Addiction Disorders (FL Autonomous Practice INITIAL Pharmacology)

The National Institute of Drug Abuse (NIDA) reports findings on the cost of drug use. Data from NIDA suggests that illicit drug use is very costly to the United States, costing more than $740 billion each year in costs related to crime, lost work productivity, and health care. See table 1, adapted from the NIDA(National Institute on Drug Abuse, 2017).

Substance abuse issues are a genuine concern in the management of pain. Inappropriate prescriptions of pain medications have the potential to increase patient's chances of medication abuse. Below are some statistics regarding the current state of substance abuse.

• In 2016, 48.5 million individuals in the United States misused prescription drugs or used illicit drugs. Sixty-six percent of the 630,000 drug overdose deaths were due to illicit or prescription opioids. The number of opioid overdoses in the emergency department increased by 30 percent from July 2016 to September 2017 (Hoots et al., 2018).
• According to the Center for Disease Control and Prevention (CDC), 41 people die each day in the United States from an overdose of prescription painkillers (Center for Disease Control, 2020).
• Overdoses from synthetic opioids increased from 3.1 per 100,000 people in 2015 to 6.2 people per 100,000 people in 2016 (Hedegaard et al., 2017).
• Between 1999 and 2015, drug overdose deaths have tripled (Black et al., 2020).
• Research shows that white individuals account for 88% of those who reported non-heroin opioid substance abuse, and most of these individuals lived in rural settings.
• About 53 percent of people who have ever tried heroin develop heroin abuse or dependence (Strain et al., 2020).
• Approximately 10-20 percent of people who get a prescription of opioids for non-cancer pain go on to develop an opioid use disorder (OUD) (Degenhardt et al., 2015).

Many brain functions and their structure are affected by addiction, including reward, executive function learning and memory, motivation, and inhibitory control. These functions are critical to living and living functionally.

Dopamine is a chemical that is linked to the reward center. Food and sex stimulate the dopaminergic center and can partly be described as essential for survival. Opioids work on the same reward center and increase dopamine levels even more than food and sex. Amphetamines can increase dopamine by tenfold.

Repeated drug use changes the brain. For example, D2 receptors are lower in those who repeatedly use cocaine. Lower dopamine levels are problematic because dopamine D2 receptors control behavior based on potential consequences. Therefore, this physiological mechanism may partially explain negative choices made by cocaine users.

Social circumstances and stress can significantly affect drug use. When rats were caged (more stressed), they used more cocaine than those who were able to roam free (NIDA, 2020a).

Another study showing how stress affects drug use looked at those fighting in the Vietnam war. It showed that 60-70 percent of men who had opiate addiction in Vietnam were not using opiates 8-10 months after their return, suggesting that stress increases drug use.

The Controlled Substance Act divided drugs and other substances into five schedules, updated annually here. Schedule I controlled substances have no accepted medical use in the United States; it includes heroin and lysergic acid diethylamide (LSD).

Schedule II and IIN substances may potentially be abused and may lead to severe physical or psychological dependence. Schedule II narcotics include oxycodone (OxyContin, Percocet), hydrocodone (Vicodin, Zohydro ER), Fentanyl (Sublimaze, Duragesic), methadone (Dolophine), hydromorphone (Dilaudid), morphine, opium, and codeine.

Schedule III or IV substances have less abuse potential than those substances that are Schedule I or II. They are at high risk for psychological dependence and low to moderate risk of physical dependence. Examples of medications in this class include buprenorphine (Suboxone) and products with less than 90 milligrams of codeine per dosage unit, such as Tylenol with codeine. Schedule III includes anabolic steroids such as Depo-Testosterone and ketamine.

Schedule IV controlled substances have a lower potential for abuse when compared to Schedule III controlled substances. Examples of this class include benzodiazepines, midazolam (Versed), tramadol (Ultram) and carisoprodol (Soma).

Schedule V controlled substances have a low abuse potential relative to Schedule IV and include cough preparations that contain less than 200 milligrams of codeine per 100 milliliters or per 100 grams, such as Robitussin AC.

Most controlled substances alter mood, feeling, or thought due to their effect on the central nervous system. Medications likely to produce euphoria are more likely to be abused, but medications may be abused to aid in sleep, reduce pain, reduce anxiety, reduce depression and improve energy.

Understanding how to use opioids appropriately will reduce the risk of addiction. The management of pain may include medications, behavioral interventions, physical medicine, neuromodulation, medical interventions, or surgery. A multidisciplinary approach is typically used in the management of chronic pain.

Current treatments in chronic pain management result in approximately a 30% reduction in pain. One of the problems encountered is that general practitioners have limited training in the management of chronic pain. The use of a pain management specialist is often needed to manage pain properly.

The treatment plan should be established before initiating treatment. In this plan, the patient and the provider should discuss the benefits, risks, and alternatives before starting treatment. In addition, the clinician needs to discuss how the patient will be monitored, including how the patient will be evaluated for potential misuse of the prescribed medication. The use of written documents is often included in the plan. Documents may include agreements, treatment plans, and informed consent. It is essential that the clinician document that decision-making was implemented, including informed consent, goal setting was discussed, and a monitoring plan was defined.

When high doses of opioid prescriptions are given, there is an increased risk of overdose death. Therefore, the clinician must discuss and limit the amount of opioids prescribed. The CDC recommends that providers prescribe no more than 90 morphine milliequivalents per day (Dowell et al., 2016).

The World Health Organization (WHO) analgesic ladder was created to manage cancer pain and was published in the 1980s (World Health Organization, 2021). Key points of the analgesic ladder include:

1. Medications are given through the most comfortable route (preferably orally).
2. A stepwise approach should be followed, starting with non-opioid medications with or without adjuvant medications.
3. Managing mild to moderate enduring or progressive pain with opioids, with or without adjuvant medications, with or without non-opioids.
4. Considering the use of more potent opioids such as morphine with or without adjuvant medications with or without non-opioids for persistent pain or increasing pain.
5. Administering analgesic pain medication used for moderate to severe chronic pain on a fixed schedule (not as needed).

This approach is 80-90% effective.

Adjunctive medications enhance the analgesic effect, reduce side effects, and assist with co-existent symptoms. Patients respond distinctively to different treatments regarding efficacy and side effects. Trial and error are often used in the treatment of chronic pain.

