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Controlled Substances

Introduction   

Pain is complex and subjective. The experience of pain can significantly impact an individual's quality of life. According to the National Institute of Health (NIH) (40), pain is the most common complaint in a primary care office, with 20% of all patients reporting pain. Chronic pain is the leading cause of disability, and effective pain management is crucial to health and well-being, particularly when it improves functional ability. Effective pain treatment starts with a comprehensive, empathic assessment and a desire to listen and understand. Nurse Practitioners are well-positioned to fill a vital role in providing comprehensive and empathic patient care, including pain management (23).

While the incidence of chronic pain has remained a significant problem, how clinicians manage pain has significantly changed in the last decade, primarily due to the opioid epidemic. This education aims to discuss pain and the assessment of pain, federal guidelines for prescribing, the opioid epidemic, addiction and diversion, and recommendations for managing pain.

Definition of Pain

Understanding the definition of pain, differentiating between various types of pain, and recognizing the descriptors patients use to communicate their pain experiences are essential for Nurse practitioners involved in pain management. By understanding the medical definition of pain and how individuals may communicate it, nurse practitioners can differentiate varying types of pain to target assessment.

According to the International Association for the Study of Pain (27), pain is "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or terms of described such in damage." The IASP, in July 2020, expanded its definition of pain to include context further.

Their expansion is summarized below:

• Pain is a personal experience influenced by biological, psychological, and social factors.
• Pain cannot be inferred solely from activity in sensory neurons.
• Individuals learn the concept of pain through their life experiences.
• A person's report of an experience in pain should be respected.
• Pain usually serves an adaptive role but may adversely affect function and social and psychological well-being.
• The inability to communicate does not negate the possibility of the experience of pain.

Types of Pain

Pain originates from different mechanisms, causes, and areas of the body. As a nurse practitioner, understanding the type of pain a patient is experiencing is essential for several reasons (23).

• Determining an accurate diagnosis. This kind of pain can provide valuable clues to the underlying cause or condition.
• Creating a treatment plan. Different types of pain respond better to specific treatments or interventions.
• Developing patient education. A nurse practitioner can provide targeted education to patients about their condition, why they may experience the pain as they do, its causes, and treatment options. Improving the patient's knowledge and control over their condition improves outcomes.

Acute Pain

Acute pain is typically short-lived and is a protective response to an injury or illness. Patients are usually able to identify the cause. This type of pain resolves as the underlying condition improves or heals (12).

Chronic Pain

Chronic pain is diagnosed when it continues beyond the expected healing time. Pain is defined as chronic when it persists for longer than three months. It may result from an underlying disease or injury or develop without a clear cause. Chronic pain often significantly impacts a person's physical and emotional well-being, requiring long-term management strategies. The prolonged experience of chronic pain usually indicates a central nervous system component of pain that may require additional treatment. Patients with centralized pain often experience allodynia or hyperalgesia (12).

Allodynia is pain evoked by a stimulus that usually does not cause pain, such as a light touch. Hyperalgesia is the effect of a heightened pain response to a stimulus that usually evokes pain (12).

Nociceptive Pain

Nociceptive pain arises from activating peripheral nociceptors, specialized nerve endings that respond to noxious stimuli. This type of pain is typically associated with tissue damage or inflammation and is further classified into somatic and visceral pain subtypes.

Somatic pain is most common and occurs in muscles, skin, or bones; patients may describe it as sharp, aching, stiffness, or throbbing.

Visceral pain occurs in the internal organs, such as indigestion or bowel spasms. It is more vague than somatic pain; patients may describe it as deep, gnawing, twisting, or dull (12).

Neuropathic pain

Neuropathic pain is a lesion or disease of the somatosensory nervous system. Examples include trigeminal neuralgia, painful polyneuropathy, postherpetic neuralgia, and central poststroke pain (10).

Neuropathic pain may be ongoing, intermittent, or spontaneous pain. Patients often describe neuropathic pain as burning, prickling, or squeezing quality. Neuropathic pain is a common chronic pain. Patients commonly describe allodynia and hyperalgesia as part of their chronic pain experience (10).

Affective pain

Affective descriptors reflect the emotional aspects of pain and include terms like distressing, unbearable, depressing, or frightening. These descriptors provide insights into the emotional impact of pain on an individual's well-being (12).

Case Study

Mary Adams is a licensed practical nurse who has just relocated to town. Mary will be the utilization review nurse at a local long-term care facility. Mary was diagnosed with Postherpetic Neuralgia last year, and she is happy that her new job will have her mostly doing desk work and not providing direct patient care as she had been before the relocation. Mary was having difficulty at work at her previous employer due to pain. She called into work several times, and before leaving, Mary's supervisor had counseled her because of her absences.

