Continuing Education Activity

Methadone is a synthetic, long-term opioid agonist medication used in the management and treatment of opioid use disorder (OUD) and for analgesic purposes in chronic pain. The drug is approved by the U.S. Food and Drug Administration (FDA) for treating moderate-to-severe pain that has not responded to nonopioid medications or as an alternative if the pain is unresponsive to other opioid drugs. Methadone is frequently prescribed to address severe pain associated with cancer, neuropathy, or other conditions in pediatric populations. This activity comprehensively reviews the indications, mechanism of action, and contraindications of methadone as a valuable agent in treating chronic pain and managing OUDs. This activity highlights the role of the interprofessional healthcare team in the utilization of methadone for detoxifying and treating OUD as a crucial component of medication-assisted treatment, which is significant in light of the ongoing opioid use epidemic.

Objectives:

• Identify appropriate indications for methadone, distinguishing between its applications in chronic pain management and opioid use disorder treatment.

• Implement evidence-based guidelines, such as those from the Substance Abuse and Mental Health Services Administration and the American Society of Addiction Medicine, in the initiation, titration, and maintenance phases of methadone treatment for opioid use disorder.

• Assess patients for response to methadone therapy, evaluate its effectiveness, manage adverse effects, and monitor for signs of misuse or diversion.

• Collaborate with an interprofessional healthcare team, including pharmacists, mental health professionals, and social workers, to provide holistic care and address the multifaceted aspects of methadone treatment.

Indications

FDA-Approved Indications

The U.S. Food and Drug Administration (FDA) has approved methadone for the treatment of moderate-to-severe pain that does not respond to non-narcotic drugs.[1] Methadone is also FDA-approved for detoxification and the treatment of opioid use disorder (OUD) as an integral part of medication-assisted treatment.[1]

Off-Label Use

Methadone is sometimes utilized for the treatment of neonatal abstinence syndrome (NAS), although this application is not FDA-approved and falls under pregnancy category C drug.[2]

Indication 1: Moderate-to-Severe Pain, Nonresponsive to Non-Narcotic Drugs

The FDA approves methadone for treating moderate-to-severe pain that remains unresponsive to nonopioid medications or as an alternative in cases where the pain does not respond to other opioid drugs. Methadone is an analgesic used in cancer patients, other terminally ill individuals, and those experiencing chronic pain pathologies. Before initiating methadone for noncancer chronic pain, the patient must undergo an assessment of risk factors that may contribute to drug misuse or diversion. In addition, it is essential to confirm that the benefits of the therapy outweigh any potential harms. Psychosocial factors contributing to underlying chronic pain, such as comorbid psychiatric disorders and issues related to social support, should be considered in the assessment.[1][3]

Methadone is an alternative in treating patients with opioid tolerance, as they may not respond to traditional analgesic regimens. In such patients, methadone dosages are adjusted or combined with other opioids as adjuvant treatments to enhance response to analgesic interventions.[3][4]

Methadone is a commonly prescribed drug to treat severe pain related to cancer or neuropathy in pediatric populations.[5] However, the use of opioid medications for analgesia in pediatric settings is considered off-label due to limited clinical data that comprehensively assess the risks and benefits in this specific population.[6]

Indication 2: Detoxification and Treatment of OUDs as Part of Medication-Assisted Treatment

Methadone and buprenorphine have FDA approval for the treatment of OUD within federally regulated opioid treatment programs. Methadone prescriptions are utilized for both detoxification and maintenance therapy. Methadone proves effective in managing opioid withdrawal symptoms, including tachycardia, diaphoresis, nausea, vomiting, and diarrhea. Abstinence rates from opioid use demonstrate better outcomes when patients undergo long-term rather than short-term methadone treatment. Methadone has been proven to enhance retention in treatment and detoxification programs, contributing to improvements in mortality rates among individuals with OUDs.[3] Clinicians should assess the availability of methadone in pharmacies when referring patients to such programs, considering that licensing and accessibility can vary significantly across states.[3][7]

Indication 3: Treatment of Neonatal Abstinence Syndrome

NAS can be due to various substance abuse during pregnancy, including alcohol, tobacco, and opioids, all of which can traverse the placenta, impacting the neonate. Supportive care is generally provided for neonates with milder cases. Pharmacologic intervention is implemented when moderate to severe withdrawal signs are present in neonates, such as seizures, often involving the use of methadone to address NAS symptoms.[2]