When starting therapy, the dose should be initiated at a low dose and titrated to obtain pain control and minimize side effects. Tolerance often develops as a patient gets used to the medication.

Treatment is typically started with a short-acting medication, and the medication is then titrated upwards to control pain while side effects are monitored. After determining the dose of the medication required to provide adequate pain relief with minimal side effects, the medication can then be converted to a sustained release form and be administered once or twice a day. When a long-acting medication is used, breakthrough medication can be given.

A periodic review of the patient's pain and clinical status is essential to assure that opioids need to be continued or discontinued. Any change in the patient's state of health, degree or nature of pain, mental health, and overall function should be noted. The clinician and patient should review the proper dosage and schedule of medication. Decisions on the benefits of pain management should focus on previously decided upon goals. A positive response to treatment can include reducing pain, improving quality of life, or improved function.

An essential role of the practitioner is prescribing controlled substances. Controlled substances have inherent risks, so the prescriber must realize that a primary goal of prescribing opioids should be to maintain patient safety. A responsible prescriber should follow multiple steps to assure safe and effective care of the patient.

Steps a prescriber can take include (Manchikanti et al., 2012):

1. Assessment and documentation of a comprehensive history including medical history, substance abuse history, current medications including dosages, route and time (including opioids), psychiatric and psychosocial history.
2. Establishing a physical and psychological diagnosis and establish medical necessity before starting or maintaining opioid therapy. Those with mental illness are at higher risk of abusing medications.
3. Screening for substance abuse history because substance abusers are at increased risk of misusing controlled substances.
4. Establishing goals in therapy regarding pain control and functional goals.
5. Using prescription monitoring programs to help determine patterns of prescription use and reducing abuse of medications. These are state-run databases that track controlled substance prescriptions and help find issues with overprescribing and misuse patterns.
6. Urine drug testing can be used to identify non-compliance or aberrant drug use.
7. Consider contraindications before prescribing opioids such as acute psychiatric instability, uncontrolled suicide risk, opioid allergy, respiratory instability, history or current abuse of substances or alcohol, current use of benzodiazepines, current use of heavy doses of other central nervous system depressants, current use of other medications that have severe drug interactions or those who practice diversion of controlled substances.
8. Judicious utilization of imaging tests and other evaluations as some testing may increase fear, foster activity restriction, encourage maladaptive behaviors and encourage requests for more opioids.
9. A written agreement between prescriber and patient when opioids are used reduces the risk of abuse, diversion, misuse, and overuse.
10. Discussing the risks and benefits of the medications.
11. Obtaining informed consent before prescribing controlled substances.
12. In general, starting opioid therapy at low doses with short-acting medications.
13. Using long-acting opioids in high doses only for severe, intractable pain that cannot be adequately managed with short-acting opioids or moderate doses of long-acting opioids.
14. Using caution when titrating with long-acting opioids and consider the potential for overdose and misuse.
15. Considering consultation for those who require high-dose opioid therapy.
16. Being the only prescriber of all opioids for a given patient.
17. Monitoring for and managing constipation.
18. Prescribing the lowest effective dose and the smallest quantity needed based on the expected length of the pain.
19. Periodically reviewing the treatment plan, including any new information about the patient, their condition and their pain, and progress toward their goals.
20. Keeping accurate records.
21. Being compliant with all laws and regulations related to controlled substances.
22. Individualizing treatment based on the patient's prior exposure to opioids, response to treatment, and adverse events.
23. Monitoring for aberrant drug-related behaviors.
24. Discontinuing chronic opioid therapy in those who repeatedly engage in aberrant drug-related behaviors, do not progress toward established goals, or those who experience significant side effects. Patients who have been taking the opioid for an extended time should have the medication tapered slowly. A 10% taper per week will minimize the symptoms of withdrawal. Some recommend a faster taper, such as 20 – 50% per week for those not addicted.

Tips to Reduce Iatrogenic Harm:

• Have an upper dosing threshold. The risk of accidental overdose increases with higher doses of opioids. Prescribers should generally avoid doses of morphine or morphine equivalents more than 90 - 200 mg/day.
• Use caution with certain medications. For example, methadone should only be used by a prescriber who is exceptionally comfortable with the medication. Fentanyl is another medication that requires extreme caution as there is unpredictable absorption – especially with the patch.
• With opioid use, respiratory depression is more likely in the older population and those who are cachectic or debilitated. Patients at high risk should be monitored more closely, and opioids should not be combined with other respiratory depressants. The dose of opioids should be started at one-third to one-half the typical starting dose in at-risk patients. Titration should be done carefully. Constipation is common, and a bowel regime should be prescribed when opioids are used.
• When starting opioid therapy, it should be initially started as a therapeutic trial. Then, the decision to continue the therapy must be carefully considered based on the trial outcomes, such as progress toward meeting goals, side effects, changes in the underlying condition causing pain, and any concern for medication misuse or addiction.
• The most significant risk of opioid use is respiratory arrest and death, and this risk is greatest when therapy is started, or the dose is increased. Opioid-induced respiratory depression is manifested by the reduced desire to breathe and reduced respiratory rates. The patient will be breathing shallowly, and CO2 retention can exacerbate the sedating effects of opioids. If this is noted, the family should call 911.
• Opioids should not be used in those with respiratory depression. Titration must be done slowly, and when changing formulations, do not overestimate the converting dosage.
• Opioid rotation – changing from one opioid regime to another to reduce adverse events and improve therapeutic outcomes - may be considered. For example, tolerance to one opioid can lessen the analgesic effects, and the use of a different opioid may result in an improved analgesic effect and fewer adverse effects.
• When opioid rotation is done, it requires the prescriber to determine the approximate equianalgesic dose, as this ratio is used to get about the equivalent analgesic effect. When switching from one opioid to another, the dose should be reduced by 25 – 50% to prevent adverse effects. Multiple computer programs or applications for mobile devices are available to help with this conversion.
• Avoid combinations of opioids and benzodiazepines. When these two classes are combined, mainly if more than 100 mg of morphine or morphine equivalents per day are used, the risk of accidental overdose is high.
• Pay attention to drug-to-drug and drug-to-disease interactions.