Mary wants to establish primary care immediately because she needs ongoing pain treatment. She is hopeful that, with her new job and pain under control, she will be able to continue a successful career in nursing. When Mary called the primary care office, she specifically requested a nurse practitioner as her primary care provider because she believes that nurse practitioners tend to spend more time with their patients.

Assessment

The assessment effectively determines the type of treatment needed, the options for treatment, and whether the patient may be at risk for opioid dependence. Since we know that chronic pain can lead to disability and pain has a high potential to negatively affect the patient's ability to work or otherwise, be productive, perform self-care, and potentially impact family or caregivers, it is imperative to approach the assessment with curiosity and empathy. This approach will ensure a thorough review of pain and research on pain management options. Compassion and support alone can improve patient outcomes related to pain management (23).

Record Review

Regardless of familiarity with the patient, reviewing the patient's treatment records is essential, as the ability to recall details is unreliable. Reviewing the records can help identify subtle changes in pain description and site, the patient's story around pain, failed modalities, side effects, and the need for education, all impacting further treatment (23).

Research beforehand the patient's current prescription and whether or not the patient has achieved the maximum dosage of the medication. Analysis of the patient's past prescription could reveal a documented failed therapy even though the patient did not receive the maximum dose (23).

A review of documented allergens may indicate an allergy to pain medication. Discuss with the patient the specific response to the drug to determine if it is a true allergy, such as hives or anaphylaxis, or if the response may have been a side effect, such as nausea and vomiting.

Research whether the patient tried any non-medication modalities for pain, such as physical therapy (PT), occupational therapy (OT), or Cognitive Behavioral Therapy (CBT). Note any non-medication modalities documented as failed therapies. The presence of any failed therapies should prompt further discussion with the patient, family, or caregiver about the experience. The incompletion of therapy should not be considered failed therapy. Explore further if the patient abandoned appointments.

Case Study

You review the schedule for the week, and there are three new patient appointments. One is Mary Adams. The interdisciplinary team requested and received Mary's treatment records from her previous primary care provider. You make 15 minutes available to review Mary's records and the questionnaire Mary filled out for her upcoming appointment. You see that Mary has been diagnosed with Postherpetic Neuralgia and note her current treatment regimen, which she stated was ineffective. You write down questions you will want to ask Mary. You do not see evidence of non-medication modalities or allergies to pain medication.

Pain Assessment

To physically assess pain, several acronyms help explore all the aspects of the patient's experience. Acronyms commonly used to assess pain are SOCRATES, OLDCARTS, and COLDERAS. These pain assessment acronyms are also helpful in determining treatment since they include a character and duration of pain assessment (23).

Inquire where the patient is feeling pain. The patient may have multiple areas and types of pain. Each type and location must be explored and assessed. Unless the pain is from a localized injury, a body diagram map, as seen below, is helpful to document, inform, and communicate locations and types of pain. In cases of Fibromyalgia, rheumatoid arthritis, or other centralized or widespread pain, it is vital to inquire about radiating pain. The patient with chronic pain could be experiencing acute pain or a new pain site, such as osteoarthritis, that may need further evaluation and treatment (23).

Inquire with the patient how long their pain has been present and any associated or known causative factors. Pain experienced longer than three months defines chronic versus acute pain. Chronic pain means that the pain is centralized or a function of the Central Nervous system, which should guide treatment decisions.

To help guide treatment, ask the patient to describe their pain. The description helps identify what type of pain the patient is experiencing: Allodynia and hyperalgesia indicate centralized pain; sharp, shooting pain could indicate neuropathic pain. Have the patient rate their pain. There are various tools, as shown below, for pain rating depending on the patient's ability to communicate. Not using the pain rating number alone is imperative. Ask the patient to compare the severity of pain to a previous experience. For example, a 1/10 may be experienced as a bumped knee or bruise, whereas a 10/10 is experienced on the level of a kidney stone or childbirth (23).

Besides the 0-10 rating scale and depending on the patient's needs, several pain rating scales are appropriate. They are listed below.

The 0-5 and Faces scales may be used for all adult patients and are especially effective for patients experiencing confusion.

The Defense and Veterans Pain Rating Scale (DVPRS) is a five-item tool that assesses the impact of pain on sleep, mood, stress, and activity levels (20).

For patients unable to self-report pain, such as those intubated in the ICU or late-stage neurological diseases, the FLACC scale is practical. The FLACC scale was initially created to assess pain in infants. Note: The patient need not cry to be rated 10/10.