Although methadone is used to address opioid withdrawal symptoms in neonates, it is noteworthy that the FDA does not approve this use. Some studies have compared methadone with alternatives such as morphine or buprenorphine for treating NAS, with findings indicating that methadone exhibits superior efficacy in managing NAS compared to morphine.[8] However, studies indicate that buprenorphine may be more effective in enhancing neonatal outcomes, including birth weight and length of hospital stay, compared to methadone.[2][9]

Mainstreaming Addiction Treatment Act

The Mainstreaming Addiction Treatment (MAT) Act provision revises federal guidelines to broaden the accessibility of evidence-based treatment in addressing the opioid epidemic. Empowering all healthcare providers with a standard controlled substance license, the MAT Act allows them to prescribe buprenorphine for OUD like other essential medications. The MAT Act is designed to destigmatize the standard of care for OUD and facilitate the integration of substance use disorder treatment throughout diverse healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. Practitioners registered with the DEA and holding Schedule III authority are now authorized to prescribe buprenorphine for OUD within the bounds of state law. The Substance Abuse and Mental Health Services Administration (SAMHSA) strongly encourages eligible practitioners to exercise this privilege. Those previously registered under the DATA-Waiver program will automatically receive an updated DEA registration certificate to reflect these changes, and no further action is required on their part. Practitioners are no longer restricted by patient limits for treating individuals with OUD using buprenorphine. The need for separate tracking of patients treated with buprenorphine or prescriptions written has been eliminated.

Pharmacy staff is now permitted to fill buprenorphine prescriptions using the DEA number of the prescribing authority, and a DATA 2000 waiver from the prescriber is no longer necessary. However, it is worth noting that the dispensing software at certain pharmacies may still necessitate X-Waiver information for processing. Practitioners must adhere to any applicable state limitations related to treating patients with OUD. Contact information for State Opioid Treatment Authorities can be found at https://www.samhsa.gov/medicationassisted-treatment/sota.

Mechanism of Action

Methadone is a synthetic opioid that acts as a full agonist at the μ-opioid receptor while also affecting other opioid receptors. These μ-opioid receptors are located in different parts of the central nervous system (CNS), such as the brainstem, locus coeruleus, periaqueductal gray matter, and various parts of the gastrointestinal tract. These receptors are crucial in modulating various neurochemical activities linked to analgesia, euphoria, and sedation. Methadone activates the μ-receptors, initiating the same pathways. This activation results in downstream effects through G-protein signaling, including inhibiting neuronal transmission of pain afferents from the spinal cord, producing analgesic effects. In addition, it induces receptor internalization and recycling, contributing to reduced opioid tolerance in patients.[10][11]

Furthermore, methadone is a noncompetitive antagonist to the N-methyl-d-aspartate (NMDA) receptor, potentially enhancing its efficacy in managing neuropathic pain.[6][10][12] In the treatment of opioid addiction, clinicians titrate methadone to a higher daily dose, preventing withdrawal signs and establishing a narcotic blockade to deter euphoria from other shorter-acting opioids. The extended half-life of methadone of approximately 8 to 60 hours results in a less severe withdrawal time course and milder symptoms.[10][11][13]

Administration

Available Dosage Forms and Strengths

Methadone is accessible in various formulations, including a lipophilic hydrochloride salt, and can be administered orally, intramuscularly (IM), intravenously (IV), subcutaneously, epidurally, and intrathecally.[14][15][16] The choice of dosing and formulation is contingent upon the intended purpose, with oral formulations in tablet or concentrated syrup being the most prevalent. A general dosing regimen guideline is provided.

Adult Dosage

Pain management: In pain management scenarios, tailored dosing regimens are crucial, with recommendations varying for opioid-naive individuals and opioid-tolerant patients.