The Centers for Disease Control and Prevention (CDC) 2016 Guideline for Prescribing Opioids for Chronic Pain (Dowell et al., 2016) reiterates the need for adequate pain control and the challenges involved, particularly in chronic pain control. It recommends that providers utilize the "full range of therapeutic options" to treat chronic pain. The report states that it is hard to quantify the number of individuals who could benefit from long-term opioid medications.

The report states that between 1999 and 2014, more than 165,000 people died from opioid overdoses. Using DSM-IV diagnosis criteria, in 2013, approximately 1.9 million individuals either abused or were dependent on opioids. Research has found practices that have contributed to the opioid overdose epidemic, the most important of which are prescribing high doses of opioids, overlapping opioid and benzodiazepine prescriptions, and the use of extended-release opioids for acute pain (Dowell et al., 2016).

To prevent prescription drug abuse, the clinician needs to assure:

• Patients are assessed and reassessed.
• Treatment agreements are used.
• Prescription monitoring occurs.
• Safe prescription methods are practiced.

Patients' risks should be assessed, and contraindications should be immediately identified. Contraindications to opioid treatment include those who have an erratic follow-up, suffer from current untreated addiction, or have poorly controlled mental illness.

When taking a patient history, document the opioid currently prescribed, its dose, the frequency of use, and duration. It is essential to query the State Prescription Drug Monitoring Program (PDMP) to confirm the patient's medication use. Also, it is essential to contact past providers to obtain medical records.

Before controlled substances are prescribed, history of illegal substance use, alcohol use, tobacco use, prescription drug use, family history of substance abuse and psychiatric disorders, history of sexual abuse, legal history, behavioral problems, employment history, marital history, social network, and cultural background should be assessed. History of substance abuse does not prohibit treatment with opioids but may necessitate more intensive monitoring or referral to an addiction specialist.

Multiple tools are available to evaluate opioid risk. The Opioid Risk Tool is a tool used in primary care to screen adults for the risk of aberrant behaviors when prescribed opioids for chronic pain. It is a copyrighted tool, encompasses five questions, and takes about one minute to use. It classifies a patient as low, moderate, or high risk to abuse opioids. Those who are high risk have a high likelihood of aberrant drug-related behavior. It is not validated in individuals without pain. The five questions include asking about family and personal history of substance abuse (alcohol, prescription drugs, or illegal drugs), age (risk is 16-45 years old), psychological disease, and preadolescence sexual abuse history. The questions are scored with different points assigned for each question, which is variable between men and women, and the total score is tallied.

Regular follow-up is essential and should occur at a minimum of every three months. When assessing the pain patient, the five A's should be assessed: analgesia, addiction, activities of daily living, adherence, and adverse effects. Part of follow-up should be urine drug testing, which can detect medication adherence and illicit and non-prescription drug use. It is critical that the clinician adequately document any interactions with patients, assessments, and results of testing and treatment plans.

Written treatment agreements, which should be used between prescribers and patients when controlled substances, help guide the conversation between patient and prescriber. It discusses expectations, the risks, and the monitoring of the controlled substances. (Table 2).

As of 2021, prescription monitoring programs are available in all states except Missouri. They provide an online database that lists all prescriptions of controlled substances dispensed for each patient by pharmacies. Ideally, the prescriber should check the database before prescribing controlled substances. If a patient has an undisclosed prescription for controlled substances, it is prescription drug misuse.

When abuse/misuse is detected, how should the clinician respond? If it is a single, minor deviation, then counseling and more intensive monitoring may be needed. Tapering controlled substances to reduce the risk of withdrawal is appropriate in more severe or persistent misuse cases. When diversion is the cause of misuse, immediate removal of the prescription is likely the best course. If a substance abuse disorder is suspected, a referral to an addiction specialist is recommended.

Naloxone is a drug that is used to reverse an opioid overdose rapidly. It reestablishes typical respiration rates for an individual whose respirations have slowed or stopped due to opioid overdose. Currently, there are three formulations of naloxone.

• Injectable naloxone: It is given by paramedics, ER physicians, and other specially trained first responders.
• Auto-injectable: This is marketed under the trade name of EVZIO, and it is a prefilled injection device injected quickly into the patient's outer thigh. Once it is activated, the device gives verbal instructions on using it, comparable to automated defibrillators.
• Prepackaged Nasal Spray: NARCAN is the trade name for a prefilled, needless device that does not need to be assembled and is sprayed into the nostril of a supine patient.

Both EVZIO and NARCAN are used for emergencies in the home. Laws regarding naloxone prescription and administration vary from state to state.

Take precautions when administrating naloxone; regardless of the setting, the patient must be continuously monitored until trained emergency personnel arrive. Once the patient has been transferred to a health professionals' care, they will require observation for at least another two hours to ensure that respirations do not slow down or stop.

Naloxone is a safe medication. It can sometimes cause withdrawal symptoms that may be unpleasant, but they are not life-threatening, such as headaches, alterations in blood pressure, rapid heartbeat, sweating, vomiting, and tremors (FDA, 2020).

Individuals at risk for relapse among those in treatment include (McKay, 2020) those with low motivation after several weeks of treatment, hanging out in areas where use is common (e.g., bars, parties where substances are being used), ongoing craving, continued use, spending time with people who support/encourage substance use after several weeks of treatment.

More intensive monitoring may need to occur in those who are not achieving early treatment goals, including not developing coping behaviors, not developing sources of social support, not committing to abstinence, and not attending meetings/appointments directed at enhancing sobriety (McKay, 2020).

Psychosocial interventions are critical in the management of substance use disorders. These include counseling, teaching patients about self-management skills, and mutual help groups. Clinicians should help clients attain self-management skills, help them set appropriate goals, identify barriers, and create a plan to defeat barriers (McKay, 2020). Self-management also includes encouraging patients to engage in healthy lifestyles such as healthy eating, regular exercise, and stress management.

It is also critical that those suffering from addiction need to be connected to other sources of support, including maintaining employment, engaging in volunteer work, engaging in hobbies, educational endeavors (such as parenting classes and employment training), and participating in help groups.

