Continuing Education Activity

This activity focuses on the critical evaluation and management of opioid use disorder (OUD), a pervasive condition significantly diminishing patients' quality of life and contributing to a widespread epidemic in the United States. With over 16 million affected globally and 2.1 million in the United States, the course emphasizes the urgency of identifying and promptly treating persistent opioid use and misuse. Participants will review evidence-based treatment options, including methadone and buprenorphine, and examine their roles in both the acute phase for detoxification and long-term management. The program also discusses the Mainstreaming Addiction Treatment (MAT) Act, which empowers healthcare providers to prescribe buprenorphine without the previous X-Waiver limitations. Furthermore, the course explores the multidimensional approach to treatment, including behavioral therapy, peer support, and the integration of nonpharmacologic interventions, reinforcing the need for an interprofessional team in optimizing patient care. Overall, this activity will equip healthcare professionals with the knowledge and skills necessary to navigate the intricate landscape of OUD, emphasizing a patient-centered, evidence-based, and interdisciplinary approach to improve outcomes and address the ongoing opioid epidemic.

Objectives:

• Identify the symptoms of opioid use disorder and opioid-related medical emergencies. 
• Implement appropriate evaluation and diagnosis strategies for opioid use disorder.
• Differentiate the various treatment options for opioid use disorder, including pharmacologic and nonpharmacologic strategies. 
• Collaborate effectively with other healthcare professionals to diagnose, treat, and comprehensively manage opioid use disorder.

Introduction

Opioid use disorder (OUD) is defined as the chronic use of opioids that causes clinically significant distress or impairment. Symptoms of this disease include an overpowering desire to use opioids, increased opioid tolerance, and withdrawal syndrome when opioids are discontinued. Thus, OUD can range from dependence on opioids to addiction.[1] OUD affects over 16 million people worldwide and over 2.1 million in the United States. Strikingly, there are as many patients using opioids regularly as there are patients diagnosed with obsessive-compulsive disorder, psoriatic arthritis, and epilepsy in the United States. More than 120,000 deaths worldwide every year are attributed to opioids.[2] Examples of opioids include heroin (diacetylmorphine), morphine, codeine, fentanyl, and oxycodone.

 A rise in the prevalence of OUD and opioid deaths lends to the importance of clinicians' appreciation for the complexity of OUD. OUD typically involves periods of exacerbation and remission, but the vulnerability to relapse occurs throughout a patient's lifetime. Stressful events, loss of economic stability, and relationship issues can increase the risk of relapse. Opioid addiction is similar to other chronic relapsing conditions; signs and symptoms can be severe, and treatment adherence is often problematic. 

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a  controlled substance certificate to prescribe buprenorphine for OUD, just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and strives to integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act eliminated the DATA-Waiver (X-Waiver) program that was previously required to prescribe medications for the treatment of OUD. All DEA-registered practitioners with Schedule III prescribing authority may now prescribe buprenorphine for OUD in their practice if permitted by applicable state law. Prescribers previously registered with a DATA Waiver will receive a new DEA registration certificate reflecting this change without further action. Additionally, there are no longer limits on the number of patients with OUD that a practitioner may treat with buprenorphine or tracking of patients treated with buprenorphine required. Pharmacists can now dispense buprenorphine prescriptions using the prescribing authority's DEA number. Of note, prescribers are still required to comply with any applicable state limits regarding the treatment of patients with OUD. Information on State Opioid Treatment Authorities (SOTA) can be found at SAMHSA.gov. 

Etiology

Opioid dependence and addiction are products of many biological, environmental, genetic, and psychosocial factors.[3] Most opioids in use are prescribed, but many are also obtained illegally. After a relatively brief period, many patients taking opioids demonstrate opioid dependence. Opioid dependence can manifest as physical dependence, psychological dependence, or both. Opioid-dependent patients will experience withdrawal if opioids are stopped abruptly. Thus, many opioid-dependent patients will seek continued access to opioids, by legal or illegal means, to prevent withdrawal. Ongoing opioid dependence may lead to addiction and uncontrolled opioid use. 