• Opioid-naive: For opioid-naive individuals, the recommended oral dosage is 2.5 mg every 8 hours, with the option for incremental dose increases approximately once per week if necessary.[16]

• Opioid-tolerant: For opioid-tolerant patients, a methadone dosage of 10 mg orally is approximately equivalent to a 15-mg dose of oral morphine. Following dosing charts that provide equivalent dosing and conversion factors tailored to the individual patient is advised.[16]

Opioid use disorder: According to the American Society of Addiction Medicine (ASAM) guidelines of 2020, the following recommendations are outlined for the initiation, titration, and maintenance phases.[17]

• Initiation (induction): The recommended initial dose ranges from 10 to 30 mg, and reevaluation is advised within 2 to 4 hours, once peak levels have been attained. The timing of reassessment should not impede the initiation of methadone. Due to the risk of toxicity within the initial 2 weeks, maintaining a focus on tolerance is paramount for safety. Federal regulations mandate that the initial dose should not surpass 30 mg, and the total dose on the first day should not exceed 40 mg. For individuals with minimal or no opioid tolerance, reinitiating methadone after a relapse is advisable at a lower dose range of 2.5 to 10 mg.

• Titration: Due to methadone's extended half-life, caution is essential to prevent rapid dose escalation within the initial 1 to 3 weeks of therapy. Doses do not consistently align with blood concentration levels. Therefore, dosing decisions should be individualized based on the patient's response, recognizing that there can be considerable variation between individuals. Methadone is increased by no more than 10 mg approximately every 5 days based on opioid withdrawal symptoms and sedation. Although a low methadone dose of <30 mg/d can alleviate acute withdrawal, it may not effectively suppress cravings. Patients should be informed that experiencing discomfort is expected during the initial days of methadone titration. 

• Maintenance: Some individuals may respond to a daily dosage of 30 to 60 mg, whereas most patients manage well when their initial dose is progressively elevated to a maintenance level ranging from 60 to 120 mg/d. Higher doses, specifically within the range of 80 to 100 mg/d, tend to enhance retention in treatment compared to lower doses. In certain cases, dosages exceeding 120 mg/d may be cautiously considered, especially for patients misusing highly potent opioids such as fentanyl and other synthetic opioids.

• Pregnancy: Maintenance treatment should be continued in pregnant women with OUD. Buprenorphine should be considered instead, as it is known to cause less sedation in neonates.[18] According to a recent study, the use of buprenorphine during pregnancy is associated with a lower risk of adverse neonatal outcomes than methadone. However, the risk of adverse maternal effects is similar for buprenorphine and methadone.[19] 

• Lactation: Breastfeeding infants of mothers undergoing methadone maintenance therapy receive an approximate dose equivalent to 1% to 3% (occasionally 5% to 6%) of the mother's weight-adjusted methadone dosage. Although breastfeeding may potentially diminish neonatal withdrawal symptoms, it does not necessarily lead to a reduction in the dosage of opiates used for therapy.[20] According to the American College of Obstetricians and Gynecologists (ACOG) guidelines and the SAMHSA, breastfeeding is encouraged in patients who are stable on methadone maintenance therapy and are not using illicit drugs.[21]

Opioid withdrawal: Managing opioid withdrawal in both adults and neonates involves carefully tailored dosing strategies.

• Adults: Oral dosing for adults is initiated at 10 to 20 mg and is incrementally adjusted until the withdrawal symptoms are controlled, usually about 40 mg. Stabilization of dosing is recommended for 2 to 3 days, followed by a gradual reduction in dose by 10% to 20% daily while monitoring for withdrawal symptoms.

• Neonates: The oral dosage in neonates begins at 0.05 to 0.1 mg/kg every 6 hours until withdrawal symptoms stabilize. Subsequently, the dose should be systematically decreased by 10% to 20% daily, with ongoing serial monitoring of withdrawal symptoms.[2]

Other considerations: This introductory overview delves into the distinctive features of its oral bioavailability, hepatic metabolism, and renal considerations, offering essential insights to optimize therapeutic outcomes and minimize potential risks in patient care.