A significant part of treatment is relapse prevention. Relapse prevention includes:

• education of potential triggers of relapse
• early warning signs of relapse
• strategies to respond to triggers and early warning signs of relapse
• patients should identify supportive individuals, including family members, friends, and sponsors

Monitoring clinical status can be done using standardized quantitative instruments that have been shown to detect improvement and deterioration. Monitoring will provide insight to both the clinician and provider regarding progress or deterioration in their battle with addiction and offer clues when more rigorous intercession is indicated. It also provides a platform for communication between provider and patient. These tools are more likely to identify early relapse when patients are more likely to be open to more rigorous intercession (McKay, 2020).

Key features that are measured include:

• Assessment of any recent use
• How much has the patient been using (number of days of use or average amount of usage)
• Degree of cravings
• Degree of depression or sleep difficulty
• Any exposure to high-risk situations or individuals
• Involvement in treatment programs
• Employment status and engaging in activities that provide meaning
• Degree of social support

Continued care in those with substance abuse disorder is more effective than no treatment in improving outcomes. Interventions used in continued care of those with SUD include case management, couples counseling, telephone calls, home visits, and linking patients to services.

Recovery management, which focuses on the long-term management of addiction, involves regular monitoring of patients and their substance abuse progress. Mixed results regarding the effectiveness of these programs have been demonstrated (McKay, 2020). Strategies used in this program include a clinical evaluation every few months and testing for substance abuse. If a need for more intensive treatment is indicated, the patient is referred to a linkage community program to help get the patient into more intensive treatment.

Extended continuing care offers multiple interventions, including an initial in-person evaluation with follow-up telephone calls. It includes evaluating risk factors and protective factors to help assess the patient's risk of relapse. The use of cognitive-behavioral therapy is an integral part of the program. Contact with a provider occurs every week for two months, then every other week for one year, and then once a month. When an individual is identified as high-risk, they get stepped-up care. Research that is based on this model has found mixed results (McKay, 2020).

Other interventions that may be used in those with substance use disorder include home visits by a nurse, mobile texting, intensive case management, extended employee assistance programs, couples relapse prevention, smartphone-based automated recovery support, and mindfulness-based relapse prevention.

Patients with OUD may present very differently depending on their current state. They may be acutely intoxicated, in opioid withdrawal, or completely asymptomatic. Acutely intoxicated individuals may be sedated, have injection marks, have pinpoint pupils, or slurred speech. Patients in withdrawal may present with a runny nose, sweating, yawning, myalgia, agitation, anxiety, sleeping difficulty, diarrhea, nausea, vomiting, dilated pupils, and abdominal cramping.

Those who have severe OUD be involved in illegal activity to fund their drug habit. When the disease becomes severe, engaging in activities to fund the drug habit may be a central component of the individual's existence. Many people with a drug habit who engage in illegal activity are not necessarily sociopathic. When the drug habit is controlled, patients often return to "normal" lives.

Individuals with OUD often have many health complications. Individuals may appear in poor general health, but some with a mild disorder may appear healthy. Infections are commonly associated with OUD. Injection drug users are more likely to suffer from cellulitis, abscesses, osteomyelitis, hepatitis B and C, HIV, and endocarditis. In addition, drug users are more likely to suffer from systemic bacterial infections such as tuberculosis and pneumonia. Those who chronically abuse opioids may suffer from bowel issues. Opioid use often leads to constipation and other issues such as bloating, abdominal pain, poor appetite, and ileus (Strain et al., 2020).

Opioid-induced hyperalgesia can result from the chronic use of opioids, a condition where there is an increased sensitivity to pain, which can be severe and chronic. Opioid-induced hyperalgesia typically abates after withdrawal from opioids.

Opioid-associated liver fibrosis is a well-known phenomenon. Research has suggested the liver fibrosis and liver-related morbidity and mortality are associated with heroin use independent of other comorbidities such as hepatitis C, HIV, and other substance use (Strain et al., 2020).

Screening tools for opioid use include the Rapid Opioid Dependence Screen (RODS) and the OWLS. The RODS is an eight-item tool, and the OWLS is a four-item tool. If the screening is positive, then a complete evaluation using the DSM-5 criteria should be implemented.

A substance use history should include the amount, duration, and frequency of opioid use. When taking a history, it is helpful to determine how much drug is consumed. Users may describe how much drug is being used in a fraction of grams or number of bags. Those with an OUD may use heroin 2-6 times each day (Strain et al., 2020). According to one source, a typical quarter bag has enough heroin to inject several times a day and costs about 25 dollars. Users often use between 20-200 dollars per day (Strain et al., 2020).

Determining when the last use occurred can help evaluate any signs of acute complications from recent drug use, such as any chance for overdose or withdrawal. It is also essential to determine what other drugs are being used, especially benzodiazepines and alcohol, as withdrawal from these agents can be life-threatening. Determine if they have any active-controlled substance prescriptions and the route of ingestion. Opioids are typically injected, taken intranasally, or less commonly smoked.

Part of the assessment is to determine if the patient has been using larger doses over time to determine if tolerance is present as it is one criterion for SUD. Patients with tolerance are more likely to develop withdrawal if they abruptly stop opioids. Many people initially use heroin to get high but then need it to avoid withdrawal.

The assessment should include an evaluation of any occupational, psychological, or social issues from drug use. Determining treatment history helps determine the degree of the OUD. The assessment should include evaluating the type of treatment, including supervised withdrawal, counseling, self-help groups, MAT, residential treatment, or inpatient treatment. Determining the length of the most prolonged abstinence can help predict prognosis, as patients who have had one year of abstinence from heroin predicts a good prognosis (Strain et al., 2020).

The physical examination can detect signs of opioid use and physical consequences of use. Signs of chronic intravenous opioid use include track marks (calluses or scars over subcutaneous veins from repeated injections), and a deviated nasal septum may indicate intranasal drug use. The physical consequence of use may include infections; a heart murmur may suggest subacute bacterial endocarditis, and hepatomegaly may suggest acute hepatitis. Opioid withdrawal may be suggested by yawning, runny nose, muscle twitching, watery eyes, piloerection, and hyperactive bowel sounds.

Laboratory evaluation should include evaluating hepatitis and HIV and a general laboratory evaluation, including a complete blood count and liver and kidney function evaluation. Urine drug tests may be done to look for metabolites of heroin and morphine. Not all substances can be detected if used in the last three days, but chronic users may have a longer detection window. Some opioids are not detected on typical urine drug tests, such as oxycodone, methadone, and buprenorphine.