(21).

Assess contributors to pain such as insomnia, stress, exercise, diet, and any comorbid conditions. Limited access to care, socioeconomic status, and local culture also contribute to the patient's experience of pain (23). Most patients have limited opportunity to discuss these issues, and though challenging to bring up, it is compassionate and supportive care. A referral to social work or another agency may be helpful if you cannot explore it fully.

Assess for substance abuse disorders, especially among male, younger, less educated, or unemployed adults. Substance abuse disorders increase the likelihood of misuse disorder and include alcohol, tobacco, cannabis, cocaine, and heroin (29).

Inquire as to what changes in function the pain has caused. One question to ask is, "Were it not for pain, what would you be doing?" As seen below, a Pain, Enjoyment, and General Activity (PEG) three-question scale, which focuses on function and quality of life, may help determine the severity of pain and the effect of treatment over time.

(21).

Assess family history, mental health disorders, chronic pain, or substance abuse disorders. Each familial aspect puts patients at higher risk for developing chronic pain (23).

Evaluate for mental health disorders the patient may be experiencing, particularly anxiety and depression. The Patient Health Questionnaire (PHQ4) is a four-question tool for assessing depression and anxiety.

In some cases, functional MRI or imaging studies effectively determine the cause of pain and the treatment. If further assessment is needed to diagnose and treat pain, consult Neurology, Orthopedics, Palliative care, and pain specialists (23).

Case Study

You used OLDCARTS to evaluate Mary's pain and completed a body diagram. Mary is experiencing allodynia in her back and shoulders, described as burning and tingling. It is exacerbated when she lifts, such as moving patients at the long-term care facility and, more recently, boxes from her move to the new house. Mary has also been experiencing anxiety due to fear of losing her job, the move, and her new role. She has moved closer to her family to help care for her children since she often experiences fatigue. Mary has experienced a tumultuous divorce in the last five years and feels she is still undergoing some trauma.

You saw in the chart that Mary had tried Gabapentin 300 mg BID for her pain and inquired what happened. Mary explained that her pain improved from 8/10 to 7/10 and had no side effects. Her previous care provider discontinued the medication and documented it as a failed therapy. You reviewed the minimum and maximum dosages of Gabapentin and know Mary can take up to 1800mg/day.

During the assessment, Mary also described stiffness and aching in her left knee. She gets a sharp pain when she walks more than 500 steps, and her knee is throbbing by the end of the day. Mary rated the pain a 10/10, but when she compared 10/10 to childbirth, Mary said her pain was closer to 6/10. Her moderate knee pain has reduced Mary's ability to exercise. She used to like to take walks. Mary stated she has had knee pain for six months and has been taking Ibuprofen 3 – 4 times daily.

Since Mary's pain is moderate, you evaluate your options of drugs for moderate to severe pain.

Opioid Classifications and Drug Schedules

A comprehensive understanding of drug schedules and opioid classifications is essential for nurse practitioners to ensure patient safety, prevent drug misuse, and adhere to legal and regulatory requirements. Nurse practitioners with a comprehensive understanding of drug schedules and opioid classifications can effectively communicate with colleagues, ensuring accurate medication reconciliation and facilitating interdisciplinary care. Nurse practitioners’ knowledge in facilitating discussions with pharmacists regarding opioid dosing, potential interactions, and patient education is essential (49).

Drug scheduling became mandated under the Controlled Substance Act. The Drug Enforcement Agency (DEA) Schedule of Controlled Drugs and the criteria and common drugs are listed below.

(Pain Physician, 2008)

Listed below are drugs classified by their schedule and mechanism of action. "Agonist" indicates a drug that binds to the opioid receptor, causing pain relief and also euphoria. An agonist-antagonist indicates the drug binds to some opioid receptors but blocks others. Mixed antagonist-agonist drugs control pain but have a lower potential for abuse and dependence than agonists (7).

(41).

Commonly Prescribed Opioids, Indications for Use, and Typical Side Effects

Opioid medications are widely used for managing moderate to severe pain. Referencing NIDA (2023), this section aims to give healthcare professionals an overview of the indications and typical side effects of commonly prescribed Schedule II opioid medications, including hydrocodone, oxycodone, morphine, Fentanyl, and hydromorphone.

Opioids are derived and manufactured in several ways. Naturally occurring opioids come directly from the opium poppy plant. Synthetic opioids are manufactured by chemically synthesizing compounds that mimic the effects of a natural opioid. Semi-synthetic is a mix of naturally occurring and man-made (35).