• Methadone exhibits high oral bioavailability, with detectable plasma levels within 30 minutes and a subsequent decline after 24 hours. It is essential to take these pharmacokinetic characteristics into account, particularly in frail patients or those with altered hepatic clearance, to mitigate the risk of overdose.[13] 

• Methadone undergoes hepatic metabolism mediated by CYP3A4 and CYP2B6, resulting in the formation of inactive metabolites. Furthermore, it is crucial to consider and monitor potential interactions with other drugs metabolized in the liver.[13]

• As methadone undergoes hepatic metabolism, dosing adjustments are generally unnecessary in patients with renal impairment. However, caution is advised, particularly in cases of end-stage renal disease.[3]

• The recommended dose for parenteral administration typically ranges from 50% to 80% of the oral dose, and transitioning to methadone from another opioid requires caution. Utilizing dosing ratios can be beneficial in accurately calculating the appropriate dosage.[10]

• SAMHSA recommends employing either the Clinical Opioid Withdrawal Scale (COWS) or the Clinical Institute Narcotic Assessment (CINA) for the assessment of withdrawal symptoms.

• According to the ASAM and Centers for Disease Control and Prevention (CDC) practice guidelines in 2022, it is noted that morphine milligram equivalents (MME) do not apply to the management of OUD. MME is a numerical measure allowing for the comparison of the relative potency of various opioids in the context of pain management. A dosage of ≥50 MME per day is unlikely to provide additional pain relief or functional benefits. Before considering an escalation to a dosage of 90 MME per day or more, it is crucial to reassess the individual's benefits and risks. Special caution is advised when converting methadone doses due to its extended and variable half-life, with the peak respiratory depression occurring later and persisting longer than the peak analgesic effect.[14][17]

Adverse Effects

As with other opioid medications, the typical adverse effects of methadone stem from excessive opioid receptor activity,[16][17] including, but are not limited to, diaphoresis or flushing, pruritus, nausea, dry mouth, constipation, sedation, lethargy, respiratory depression, adrenal insufficiency, hypotension, and hyperhidrosis.[22]

Methadone is also associated with QTc prolongation (>450 ms) and leads to cardiac dysfunction and severe hypoglycemia in certain patient populations.[23][24]

Box Warnings

Risks associated with the concomitant use of benzodiazepines and other CNS depressants: Combining opioids with benzodiazepines or other CNS depressants, such as alcohol, can lead to significant sedation, respiratory depression, coma, and even fatal outcomes. Prescribing methadone and benzodiazepines or CNS depressants simultaneously should be reserved for cases where alternative treatment options are inadequate. In addition, it is advisable to minimize dosages and durations to the essential minimum and closely monitor patients for signs of sedation and respiratory depression.[25]

Addiction, abuse, and misuse of the drug: The FDA warns that methadone injection injection poses risks of opioid addiction, abuse, and misuse, potentially leading to a fatal overdose. A thorough risk-benefit evaluation is essential before prescribing methadone injection, and ongoing patient monitoring is crucial to detect and address any potential misuse.

Life-threatening QT prolongation: Methadone injection treatment has been associated with life-threatening QT interval prolongation and Torsades de pointes. Although most cases involve patients receiving high, multiple daily doses of methadone for pain management, instances have also been reported in patients receiving standard doses for opioid addiction maintenance treatment. Therefore, it is crucial to closely monitor patients with risk factors for prolonged QT interval, a history of cardiac conduction abnormalities, or medications that impact cardiac conduction. In addition, regular monitoring for changes in cardiac rhythm should be implemented during the initiation and titration of methadone injection.[26]

Regulations for the distribution and use of methadone for OUD: To address opioid dependence through maintenance and detoxification, methadone administration must adhere to both federal and state laws.

Methadone products, when used to manage opioid addiction in detoxification, must only be dispensed or prescribed by opioid treatment programs, institutions, or practitioners certified by SAMHSA and sanctioned by the state authority. Certified treatment programs are obligated to prescribe and dispense methadone in accordance with the treatment requirements outlined in the Federal Opioid Treatment Standards (42 CFR 8.12).

Interactions with drugs affecting CYP450 enzymes: The concomitant use of methadone with inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 may result in elevated methadone plasma concentrations, potentially leading to fatal respiratory depression. Discontinuation of concurrently administered CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers may increase methadone concentration. Therefore, it is advisable to contemplate dosage reduction when making changes to concomitant medications that could potentially elevate methadone levels. Notably, CYP2B6 polymorphisms can influence methadone plasma concentrations.[27]

Contraindications

According to ASAM, hypersensitivity, severe respiratory depression, severe bronchial asthma, and paralytic ileus are contraindications for the use of methadone.[17] As methadone can cause CNS depression and respiratory compromise, caution is advised when using methadone in patients with CNS-related pathologies such as trauma, increased intracranial pressure, dementia, and delirium. Methadone should not be used in conjunction with medications or substances with similar depressant effects, including other opioids, benzodiazepines, alcohol, and antipsychotics unless deemed necessary. Caution is warranted when using drugs that may either increase methadone clearance or decrease its effects to prevent the precipitation of withdrawal symptoms.