There are many causes of false positives and false negatives. False positives for amphetamines can occur using pseudoephedrine, phenylephrine, trazodone, bupropion, amantadine, desipramine, and chlorpromazine. False positives for opioids can occur with poppy seeds, fluoroquinolones, quinine/tonic water, and rifampin. More sensitive testing should occur using mass spectrometry, gas chromatography, or liquid chromatography if there is a suspected false positive (Strain et al., 2020).

A good screening question is asking, "how often did you use cannabis in the last year?" If the patient answer is more than one time, there is a 55 percent positive predictive value and a negative predictive value of 99 percent for detecting CUD (Gorelick, 2020).

Evaluate for signs/symptoms of CUD such as social, academic, or work impairment; or worsening underlying mental health issues. Physical exam findings suggesting CUD includes chronic conjunctival injection, tachycardia, yellowing of the fingertips, and cannabis odor on the clothes. Drug testing is not typically used for screening purposes in primary care but may be used in high-risk populations or places of employment. All positive screening tests should be evaluated further, including screening for other drugs of abuse.

Determining if a patient has mild, moderate, or severe CUD is done for those with a positive screening test. Patients with CUD often deny use when there is reliable/objective evidence that there is ongoing use. If more than two DSM-V criteria are met, the diagnosis of CUD is made. Here is a list of the DSM-V criteria for CUD (American Psychiatric Association, 2013).

• Taking in larger amounts/longer period than intended
• Craving
• Continued use even though problems caused by the use
• Recurrent use when it is hazardous
• Persistent desire or inability to cut down on the use
• Failure to fulfill significant life responsibility due to use
• A large amount of time spent in activities to get, use, or recover from the drug
• Tolerance
• Withdrawal
• Occupational, social or recreational activities given up due to the drug
• Use despite a physical/psychological problem caused by the use

Detoxification, also known as medically supervised opioid withdrawal, is the use of pharmacotherapy to reduce the signs/symptoms of withdrawal in individuals who are using opioids. Detoxification aims to help the patient safely move to continued treatment and maintain abstinence from opioids. Detoxification alone does not lead to abstinence, but it is the first step.

Abstinence requires the patient to address ongoing cravings and many of the psychosocial factors that led to addiction. Addressing the consequences of addiction are another important key factor in the treatment of addiction. Consequences include the addiction's damage to personal relationships, finances, mental/physical health, and employment.

Detoxification is only fully realized when a patient is off all opioids or transitioned to naltrexone. Patients maintained on buprenorphine or methadone are still dependent on opioids.

There are many reasons a person may abruptly stop taking opioids. When opioids are stopped abruptly, detoxification may be done to relieve suffering. Reasons people may stop abruptly include a patient being hospitalized for an acute illness and unable to obtain the illicit opioid, the patient ran out of access to the drug or money to purchase the drug, a person presenting for treatment of OUD, legal issues (e.g., getting incarcerated), the provider who supplied the medication is no longer prescribing the medication or the user wants to stop using the drug.

Pregnant women with OUD should continue MAT with an opioid agonist and not go through medically supervised withdrawal (ACOG, 2019). While it may be done safely during pregnancy, there is a high relapse rate. Relapse can lead to a bevy of problems, including exposure of the baby/mother to drugs, preterm labor, abruptio placentae, fetal growth delay, and even mother/fetal death (Sevarino, 2020). If the mother does not want to use opioid agonists, a slow taper can be performed under medical supervision, which is most safely performed in the second trimester (Sevarino, 2020).

Monitoring patients going through opioid withdrawal should be done with a structured instrument and a thorough physical assessment which will help guide medical management. A standard tool used is the Clinical Opioid Withdrawal Scale (COWS) (Wesson & Ling, 2003). It rates 11 signs/symptoms on a 0 to 5 scale and has a high interrater correlation coefficient (Sevarino, 2020). Testing should be repeated during withdrawal to monitor for progression or improvement.

For individuals with opioid dependence, there are many options. Some suggest the use of buprenorphine over methadone (Sevarino, 2020). Both agents are equivalent efficacious, but methadone is associated with a higher overdose risk, and buprenorphine is easier to prescribe in an outpatient setting (Gowing, 2017). Sevarino (2020) suggests that buprenorphine better manages withdrawal symptoms in detoxification as the taper gets close to the end.

In Kentucky, "buprenorphine may be prescribed for supervised withdrawal or as a maintenance treatment for a patient diagnosed with opioid use disorder" (Kentucky Administrative Regulations, 2021). Buprenorphine should not be prescribed for those with a known hypersensitivity to naloxone or a pregnant patient (unless in consultation with an obstetrician/maternal-fetal medicine specialist who has obtained a DATA 2000 waiver that concludes the benefits outweigh the harms) (Kentucky Administrative Regulations, 2021). Treatment must occur in the APRN's office or another health care facility under supervision. For a patient transitioning from methadone to buprenorphine, treatment is limited to a maximum of one week (Kentucky Administrative Regulations, 2021).

Clonidine or lofexidine can be used in withdrawal but are not as effective as buprenorphine or methadone. Patients treated with opioid agonists are more likely to complete treatment and are less likely to have a positive urine screening after treatment (Gowing, 2017). In addition, methadone was found to be more effective in the management of withdrawal symptoms.

Clonidine and lofexidine are equally effective in managing withdrawal, but lofexidine is approved by the FDA and is better tolerated (Pergolizzi et al., 2019).

Buprenorphine is often used in acute detoxification. Because it has many benefits (Sevarino, 2020):

• Safer in overdose than methadone
• The high affinity of the mu-opioid receptor
• Slow dissociation from the receptor
• Long duration of action

Caution must be used with buprenorphine as it can bring on or exacerbate withdrawal from opioids. The patients must be in a mild to moderate withdrawal state before taking the first dose of buprenorphine (COWS score of 10-12). The dose will reverse the withdrawal symptoms as it leads to opioid agonism.

While buprenorphine can lead to respiratory depression, it is much less likely to cause this than methadone. It is a partial agonist of the mu-opioid receptors reducing the likelihood of severe respiratory depression. It is more likely to be fatal in overdose if combined with alcohol or benzodiazepines or it is injected.

