustained abstinence rates for the sponsors. This suggests that providing direction and support to other newer addicts is a way to enhance the likelihood of one's own abstinence [158]. In addition to being a sponsor, having a sponsor also is associated with positive outcomes. One analysis explored the predictors and outcomes of having a 12-step sponsor among individuals receiving treatment for stimulant use disorders [159]. Four types of 12-step groups were evaluated: NA, AA, Cocaine Anonymous, and Crystal Meth Anonymous. Factors evaluated were the extent to which participants obtained sponsors, the extent to which other predictors (e.g., beliefs, expectations) were associated with having a sponsor, and the effect of sponsorship at the end of treatment. Participants in the 12-step facilitation intervention had higher sponsorship rates at the end of treatment and at three-month follow-up, and end-of-treatment sponsorship predicted a higher likelihood of abstinence and no drug-related problems at follow-up [159].

Improvement in psychologic functioning as a result of NA involvement has been observed by Christo and Sutton [160]. Among the 200 NA members in their study, those who had been off drugs and involved with NA for longer periods tended to have lower trait anxiety and higher self-esteem scores, with those abstinent for more than three years exhibiting levels of anxiety and self-esteem similar to those of a comparison group of 60 students from a vocational training college [160].

Methadone Anonymous

MA was begun in 1991 when a staff member of a methadone maintenance treatment clinic in Baltimore attended an NA meeting and observed a woman receiving an "Anniversary Chip" in recognition of abstinence from heroin, only to be told to return the chip when she shared that methadone maintenance helped make it possible. This staff person went on to develop a 12-step program for methadone patients [161].

MA is based on the belief that "methadone is a therapeutic tool of recovery that may or may not be discontinued in time, dependent upon the needs of the individual," and that continued abstinence from drugs of abuse, including alcohol, is the foremost goal of recovery [162]. Most MA meetings are hosted by methadone clinics, and there are more than 1,000 MA clinics worldwide [163].

There are very few published studies involving MA. One study found that, similar to other 12-step programs, MA members undergo a spiritually-mediated transformation in their recovery process, with members describing methadone as the core of the group experience and an aid to spiritual transformation [164]. Length of time in MA has been found to be associated with reductions in the use of other substances as well, including alcohol, cocaine, and marijuana. Clients in methadone maintenance programs have rated components of MA to be significantly more helpful to recovery than methadone treatment components, suggesting that MA participation has benefits not available in professionally-driven methadone therapy programs [161].

ACUPUNCTURE

Auricular acupuncture is the most common acupuncture approach for substance abuse, including opioid abuse and dependence, in the United States and the United Kingdom. This technique consists of bilateral insertion of acupuncture needles in the outer ears [165]. There is controversy surrounding the presumed mechanism of action of acupuncture. Western scientists attempt to explain its action on the body's electromagnetic system, with the acupuncture needle creating a difference in electrical potential that stimulates extracellular ion flow. Chinese practitioners, who have been using acupuncture for several thousand years to treat a wide range of maladies, attribute its effects to unblocking or removing an excess of qi, or life energy, along key channels referred to as meridians [166].

Results from well-designed studies indicate that auricular acupuncture treatment is not sufficient in efficacy as a stand-alone treatment for opioid dependence. The placebo response rate is substantial, and the body of evidence does not demonstrate the type of qualitative and quantitative rigor needed to validate acupuncture efficacy in the treatment of opioid-addicted patients. Common adverse events from acupuncture include needle pain, fatigue, and bleeding; fainting and syncope are uncommon. Feelings of relaxation are reported by as many as 86% of patients [165]. There is some evidence that differences in efficacy may be influenced by racial physiologic differences among persons of European and Asian descent [165].

A 2016 review of 199 studies found that contradictory results, intergroup differences, and acupuncture placebo effects made it difficult to evaluate the effectiveness of acupuncture for drug addiction treatment [167]. The authors of another review looked at clinical trials of 100-Hz electroacupuncture for detoxification treatment. They found a potential for the treatment to allay opioid-associated depression and anxiety but no effect for opioid craving [168].

INTERVENTIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

For those who are not proficient in English, it is important that information regarding the risks associated with the use of opioids and available resources be provided in their native language, if possible. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required. Interpreters can be a valuable resource to help bridge the communication and cultural gap between patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. In any case in which information regarding treatment options and medication/treatment measures are being provided, the use of an interpreter should be considered. Print materials are also available in many languages, and these should be offered whenever necessary.

17. MANAGEMENT OF COMORBID PSYCHOPATHOLOGY

Psychiatric comorbidity often accompanies opioid dependence and plays an important role in treatment outcome. Multiple national population surveys have found that roughly 50% of those who experience mental illness during their lives will also experience a substance use disorder and vice versa [169,170]. More than 60% of adolescents in community-based substance abuse treatment programs also meet diagnostic criteria for another mental illness [171]. An estimated 43% of individuals in treatment for nonmedical use of prescription opioids have a diagnosis or symptoms of a mental health disorder, particularly depression and anxiety [172].

Major depression prevalence among opioid-dependent patients is estimated to be 20% to 30% lifetime and 10% to 20% at enrollment in treatment. Depression is also associated with the use of prescription opioids for chronic pain and worse treatment outcomes. Approximately 50% of patients with chronic pain have a comorbid psychiatric condition, and 35% of patients with chronic back and neck pain have a comorbid depression or anxiety disorder [37,138,173,174]. The prevalence of depression is lower in out-of-treatment patients than in those seeking treatment and is associated with increased retention in methadone treatment. Thus, depression has a mixed effect on prognosis. It appears to be a motivating factor in treatment-seeking while at the same time interfering with treatment effectiveness [37,138,173,174]. In addition, opioid-dependent patients with Axis I psychiatric comorbidity often require significantly higher methadone doses [57].

Psychiatric comorbidity is especially pronounced with serious mental illness, which is defined by the Substance Abuse and Mental Health Services Administration as individuals 18 years of age or older having, at any time during the past year, a diagnosable mental, behavior, or emotional disorder that causes serious functional impairment that substantially interferes with or limits one or more major life activities [175]. Approximately one in four individuals with a serious mental illness (e.g., major depression, schizophrenia, bipolar disorder) have a comorbid substance use disorder [176].

A main issue in managing comorbid conditions is the differentiation of independent versus substance-induced disorders, as therapeutic plans differ for the two conditions [173]. Substance abuse can result in changes in mood, appetite, sleep patterns, beliefs, and perceptual experiences, all of which may present as psychiatric disorders but resolve with stabilization of drug use. Treatment should not focus solely on the non-substance-use psychiatric diagnosis, as symptom reduction will not translate into reduced drug use. Active substance use can also alter the presentation of personality and diagnosis of a personality disorder [177].

ASSESSMENT

It is important to assess dependent opioid users for other psychiatric and substance use disorders, especially alcohol and cocaine dependence because they are frequent comorbidities in opioid-dependent patients and can aggravate depressive symptoms [104,176]. Bipolar illness is rare but has substantial treatment implications. Anxiety disorders frequently co-occur with depression, and traumatic experiences and post-traumatic stress disorder are common and should be thoroughly evaluated and treated [138,176]. Independent disorders are psychiatric conditions occurring during periods of sustained abstinence or having an onset before the substance-use disorder. A positive family history can aid in identifying an independent psychiatric disorder.

Comprehensive assessment tools can reduce the chance of a missed or incorrect diagnosis. Patients with psychiatric comorbidities often exhibit symptoms that are more persistent, severe, and resistant to treatment compared to patients who have either disorder alone [178,179,180,181]. Assessment is critical to identify concomitant medical and psychiatric conditions that may need immediate attention and require transfer to a higher level of care [104]. The ASAM recommends that clinicians also assess social and environmental factors to identify facilitators and barriers to treatment, specifically to pharmacotherapy [104].