Drug-Drug Interactions

The examples listed below do not constitute an exhaustive list of drug interactions but provide some commonly documented drug interactions that should be monitored when using methadone.[16]

Drugs that may increase methadone effects and overdose risk: These drugs include ciprofloxacin, benzodiazepines,[25] alcohol, fluconazole, cimetidine, fluoxetine, urine alkalizing agents, and grapefruit juice.[28]

Drugs that may decrease methadone effects and risk of withdrawal symptoms: These drugs include efavirenz, phenobarbital, phenytoin, carbamazepine, urine acidifying agents, and rifampin.[29]

Monitoring

Patients should be monitored for adverse outcomes using assessment tools designed to determine the risk level for opioid abuse, loss to treatment, diversion of drugs, adverse effects, and overdose.[30][31] Assessment tools are accessible to establish criteria for urine drug screens, clinical health assessments, and psychosocial determinants. Before initiating treatment, it is essential to establish a clinical baseline and assess comorbid conditions. Clinicians should also examine the prescription drug monitoring program (PDMP) data to cross-reference opioid prescription history.[31]

Once treatment begins, healthcare providers should titrate the dosage carefully, as methadone has a narrow therapeutic index. The recommended target value for therapeutic drug monitoring is 400 μg/mL.[32] Individuals should undergo frequent reassessment during the initial therapy and when changing doses. Those at low risk for adverse outcomes should be monitored once every 3 to 6 months after achieving therapeutic levels of methadone. In contrast, individuals at high risk for adverse outcomes may require weekly monitoring.

Healthcare providers should adhere to guidelines for monitoring more severe adverse effects, including, but not limited to, QTc prolongation, drug interactions, hypoglycemia, hypotension, and adrenal insufficiency.

QTc Prolongation >450 ms

Baseline electrocardiograms should be obtained for all patients, with a follow-up within 30 days to assess for acute changes. Annual repeat electrocardiograms are recommended. If the methadone dose exceeds 100 mg/dL or if the patient is symptomatic, additional cardiac assessments should be conducted. In cases where the QTc interval exceeds 500 ms, healthcare providers should consider reducing the methadone dose or discontinuing it, opting for alternative therapies such as buprenorphine-naloxone.[23]

Drug Interactions due to CYP3A4 Metabolism

Methadone levels can be influenced by drug interactions through CYP3A4 metabolism, leading to either an increase or decrease, potentially resulting in overdose or withdrawal symptoms. It is essential to closely monitor patients taking medications that may impact clearance, being vigilant for signs of withdrawal or overdose.[33] 

Hypoglycemia 

Individuals at high risk for hypoglycemia, such as cancer patients and those experiencing rapid dose escalation, should undergo regular serum glucose screening. Signs indicating a patient is experiencing hypoglycemia include unexplained lethargy, perspiration, and palpitations.[24]

Ileus and Urinary Retention

The concomitant use of anticholinergics may increase the risk of urinary retention and ileus. Healthcare providers should monitor patients for signs of urinary retention or decreased gastric motility when methadone is administered concurrently with anticholinergic medications.[34]

Hypotension

Methadone has the potential to induce orthostatic hypotension and syncope in ambulatory patients. Vital signs should be monitored after the initiation or titration of methadone. Thus, it is advisable to refrain from using methadone in patients experiencing shock.

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported, characterized by nausea, vomiting, anorexia, weakness, dizziness, and hypotension. Adrenal insufficiency management involves measures such as discontinuing or reducing the dose of opioids and initiating corticosteroid replacement therapy.[35] Notably, methadone-induced adrenal insufficiency can also manifest with hypercalcemia.[36][37]

Toxicity

Signs and Symptoms of Overdose

Methadone overdose can induce severe respiratory depression, potentially resulting in fatalities. Signs of overdose include extreme lethargy, somnolence, stupor, coma, miosis, bradycardia, hypotension, respiratory sedation, and cardiac arrest. The concurrent use of opioids with other drugs that affect serotonergic neurotransmission has resulted in serotonin syndrome.