In most cases, the APRN should recommend an in-office observed induction. However, suppose it is not inducted into the office. In that case, the APRN should document why it was not and implement an appropriate home-based induction as recommended by SAMHSA or the American Society of Addiction Medicine (ASAM). In addition, the utilization of any opioid withdrawal protocol should be documented with a standardized tool (e.g., clinical opioid withdrawal scale) (Kentucky Administrative Regulations, 2021).

The first dose of buprenorphine should not be more than four milligrams. Another dose may follow if symptoms continue, and the dose should not be more than 16 milligrams of buprenorphine on the first day of treatment (Kentucky Administrative Regulations, 2021).

Buprenorphine has effectiveness in medically supervised withdrawal that is similar if not better than methadone and better than clonidine (Sevarino, 2020). Buprenorphine is administered either on an outpatient basis or directly supervised in a clinic. When the dose is administered in a clinic, the first dose, typically 2-4 mg, is given when the patient has a COWS score of 12 or more. The patient typically reports relief within an hour, but some feel better within 10 minutes (Sevarino, 2020). If clinically stable, the patient is observed and then sent home, and the patient is often given a second dose and told to take the medication if needed in six hours or beyond and then come back to the clinic the next day. Patients who require more than 8 mg of buprenorphine are typically better suited for the inpatient setting.

If symptoms are not controlled after the first dose, another 4 mg can be given at one hour, typically resolving symptoms. The patient may then go home. If the patient is given a second dose, another dose is not given to the patient at home. The clinician could consider an alpha-2 adrenergic agonist or other medications to control symptoms.

When the medication is started at home, the patient may enter into mild to moderate withdrawal. At that point, a second dose can be given six or more hours later if symptoms are not controlled.

When to start buprenorphine depends on the half-life of the opioid being abused. Medications with short half-lives (e.g., oxycodone) typically take the first dose of buprenorphine 6-12 hours after stopping the opioid. For those on methadone, buprenorphine should be given about 36 hours after the last dose, and before switching, the dose should be weaned to 30 mg/day (Sevarino, 2020).

If withdrawal symptoms worsen after the first dose, the next dose (if on short-acting opioids) or until the following day (if long-acting opioids) should be held. The patient should be treated with clonidine and adjunctive medications to treat other symptoms such as anxiety, insomnia, abdominal cramping, nausea, diarrhea, or muscle spasms.

Treating acute withdrawal typically lasts 5-10 days, but longer tapers have improved symptom control. Longer tapers have been shown to reduce drug relapses and improve the effectiveness of treatment (Sevarino, 2020).

After the first day, that goal is to stabilize the patient and minimize withdrawal symptoms. A similar total dose is given to the patient on the second day in one dose, commonly 8 mg. For patients with continued withdrawal symptoms, the dose can be raised by 4 mg (Sevarino, 2020). Those who have significant cravings and withdrawal symptoms on day three typically do not have successful detoxifications, and other options may need to be considered (Sevarino, 2020).

After 24 hours of controlled withdrawal symptoms, the buprenorphine can be tapered. Due to its long duration of action, the taper can occur rapidly. For individuals on 12 mg, a tapering of 2 mg a day can occur, and if on 16 mg the first day, the dose can be reduced by 4 mg and then 2 mg a day. Sometimes withdrawal symptoms occur at lower doses. At that point, the dose may be maintained, adjunctive medications may be used, or if the patient is receiving a home-based taper, then moving the patient to an office-based taper may occur (Sevarino, 2020).

Methadone can also be used for detoxification. It does have some concern for overdose and must be supplied in a supervised setting. The dosing has the goal of controlling withdrawal symptoms and avoiding oversedation. An initial dose of 10 to 20 mg is given with a maximum dose of 30 to 40 mg over the first 24 hours. There are varying dosing programs, but typically durations include at least 14 days for outpatient and five days for inpatient treatment (Sevarino, 2020).

The dose on day 2 is dependent on the clinical status of the patient. A taper of the methadone can be started after day two and can be tapered over one week or more. After a taper occurs, relapse is a concern, and maintenance doses should be considered.

Alpha-2 adrenergic agonists can significantly reduce signs and symptoms of withdrawal. Common agents in this class include lofexidine and clonidine. They help treat the symptoms of diarrhea, nausea, abdominal cramping, sweating, irritability, and anxiety and are less effective for insomnia, cravings, and muscle aches. These agents are not typically used as primary agents in opioid withdrawal in favor of buprenorphine or methadone. They are often used as adjunctive treatments to help manage symptoms (Gowing et al., 2016).

In settings where opioids are prohibited (such as prisons), alpha-2 adrenergic agonists are often used as a first-line agent. These agents are very sedating and sometimes abused for this purpose, but the risk is low. In addition, these medications reduce anxiety by lowering noradrenaline levels and reduce withdrawal symptoms by reducing hyperactivity in the locus coeruleus (Sevarino, 2020).

Pregnancy, hypotension, psychosis, renal insufficiency, and cardiac instability are contraindications to the use of alpha-2 adrenergic agonists. Side effects include sedation, dry mouth, constipation, and hypotension. Therefore, Alpha-2 adrenergic agonists should not be mixed with tricyclic antidepressants.

Clonidine is dosed at 0.1, 0.2, or 0.3 mg two times a day. Symptom relief is typically noted within 30 minutes. The patch is used in some settings, but effects are not noted for three days as it takes a while for blood levels to become adequate with the patch.

One strategy for dosing for the first day is giving 0.1-0.2 mg of the dose (higher dose for patients over 200 pounds) if the blood pressure is 90/60 mm Hg or higher and a heart rate greater than 60 beats/minute. Vital signs are rechecked in 45-60 minutes and if the blood pressure and heart rate do not drop below the above levels and symptoms are still present, then another 0.1 mg dose can be repeated every 45-60 minutes for up to four doses (Sevarino, 2020). For uncontrolled symptoms changing to buprenorphine-naloxone or methadone may be considered.

For the second to the fourth day, the patient can receive the same total dose as the first day, dived three or four times a day. Finally, on day five tapering begins, by reducing the dose by 0.1 to 0.2 mg a day; if tapering is done too fast, rebound hypertension may occur. Clonidine can also be used as an adjunct to withdrawal with buprenorphine or methadone.