TREATMENT APPROACH

Treatment should initially focus on stabilization of the patient's substance use disorder, with an initial goal of two to four weeks abstinence before addressing comorbidities. Patients who persistently display symptoms of a psychiatric disorder during abstinence should be considered as having an independent disorder and should receive prompt psychiatric treatment [177].

Although depressive symptoms often improve following treatment admission, significant symptoms will persist in some patients [138]. Antidepressant medications can be effective in patients dually diagnosed with opioid dependence and depression when used at adequate doses for at least six weeks [182]. Factors emphasizing prompt antidepressant treatment include greater severity of depression, suicide risk, and co-occurring anxiety disorders [138].

SSRIs are generally safe and well-tolerated, but clinical trials with these agents in methadone patients have been negative [138]. Therefore, SSRIs may be considered first-line treatment based on their safety profile, but if the patient does not respond, then TCAs or newer generation agents should be considered. SSRIs in combination with cognitive-behavioral therapy have been found to be highly effective for treating clients with comorbid depression [170]. More stimulating antidepressants, such as venlafaxine and bupropion, may be suitable in patients with prominent low energy or past or current symptoms consistent with attention deficit hyperactivity disorder (ADHD) [138]. The utility of nonpharmacologic treatments should be emphasized. Psychosocial therapies are as effective as pharmacotherapy in the treatment of mild-to-moderate depressive and anxiety symptoms. Treatment of personality disorders is nonpharmacologic [177]. If depression persists, psychosocial modalities, such as cognitive therapy, supportive therapy, or contingency management, have some evidence to support their efficacy in opioid-dependent patients [138,170].

In the treatment of insomnia and anxiety, trazodone and nefazodone are helpful agents, although nefazodone should be used with caution because of reports of liver toxicity. Mirtazapine, a sedating antidepressant, is a logical alternative. A baseline ECG is recommended prior to a TCA trial in opioid users [138]. Benzodiazepines for anxiety should be avoided due to the liability of abuse and the potential of drug-seeking behavior, which is detrimental to treatment. Effective alternatives to benzodiazepines include antidepressants and anticonvulsant mood stabilizers. Sedating atypical antipsychotics may also be useful but should be used with caution due to potential side effects [138].

Medical comorbidities that may impact mental status and treatment response include [138]:

- Hypothyroidism

- HIV infection

- Hepatitis C and B

- Chronic lung disease

- Hypertension

- Diabetes

- Cardiovascular disease

The presence of comorbid conditions increases severity and complicates recovery. Patients with comorbid disorders demonstrate poorer treatment adherence and higher rates of treatment dropout [180,183]. A natural outgrowth of increased severity has been greater interest in and use of integrated treatment, compared with separate treatment of combined conditions [170]. Integrated treatment refers to a treatment focus on two or more conditions and the use of multiple treatments (e.g., combination of psychotherapy and pharmacotherapy). It is an approach supported by research that demonstrates the superiority of an integrated approach [184,185,186,187,188].

TREATING POLYSUBSTANCE ABUSE/DEPENDENCE

As noted, polysubstance use is the norm rather than the exception among opioid-dependent patients. The optimal approach to treating multiple substance abuse depends on the substances being used, the severity of the abuse, the treatment setting, familiarity of the clinician with treatment of the substance problem, and available resources for treatment. Optimal patient outcomes occur with pharmacologic and psychosocial combination therapy [177].

18. OPIOID USE DURING PREGNANCY

A portion of pregnant women with substance dependence continue using addictive substances despite awareness of the potential harm to the fetus [189]. Infants can sustain adverse effects from maternal opioid use, although it is difficult to separate factors due to opioid use from those due to the abuse of other drugs, poor prenatal care, poor nutrition, or other complications [100,190]. Reports of adverse effects of opioid use on fetuses and neonates include [189]:

- Fetal growth restriction

- Intrauterine withdrawal with increased fetal activity

- Depressed breathing movement

- Preterm delivery

- Preterm rupture of the membranes

- Meconium-stained amniotic fluid

- Perinatal death

- Neonatal abstinence syndrome (NAS)