OUD occurs in individuals from all educational and socioeconomic backgrounds. Patients at particular risk for OUD include those deficient in neurotransmitters such as dopamine or with first-degree relatives who have a substance abuse disorder.[4] Patients who have been exposed to an environment that includes opioid use may also be more likely to develop OUD. Environmental risks for OUD include peer use of opioids or exposure to opioid analgesics due to a previous injury. Patients with a history of untreated depression, post-traumatic stress disorder, anxiety, or childhood trauma are also at risk for OUD.[5] 

Epidemiology

Over 16 million people worldwide and 3 million in the United States meet OUD criteria. Concerningly, OUD results in over 120,000 and 47,000 deaths per year worldwide and in the United States, respectively.[6] In the United States, opioids have killed more people than any other drug in history. Recreational use of opioids was at its highest in 2010 and has gradually decreased as the opioid epidemic has gained attention in the United States. Up to 50% of patients on chronic opioid therapy meet the criteria for opioid use disorder.[7]

The prevalence of opioid use and dependency varies by age and gender. Men are more likely to use and become dependent on opioids. Thus, men account for the majority of opioid-related overdoses. Women are prescribed opioids for analgesia more often than men. Opioid-related deaths are highest among individuals between the ages of 40 and 50 years, while heroin overdoses are most common among individuals between the ages of 20 and 30 years.

Pathophysiology

OUD develops along a continuum of opioid use. Physical dependence on opioids may develop rapidly and is likely the result of many changes in mu-opioid receptors, including receptor desensitization, internalization, and signaling abnormalities.[8][9] Physical dependence is also responsible for withdrawal symptoms when opioids are stopped abruptly. Thus, physical dependence on opioids creates both positive and negative reinforcement for continued opioid use. Patients meet OUD criteria if their continued opioid use creates clinically significant impairment or distress. Clinically significant impairment and distress can manifest in several ways but are often the result of impairments in controlling opioid use and intense opioid cravings.[10]

History and Physical

To make the diagnosis of OUD, the patient must meet the diagnostic criteria per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).[11][12] Per the DSM-5, OUD is defined as repeated opioid use within 12 months leading to problems or distress with 2 or more of the following occurring:

1. Continued opioid use despite worsening physical or psychological health
2. Continued opioid use despite social and interpersonal consequences
3. Decreased social or recreational activities
4. Difficulty fulfilling professional duties at school or work
5. Excessive time is taken to obtain or recover from taking opioids
6. More opioids are taken than intended
7. Opioid cravings occur
8. Inability to decrease the amount of opioids used
9. Tolerance to opioids develops
10. Opioid use continues despite the dangers it poses to the user
11. Withdrawal occurs, or the user continues to take opioids to avoid withdrawal

The presence of 6 or more of these diagnostic criteria indicates severe OUD. The signs and symptoms of opioid use disorder include drug-seeking behavior, the presence of legal or social ramifications due to opioid use, multiple opioid prescriptions from different prescribers, opioid cravings, increased opioid usage over time, and symptoms of opioid withdrawal when stopping opioid use. Physical findings and complaints consistent with opioid withdrawal include muscle aches, diarrhea, rhinorrhea, nerve excitability, and chills with cessation of use. 

Evaluation

A full social and mental health history should be a part of an initial evaluation for OUD. History of injuries, trauma, previous surgeries, and hospitalization may be crucial to the evaluation to identify gateways for opioid use. If the patient uses intravenous drugs, tests should be ordered to screen for HIV and hepatitis B and C.[13][14][15] Urine drug screening for opioids should be performed before starting treatment for OUD and regularly with subsequent visits to evaluate the patient's compliance with treatment and abstinence from illicit opioid use.[16]

Treatment / Management

The treatment of OUD improves physical and psychological conditions, reduces risks of overdose, and helps with the avoidance of criminal behavior and subsequent penalties.[17][18] There are a variety of approaches to the rehabilitation and maintenance of patients with OUD. Rehabilitation begins with a cognitive behavioral approach similar to that used in the treatment of other chronic conditions. Maintenance programs include psychological support. Patients are encouraged and motivated to change through education, reward cooperation, and medications. The goal of cognitive behavioral therapy is to minimize drug relapses. Patients with OUD are encouraged to participate in self-help programs such as Narcotics Anonymous. The combination of education, motivational enhancement, and self-help assists patients to change how they think about the ways that opioids affect their lives.[19][20][19] Group therapy helps maintain self-control and restraint for patients with OUD.[21] Group therapy is also cost-effective compared to individualized therapy in treating OUD.[22]

Various forms of rehabilitation help patients recognize that change is possible. There is a need to decrease behaviors that perpetuate illicit drug use while developing new behaviors that diminish drug-related problems.[23]  Nonopioid drugs and physical therapy can provide a long-term solution to pain management instead of relying on the use of opioids, for example. Additionally, education about dealing with pain syndromes and minimizing opioid use can help build rapport and create realistic treatment goals. Cognitive behavioral therapy is most effective if combined with medications; however, there are mixed results on its effectiveness.[12][24] 

Opioid replacement, maintenance, or substitution therapy involves replacing the problematic opioid with a safer one. These alternative agents are prescribed under medical supervision. Medication-assisted treatment (MAT) and outpatient buprenorphine office therapy (OBOT) help the patient experience reduced symptoms of drug withdrawal and cravings and little or no euphoria. Opioid maintenance drugs help the patient experience reduced symptoms. Almost half of the patients can maintain abstinence from additional opioids while receiving replacement therapy.[25] 