It is recommended to monitor progress during OUD treatment. Features of a monitoring program include urine drug screening, treatment attendance, and many brief instruments (Dugosh & Cacciolo, 2019).

Individuals with OUD are likely to relapse after withdrawal, especially in the absence of a maintenance treatment program. The use of opioid agonists significantly reduces the risk of relapse.

Pharmacotherapy combined with psychosocial treatment is often used long-term to prevent relapse of OUD. Pharmacotherapy typically consists of an opioid agonist (methadone or buprenorphine) or an opioid antagonist (naltrexone). Before prescribing medications, it is essential to determine if the patient is physiologically addicted; and if so, medically supervised withdrawal may be necessary before starting naltrexone.

A non-pregnant adult who is not addicted to opioids is a candidate for addiction counseling and possibly long-acting injectable naltrexone. For the adult who is physically dependent but is post-withdrawal, long-acting injectable naltrexone may also be considered. Before starting naltrexone, withdrawal must be complete. However, withdrawal does not have to be complete before starting methadone or buprenorphine. Naltrexone is typically used by a highly motivated patient and has mild opioid use disorder (Saxon & Strain, 2019).

MAT is first-line treatment instead of psychosocial treatment alone when the patient suffers from moderate to severe opioid use disorder. In moderate to severe use disorder, the use of buprenorphine is the preferred agent. Research suggests that methadone has a better capacity to prevent relapse but is more dangerous as it has a high risk of overdose (Saxon & Strain, 2019).

Psychosocial treatment alone can be used in a handful of conditions.

• The patient had a sustained prior response to psychosocial treatment
• The patient has a strong preference for psychosocial treatment despite education regarding MAT
• The patient has mild disease, is very motivated, and has good premorbid function and a robust social support network

Shared decision-making is a crucial aspect in determining which is the best treatment option to maintain. First, a discussion regarding the risks and benefits of each treatment option should be laid out to the patient, and then a shared decision about the best treatment option should be made. Shared decision-making has been shown to improve outcomes in SUD treatment at one year.

Withdrawal treatment, also known as detoxification, lowers the risk of withdrawal symptoms. It should not be used as a stand-alone treatment but combined MAT and psychosocial treatment to prevent relapse.

The use of medication-assisted treatment MAT is considered the first-line treatment for opioid use disorder. Treatment can help patients get their life back and become productive members of society.

MAT may per done with opioid agonists (methadone), partial opioid agonists (buprenorphine), or an opioid antagonist (naltrexone). Opioid agonists squelch cravings and withdrawal as well as block the effects of other opioids.

When opioid agonists are used, patients are physically dependent on methadone or buprenorphine. Still, these patients do not have the negative behaviors associated with dependence/addiction to other opioids, including heroin (Strain, 2019).

Patients often remain on MAT with opioid agonists for years. Some patients are tapered off, and those with OUD who have the most success with a tapering have no significant alcohol use, no illicit drug use, and have a good social support network. Tapering off medication should only be done by a clinician with expertise with weaning and should be done very slowly, often over the years. Opioid agonists are associated with a reduced mortality rate (including all-cause mortality and death due to drug use) in those with a known OUD (Strain, 2019).

When a patient presents to the APRN after seeing another provider and the patient has withdrawn in the absence of relapse previously, the provider should document a history of withdrawal, teach the patient about possible withdrawal, and continue maintenance treatment at the same or a lower dose than the previous provider. In addition, the APRN should see the patient at the same frequency or more often than the previous provider was seeing the patient. After the initial prescription, APRN 201 KAR 20:065 recommends that the amount of buprenorphine prescribed should be enough to minimize cravings and opiate withdrawal, be enough to get the patient to the next visit, not above the FDA approval limit and not produce significant sedation (Kentucky Administrative Regulations, 2021).

After the initial prescription of buprenorphine, the APRN should see the patient within ten days and then no longer than ten-day intervals for the first month. For the second month after induction, the patient should be seen at intervals of no more than 14 days (Kentucky Administrative Regulations, 2021).

After two years of treatment, if it is deemed that the patient has objective signs of treatment success, the patient may be seen once every three months. At this point, the APRN should assess and document if the dose should be continued or modified. If there is evidence of non-compliance, the patient should be seen more often. If a patient must miss an appointment, the APRN should “make best efforts to see the patient as soon as possible and document the circumstances in the patient’s chart” (Kentucky Administrative Regulations, 2021).

At these visits, the APRN should collect data to incorporate into the treatment plan to support the maintenance of the plan or modification of the plan. The treatment plan should be based on a complete assessment including:

• Reviewing compliance with the treatment plan
• Reviewing KASPER or other PDMP
• Ordering and reviewing drug screens

The APRN may adjust the dose of the medication, wean the medication, modify the frequency of the visits or obtain a consultation with a specialist.

At least eight drug screens should occur every twelve months. The patient should be screened for buprenorphine, methadone, alcohol, opioids, benzodiazepines, THC, amphetamines, gabapentin, and cocaine. Two of the drug screens should be random, and a pill count should coincide. At least one of these two drug screens should be confirmed by gas or liquid chromatography/mass spectrometry. A positive drug screen should be incorporated into the decision to continue or modify treatment (Kentucky Administrative Regulations, 2021).

Lost or stolen medication should not be routinely refilled. In the case when medication is lost or stolen, the automatic refill is not appropriate. Instead, the patient should be individually assessed and consider any prior episodes of the patient losing the medication or getting the medication stolen.

After the patient is started on buprenorphine, the patient should have a treatment plan that necessitates objective behavioral modification, including a twelve-step program or mental health counseling. The patient should also have a mental health evaluation by a provider with expertise in addiction within 90 days of starting treatment. The patient needs to observe the recommendations set forth by the mental health provider (Kentucky Administrative Regulations, 2021).

The APRN who is appropriately credentialed (has a DEA waiver/registration to prescribe buprenorphine) must get four annual hours of training in addiction disorders, including 1.5 contract hours of pharmacology.

Naltrexone blocks the euphoric effects of opioids. The patient should not be withdrawing when the medication is started, as it may cause the patient to go into more severe withdrawal. When starting naltrexone, it should be medically supervised to assess for withdrawal.