Opioid withdrawal is a physiologic rebound from the chronic drug effects on brain function. In pregnant women, rapid opioid withdrawal may precipitate preterm labor; in neonates, it may be fatal [189]. NAS occurs when an infant becomes dependent on opioids or other drugs used by the mother during pregnancy [191]. It is an expected and treatable condition seen in 30% to 80% of infants born to women taking opioid agonist therapies [190]. NAS increased fivefold nationally between 2000 to 2012, coinciding with rising rates of opioid prescribing to pregnant women [192]. NAS may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, and seizures [191,193]. Withdrawal symptoms in neonates can include tremors, diarrhea, fever, irritability, jitteriness, sweating, fever, vomiting, and generalized convulsions [191,194].

The optimal treatment for NAS has not been established. Opioids are considered the first-line therapy [194]. Opioid treatment of NAS reduces the time to regain birth weight, reduces the duration of supportive care, and increases the length of hospital stay. There is no evidence of effect on treatment failure [195]. Treatment with long-acting opioids has been shown to be superior to phenobarbital and diazepam in infants with NAS [195].

Evidence Based Practice Recommendation

The World Health Organization recommends that healthcare providers should, at the earliest opportunity, advise pregnant women dependent on opioids to cease their use and offer, or refer to, detoxification services under medical supervision where necessary and applicable. Detoxification can be undertaken at any stage in pregnancy, but at no stage should antagonists (e.g., naloxone, naltrexone) be used to accelerate the detoxification process.

https://www.guideline.gov/summaries/summary/48894

Last Accessed: March 21, 2018

Strength of Recommendation/Level of Evidence: Strong/very low

Phenobarbital is generally considered a second-line agent and is effective for the treatment of withdrawal and polydrug exposure. Clonidine is also a safe second-line option for treatment of NAS symptoms that are refractory to opioid therapy [194,196]. Buprenorphine and methadone have both been shown to be safe and effective treatments for opioid use disorder during pregnancy [197]. A 2014 meta-analysis showed that methadone was associated with higher treatment retention and buprenorphine resulted in a 10% lower incidence of NAS, decreased neonatal treatment time of 8.46 days, and less morphine (3.6 mg) needed [198]. Infants whose mothers receive these medications may still experience NAS; however, it is less severe than in the absence of treatment [198].

In treating pregnant women with substance dependence, psychologic and pharmacologic treatments are often combined. Psychosocial treatments include contingency treatment, community reinforcement, behavioral marital therapy, cognitive-behavioral skills training, motivational enhancement therapy, and 12-step approaches [189].

HEROIN

Heroin rapidly crosses the placental blood barrier. Between 55% and 94% of infants born to IV heroin users exhibit signs of neonatal withdrawal, with a small minority showing neonatal seizure activity [199]. Methadone maintenance has been found to be an effective harm-reduction strategy and can reduce acute neonatal withdrawal problems, including seizures [200].

METHADONE

Pregnant women who are opioid dependent should be maintained on the lowest effective dose of methadone; detoxification, if attempted, should be done in the second trimester [189]. Outcomes are poor for patients who leave treatment. Fetal exposure can result in lower birth weight, smaller head circumference, jaundice, and thrombocytosis, although the cause of these conditions is difficult to distinguish between methadone and other concurrently-used substances. Methadone in the newborn infant will produce physical dependence and subsequent withdrawal symptoms that may not emerge until 48 hours after birth, regardless of maternal dose. Methadone-exposed infants function within a normal range of cognition at one- and two-year evaluations [189]. Methadone levels in breast milk appear to be small [201].

BUPRENORPHINE

Buprenorphine has been administered successfully to opioid-dependent pregnant women as a maintenance replacement opioid. Placental transfer may be less than methadone, reducing fetal exposure and subsequent dependence and withdrawal. Buprenorphine has a low incidence of labor and delivery complications and of neonatal abstinence syndrome [189]. Multiple small case series have examined maternal buprenorphine concentrations in breast milk and all concur that the amounts are small and unlikely to have short-term negative effects on the developing infant [202].