Management of Overdose

In cases of methadone overdose, patients should be closely monitored for oxygenation and ventilation. Naloxone should be administered if an overdose is suspected.[3]

In cases of serotonin syndrome, medications that may contribute include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs, such as duloxetine), triptans, 5-HT3 receptor antagonists, mirtazapine, tramadol, trazodone, cyclobenzaprine, and linezolid.[38][39] If serotonin syndrome is suspected, healthcare providers should discontinue methadone and provide supportive care to patients.

Enhancing Healthcare Team Outcomes

Assessing the use of methadone in various clinical scenarios demands specialized knowledge concerning its pharmacological characteristics and legal limitations. Nonprescription opioid-related deaths are a leading cause of mortality in the United States. Federal programs for detoxification and maintenance utilizing methadone or buprenorphine-naloxone play a crucial role in reducing these numbers.

Effective communication among a patient's healthcare team is crucial for optimal outcomes. Identifying patients who would benefit from methadone involves the collaboration of an interprofessional team comprising physicians, nurses, pharmacists, lab technicians, therapists, and social workers. This collaborative approach ensures a safety net for monitoring the risks associated with its use. Monitoring plays a crucial role in averting overdose, toxicity, withdrawal, and drug diversion while also assessing comorbid psychiatric diseases and other social determinants linked to improved patient outcomes. The interprofessional healthcare team should be cognizant of several factors when caring for patients who require methadone,[40] which include the following: 

• Clear communication should be maintained regarding the risks and benefits of opioid use between patients and healthcare providers [Level 1].

• Methadone use is recommended only after the failure of other opioids for chronic pain [Level 1].

• An understanding of the legalities associated with prescribing methadone should be demonstrated, aligning with state and federal laws and cross-referencing state PDMP databases [Levels 1 and 2].

• Current opioid use status should be assessed, and they should be monitored with regular urine drug screens [Level 2].

• Baseline clinical function with cardiac clearance, serum glucose, and psychiatric assessments should be evaluated. In addition, healthcare providers should determine benefit-to-harm ratios depending on other comorbidities [Levels 1 to 3].

• Medication recommendations should be obtained regarding drug interactions if the patient uses other medications [Levels 1 and 2].

• Healthcare providers should assess the patient's social support, accessibility to methadone clinics, and the likelihood of retention in methadone programs when treating them for OUD.

• Adjunct therapy or addiction specialist consultations should be provided to patients at high risk of adverse outcomes.

• Patients should be regularly monitored for adverse effects, and medications should be adjusted accordingly [Level 1].

• In overdose situations, naloxone should be administered to prevent fatalities [Level 1].[3]

Patient care involving methadone is an evolving subject, and healthcare providers must stay informed about regular updates to the literature to establish the best possible care. Clinicians need to assess the appropriateness of prescribing methadone, ensure comprehensive patient care, and communicate clearly and effectively regarding a patient's consent and understanding of the risks and benefits of methadone use.

Nursing staff play a crucial role as the first line in drug administration, monitoring patients for adverse reactions, and overseeing overall patient clinical status, adherence, and improvement. Pharmacists are essential members of healthcare teams, providing advice on medication interactions and assessing dosing requirements to prevent adverse events and ensure proper pain management for patients with comorbidities. Lab technicians contribute by conducting tests to evaluate adherence, detect abuse, and assess the risk of overdose in patients.

Psychiatrists, mental health therapists, and addiction specialists are instrumental in offering behavioral therapy, addressing comorbid psychiatric diseases, and monitoring adherence as integral components of medication-assisted treatment programs.

Social workers can provide support outside hospital settings by facilitating connections to relevant resources and assessing social determinants related to opioid abuse and retention in maintenance programs. A comprehensive team of healthcare professionals is essential to cover all aspects of patient care when prescribing methadone. Clear communication among the healthcare team is vital to maintaining an accurate care plan, reducing associated risks, improving patient outcomes, and delivering the highest quality of care possible. [Level 5]