Naltrexone is given as a daily pill or a monthly injection. Oral naltrexone is started at 25 mg per day for 2-3 days and then increased to 50 mg per day. The medication should not be started until at least one week after the last time an opiate was taken. In some situations, a naloxone challenge test (Table 6) can ensure the safety of starting the medication sooner. Injection naltrexone is given at a dose of 380 mg once a month, but it can be given once every three weeks (Strain, 2019).

Side effects of naltrexone include headache, nausea, dizziness, and fatigue. In rare situations, liver damage may occur but is usually seen with high doses and typically resolves when the medication is stopped. However, patients who stop antagonist therapy and restart opioids are at high risk for overdose secondary to loss of tolerance (Strain, 2019).

The first-line treatment in AUD is naltrexone, but acamprosate may be used. Both medications have evidence to show effectiveness (Saxon & Strain, 2019). In addition, research suggests that both agents have similar effectiveness in reducing rates of return to heavy drinking (Saxon & Strain, 2019).

Naltrexone

For alcohol use disorder, oral naltrexone is usually started at is 50 mg/day but can be increased to 100 mg/day. For patients with poor adherence to daily treatment, the use of long-acting naltrexone can be considered. The long-acting form is dosed at 380 mg intramuscularly monthly. Naltrexone can be started when the patient is drinking.

Naltrexone must be used cautiously. It is associated with hepatotoxicity – especially with high doses. Naltrexone cannot be used in those on an opioid but can be used effectively for those with both OUD and AUD.

Acamprosate

Before starting acamprosate, the patient should be abstinent. American trials for acamprosate have not been effective, and most positive research was done in Europe. When liver enzymes are increased, the use of acamprosate is recommended over naltrexone. Adjustments need to be made for renal impairment. When the creatinine clearance is less than 30 mL/min, then the medication is contraindicated. The dose should be halved in those with a creatine clearance between 30 and 50 mL/min. The use of acamprosate is recommended over naltrexone in those currently taking an opioid, although using an opioid in someone with an alcohol use disorder is not recommended (Saxon & Strain, 2019).

There is limited data on the safety of these medications in pregnant women. However, pregnant patients with heavy alcohol use are at high risk of damage to the fetus, and medication should be considered in those who continue drinking. Naltrexone is the more commonly used medication in pregnancy. Only those with expertise should treat AUD in pregnancy.

Abstinence is the optimal treatment goal as it is often difficult for patients to maintain alcohol consumption at a safe level. Those who remain abstinent have a better outcome, but any reduction in alcohol use will provide benefit.

Disulfiram is another medication that helps with AUD. When taken, it is associated with adverse effects when mixed with alcohol. It is meant to help individuals maintain abstinence. The dose for disulfiram is 125 to 500 mg a day, and it works best when taking the medication is supervised.

Naltrexone can be started without the need to detox the patient. Drinking should not occur when patients are on acamprosate or disulfiram. When acamprosate is started, it will inhibit the desire to go back to drinking. Disulfiram will lead to adverse effects when alcohol is consumed.

After treatment is started, at least weekly follow-up should occur. During these visits, the patient should be assessed, supported, and family members engaged (if indicated). In addition, patients should be monitored for treatment effectiveness, adherence, side effects, and any relapse signs.

Toxicology testing can be done and is most helpful in early treatment (Saxon & Strain, 2019). Testing is often done by urine screening and typically detects if any alcohol has been ingested in the last 72 hours, but it does not quantify how much alcohol was consumed. In addition, urine ethyl glucuronide testing can give a false positive test in those exposed to hand sanitizers.

Blood work can also be used to test for alcohol use. For those who have elevated reading of gamma-glutamyl transferase (GGT) and carbohydrate-deficient transferrin at baseline, these two tests can be used to determine if the patient has engaged in heavy drinking. GGT is nonspecific but less expensive and more widely available. Carbohydrate-deficit transferrin is specific but more expensive. Neither test is sensitive and may miss some people who have been drinking (Saxon & Strain, 2019).

Patients who have an adequate response to treatment should continue with psychosocial treatment for six to twelve months. Medication treatment should be continued for at least one year. More prolonged treatment is associated with a lower risk of recurrence, but the exact length of time to maintain treatment is unknown. Treatment with naltrexone, acamprosate, and disulfiram can be stopped abruptly, and no tapper is needed. Continued monitoring should occur after treatment when medication is discontinued.

It is challenging to determine the exact length of time required to assess if a treatment has been effective. Psychosocial treatments may take weeks to have effects. Medications tend to work faster. Those on disulfiram will quickly be able to tell if there is a success with the treatment. With naltrexone and acamprosate, it may take weeks to assess if benefits are noticed. Reductions in the frequency of heavy drinking may occur over months; this is especially relevant when drinking is not daily (Saxon & Strain, 2019).

Certain factors require a greater urgency to getting control of AUD. Those at high risk for suicide or pregnant women need to be assessed to assure treatment is effective quickly.

Individuals who do not have an adequate initial response may benefit from increasing the frequency or intensity of interventions—for example, going to more groups per week, moving from outpatient treatment to day treatment, or adding medication. Medications can also be modified. If continued drinking occurs, increasing the dose may reduce cravings. Research has shown that higher doses of naltrexone reduce alcohol cravings (Brünen et al., 2019).

Generally, naltrexone and acamprosate are first-line agents for alcohol use disorder as they have the most evidence for effectiveness. If naltrexone was used and was not effective, switching to acamprosate should be considered. If acamprosate was used first and it was not effective, switching to naltrexone should be considered. When the patient does not respond to either naltrexone and acamprosate, other options include disulfiram and topiramate.

Topiramate is sometimes used for the management of AUD. It is dosed up to 300 mg a day. Topiramate, while effective, is associated with multiple side effects that some patients cannot tolerate. The patient may experience fatigue, dizziness, cognitive impairment, depression, weight loss, or paresthesia. Topiramate is the only AUD medication that requires a taper when stopped.

Combination medications are sometimes used in the management of AUD. When one agent does not work, adding another medication with a different mechanism of action may be beneficial. For example, the use of naltrexone and acamprosate has been found to work better than individual medications (Saxon & Strain, 2019).