OXYCODONE

Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides and primarily excreted through urine. Oxycodone has been detected in breast milk, and although not found to be a teratogenic in experimental animals, it is not recommended for use in pregnancy [56]. Management of infants born to mothers abusing oxycodone is of particular concern because the drug and its metabolites are difficult to detect by the enzyme immunoassay methods typically used for urine and meconium opioid screens [203].

NALTREXONE

The literature is limited and equivocal regarding naltrexone and pregnancy. The substantial drop-out rates due to the reward-blocking and dysphoric effects of this drug have resulted in limited reports on pre- and perinatal complications. One Australian study showed no obstetric complications and healthy-appearing infants, leading the authors to conclude naltrexone is a safe alternative in select pregnant patients [189]. However, other authors have found that naltrexone can cause premature labor and fetal death, and it is considered to be pregnancy category C [8,56]. The manufacturer recommends that nursing mothers either discontinue the drug or discontinue nursing [56].

19. PROGNOSIS OF TREATMENT FOR OPIOID USE DISORDER

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [204]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [83].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [34].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [34].

20. CONCLUSION

Dependence on opioids is associated with serious morbidity and mortality, and advances in the understanding of the dependence have led to the development of effective treatments. More recently, the abuse of prescription opioids has become considerably more widespread, fueled in part by the availability of such drugs over the Internet. This has resulted in opioid abuse and dependence in populations seldom afflicted in the past. Thus, medical, mental health, and other healthcare professionals in a variety of settings may encounter patients with an opioid use disorder. The knowledge gained from the contents of this course can greatly assist the healthcare professional in identifying, treating, and providing an appropriate referral to patients with opioid use disorders.

21. GLOSSARY

Acetylation: the process of introducing an acetyl group into a compound.

Adenylate cyclase: an enzyme that converts adenosine triphosphate to cyclic adenosine monophosphate (cAMP).

Anhydrous: having no water.

Axis I mental disorders: clinical syndromes, including major mental disorders such as depression, schizophrenia, and obsessive-compulsive disorder.

Bioavailability: the amount of active drug that reaches systemic circulation after ingestion.

Congener: a compound of the same kind or category.

Cosyntropin test: a test to determine how well the adrenal glands respond to the hormone ACTH. Involves the measurement of cortisol in the blood before and after injection of cosyntropin.

Effectors: a molecule that binds to and changes the activity of a protein.

Enantiomer: either of a pair of isomers that are mirror images of each other.

Endogenous opioid: an opioid that occurs naturally in the body, such as endorphin.

Equianalgesic: having the same analgesic effect.

First-pass metabolism: reduction of drug concentration prior to systemic circulation, often due to hepatic metabolism.

Free morphine: unmetabolized morphine.

Full agonist: chemicals or drugs that bind to and activate a receptor and display full efficacy (response) at that receptor.

Glucuronidation: a detoxification pathway in the liver whereby glucuronic acid is conjugated with toxins.

Hedonic: having a positive or pleasurable effect.

Ketone: water-soluble compound produced when fatty acids are metabolized in the liver and kidney.

Kinase: an enzyme that largely acts to transmit signals and control the complex activities of cells.

Ligand: a signal-triggering molecule.

Lipophilic: fat-soluble.

Metabolite: a substance involved in metabolism, either as a by-product or as a necessary component.

Parent drug: the drug initially consumed or administered prior to metabolization.

Peptide: a short chain of amino acids.

Phosphorylation: the addition of a phosphate group to an organic molecule.

Plastic alternation: pliable or alterable exchange.

Polymorphism: genetic variation within a population.

Prodrug: a pharmacologically inactive compound that converts to an active form within the body.

Pseudoaddiction: preoccupation with and pursuit of opioid medication driven by a desire for pain relief and not for the drug's mood-altering effects. Results from poorly treated pain.

Sensorium: an individual's perception and entire sensory environment.

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