The selection of which agent or agents to use for treatment can be simple or very complex, depending on patient-specific factors. Methadone, an oral mu-receptor agonist, is commonly used in opioid replacement. It has been widely used worldwide. In the US, outpatient methadone is offered only for specially monitored clinics. Patients with OUD with physiologic features of opioid withdrawal or who are likely to relapse are eligible to receive methadone from a clinic. The advantages of methadone treatment include reduced euphoric effects, decreased narcotic cravings, and reduced transmission of infectious diseases through avoidance of intravenous drug use. Methadone maintenance is non-sedating and is medically safe, provided there is no concomitant use of other prescription or illicit drugs. The maintenance phase can be attained with careful ramping of the dose upward. Consideration must be given to the long half-life of methadone, even if all of the symptoms of withdrawal, as well as the cravings, are not quickly abated. Other ancillary medications can be used to treat the symptoms as the dose of methadone is slowly increased. The length of the maintenance phase can last years to an entire lifetime. Tapering off methadone can take weeks or months, depending on the patient's level of opioid dependence.[26][27] 

An alternative oral, long-acting opioid for maintenance therapy is buprenorphine. Buprenorphine is a partial mu-receptor agonist. Similar to methadone, Buprenorphine is gradually ramped upwards to achieve an effective dose, and not all the symptoms of withdrawal can be immediately abated. It is crucial to ensure that the patient is in opioid withdrawal before the initiation of buprenorphine to avoid the occurrence of precipitated withdrawal.[28][29] Buprenorphine is available as a sublingual tablet, sublingual film, buccal film, subcutaneous solution, transdermal patch, and intradermal implant. Sublingual tablets and films may also be combined with naloxone, a mu-opioid receptor antagonist. Naloxone is not absorbed orally and only exerts its action when injected into the bloodstream. Thus, the addition of naloxone to the buprenorphine formulation helps to deter abuse. Following induction and stabilization with sublingual tablets or the buccal film, subcutaneous solutions and intradermal implants may be used for lasting maintenance therapy.

There is no consensus among experts on whether methadone or buprenorphine therapy is superior in a broad population of patients with OUD. Thus, the agent use should be based on patient-specific factors.[30] The use of methadone maintenance may increase patient retention over buprenorphine. Additionally, methadone may treat withdrawal symptoms and cravings better than buprenorphine for patients who use fentanyl.

The length of treatment for OUD should also be individualized for each patient. Some clinicians attempt to discontinue medications for OUD after 1 year of treatment. Other clinicians suggest that treatment should be lifelong due to the risk of relapse and overdose death after patients stop treatment. If treatment is stopped, medications should be decreased slowly and adjusted if withdrawal symptoms are observed.[31][32][33]. 

Naltrexone may also be used in patients with OUD. Naltrexone works by blocking opioid effects and helps maintain abstinence from opioids by antagonizing the mu-opioid receptor. Naltrexone may only be initiated when the patient is free of physiological opioid dependence, and at least seven days without acute withdrawal symptoms are required before starting the medication. Both oral and intramuscular naltrexone are superior to placebo in maintaining abstinence from opioids, but the intramuscular form may be more effective.[34] The intramuscular form may also offer better compliance due to monthly administrations. Intramuscular naltrexone is FDA-approved for opioid dependence, and naltrexone administration following completion of treatment with buprenorphine has shown to be an effective treatment in OUD.[35][36]

Many other medications are used adjunctively to treat OUD. Clonidine may abate withdrawal symptoms while the dose of methadone or buprenorphine is being adjusted. Tizanidine helps decrease anxiety as well as muscle pain associated with opioid withdrawal. Bupropion is used to combat the symptoms of anxiety. Diarrhea, nausea, and vomiting are treated with loperamide and ondansetron, respectively. 

Differential Diagnosis

The differential diagnosis of OUD includes malingering and other substance abuse disorders. Chronic pain disorders and untreated mental health issues may also appear similar to OUD. Evaluation and identification of the underlying medical and mental health disorders are of the utmost importance in making a definitive diagnosis of OUD. Often, OUD is diagnosed in addition to other substance abuse and mental health disorders.

Prognosis

The diagnosis of OUD helps clinicians to mitigate risks for patients taking chronic opioids. Clinicians should offer naloxone to all patients with OUD.[37][38] Patients are at the highest risk for opioid-related death in the first 4 weeks of OUD treatment and for 4 weeks after treatment ends.[39] Thus, close contact with the patient should be maintained both during and after treatment.[40]

OUD treatment reduces the incidence of long-term opioid addiction while decreasing illegal opioid use and mortality. Crimes associated with drugs and the expense of dealing with HIV, sepsis, and other medical complications are also decreased. Specifically, methadone treatment is associated with a 50% reduction in all-cause mortality, as well as a 50% reduction in the incidence of hepatitis C. Methadone therapy has also been shown to decrease drug-related crimes and illicit drug use, improve social interactions, and increase rates of retention in rehabilitation programs.[41][42][43]

Complications

Addiction is the most severe complication of OUD. Addiction to opioids is the continued use of these drugs despite adverse consequences or events. Opioid addiction occurs by sensitizing the drug-reward system and amplifying compulsive drug-seeking. Specifically, chronic opioid use affects the orbitofrontal area, which is essential for regulating anxiety, emotional responses, and reward-related behaviors. Additionally, opioid addiction affects every aspect of a person's life. Legal trouble, loss of personal relationships, and significant morbidity and mortality are all consequences of opioid addiction.[39]

Opioid withdrawal is also a significant complication of OUD. Opioid withdrawal onset varies with the type of opioid used. Heroin withdrawal begins in as little as five hours, whereas methadone withdrawal may occur 2 to 3 days following the last ingestion. The duration of opioid withdrawal symptoms varies greatly by patient. Thus, symptoms may last for a few days or persist for weeks.[44]

Finally, opioid overdose may occur as a result of OUD. The risk of overdose in untreated patients with OUD is high, but there is still a significant risk of overdose in patients who have received treatment. The time of highest risk for treated patients is the period between detoxification and the start of maintenance therapy. The use and acceptance of cognitive behavioral therapy may decrease this risk. Sadly, however, the mortality rate for patients on chronic opioids remains extremely high.[45]

Deterrence and Patient Education

Methadone and buprenorphine should be considered for patients with OUD to minimize the risk of death. Naloxone is used in the acute treatment of an opiate overdose and can be given subcutaneously, intramuscularly, intravenously, intranasally, or by inhalation. It is reasonable to prescribe naloxone to any patient with OUD. Naloxone prescriptions should also be considered for a more general population of patients taking chronic opioids.[46][47] Finally, the involvement of an addiction or pain medicine specialist in the care of patients with OUD is essential to the development of a comprehensive and effective treatment plan. 

Enhancing Healthcare Team Outcomes

Appropriate treatment of OUD requires an interprofessional approach. Specifically, cognitive and behavioral therapies need to be supported by medical intervention to reduce the chance of withdrawal, relapse, and overdose. An interprofessional team, including physicians or advanced practice providers, nurses, pharmacists, therapists, and other addiction and substance use professionals, is responsible for coordinating OUD care. The tenets of comprehensive OUD care include:

1. Timely diagnosis of OUD
2. Discussion of the OUD diagnosis (focusing on the immediate and long-term effects of opioids on morbidity and mortality) 
3. Treatment of the underlying conditions associated with OUD (ie, cognitive behavioral therapy and antidepressants for major depressive disorder)
4. Prescription of naloxone for the treatment of overdose
5. Prescription of opioid replacement therapy or referral to an addiction medicine specialist to manage opioid replacement therapy
6. Referral to a rehabilitation program to promote cognitive and behavioral changes

Physicians, advanced practice providers, and pharmacists all play a role in recognizing and diagnosing OUD. While physicians and advanced practice providers may make the formal diagnosis of OUD, nurses and pharmacists may be the first to notice opioid misuse. Nurses may detect opioid misuse through patient screening and interviews. Pharmacists may identify patterns of opioid misuse by noting the duration of use, the receipt of opioid prescriptions from multiple providers, and the number of early refill requests.

All team members play a vital role in the treatment of OUD. Physicians and advanced practice providers prescribe medications for OUD, including buprenorphine under the MAT Act, and make referrals for cognitive behavioral therapies. Nurses assist with coordinating OUD therapies and educating patients on the importance of therapy adherence. Pharmacists and addiction medicine specialists provide recommendations to optimize OUD medication therapies and promote adherence to cognitive behavioral therapies. Therapists and other addiction and substance abuse professionals carry out cognitive behavioral therapies and promote adherence to medical therapies.

Ultimately, a successful, interprofessional approach will optimize OUD therapy for patients. Effective communication and coordination among all healthcare team members are integral to a successful approach. Additionally, the healthcare team should empower family members and members of the lay public to support the tenets of OUD care. This may further improve a patient's chances of successful OUD management.  

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Disclosure: Alexander Dydyk declares no relevant financial relationships with ineligible companies.

Disclosure: Nitesh Jain declares no relevant financial relationships with ineligible companies.

Disclosure: Mohit Gupta declares no relevant financial relationships with ineligible companies.