Understanding the variations in how an opioid is derived and manufactured is crucial in deciding the type of opioid prescribed, as potency and analgesic effects differ. Synthetic opioids are often more potent than naturally occurring opioids. Synthetic opioids have a longer half-life and slower elimination, affecting the duration of action and timing for dose adjustments. They are also associated with a higher risk of abuse and addiction (38).

Hydrocodone

Mechanism of Action and Metabolism

Hydrocodone is a Schedule II medication. It is an opioid agonist and works as an analgesic by activating mu and kappa opioid receptors located in the central nervous system and the enteric plexus of the bowel. Agonist stimulation of the opioid receptors inhibits nociceptive neurotransmitters' release and reduces neuronal excitability (17).

• Produces analgesia.
• Suppresses the cough reflex at the medulla.
• Causes respiratory depression at higher doses.

Hydrocodone is indicated for treating severe pain after nonopioid therapy has failed. It is also indicated as an antitussive for nonproductive cough in adults over 18.

Available Forms

Hydrocodone immediate release (IR) reaches maximum serum concentrations in one hour with a half-life of 4 hours.  Extended-release (ER) Hydrocodone reaches peak concentration at 14-16 hours and a half-life of 7 to 9 hours. Hydrocodone is metabolized to an inactive metabolite in the liver by cytochrome P450 enzymes CYP2D6 and CYP3A4. Hydrocodone is converted to hydromorphone and is excreted renally. Plasma concentrations of hydromorphone are correlated with analgesic effects rather than hydrocodone.

Hydrocodone is formulated for oral administration into tablets, capsules, and oral solutions. Capsules and tablets should never be crushed, chewed, or dissolved. These actions convert the extended-release dose into immediate release, resulting in uncontrolled and rapid release of opioids and possible overdose.

Dosing and Monitoring

Hydrocodone IR is combined with acetaminophen or ibuprofen. The dosage range is 2.5mg to 10mg every 4 to 6 hours. If formulated with acetaminophen, the dosage is limited to 4gm/day.

Hydrocodone ER is available as tablets and capsules. Depending on the product, the dose of hydrocodone ER formulations in opioid-naïve patients is 10 to 20 mg every 12 to 24 hours.

Nurse practitioners should ensure patients discontinue all other opioids when starting the extended-release formula.

Side Effects and Contraindications

Because mu and kappa opioid receptors are in the central nervous system and enteric plexus of the bowel, the most common side effects of hydrocodone are constipation and nausea (>10%).

Other adverse effects of hydrocodone include:

• Respiratory: severe respiratory depression, shortness of breath
• Cardiovascular: hypotension, bradycardia, peripheral edema
• Neurologic: Headache, chills, anxiety, sedation, insomnia, dizziness, drowsiness, fatigue
• Dermatologic: Pruritus, diaphoresis, rash
• Gastrointestinal: Vomiting, dyspepsia, gastroenteritis, abdominal pain
• Genitourinary: Urinary tract infection, urinary retention
• Otic: Tinnitus, sensorineural hearing loss
• Endocrine: Secondary adrenal insufficiency (17)

Hydrocodone, being an agonist, must not be taken with other central nervous system depressants as sedation and respiratory depression can result. In formulations combined with acetaminophen, hydrocodone can increase the international normalized ratio (INR) and cause bleeding.  Medications that induce or inhibit cytochrome enzymes can lead to wide variations in absorption.

The most common drug interactions are listed below:

• Alcohol
• Benzodiazepines
• Barbiturates
• other opioids
• rifampin
• phenytoin
• carbamazepine
• cimetidine,
• fluoxetine
• ritonavir
• erythromycin
• diltiazem
• ketoconazole
• verapamil
• Phenytoin
• John’s Wort
• Glucocorticoids

Considerations

Use with caution in the following:

• Patients with Hepatic Impairment: Initiate 50% of the usual dose
• Patients with Renal Impairment: Initiate 50% of the usual dose
• Pregnancy: While not contraindicated, the FDA issued a black-boxed warning since opioids cross the placenta, and prolonged use during pregnancy may cause neonatal opioid withdrawal syndrome (NOWS).
• Breastfeeding: Infants are susceptible to low dosages of opioids. Non-opioid analgesics are preferred.

Pharmacogenomic: Genetic variants in hydrocodone metabolism include ultra-rapid, extensive, and poor metabolizer phenotypes. After administration of hydrocodone, hydromorphone levels in rapid metabolizers are significantly higher than in poor metabolizers.

Oxycodone

Mechanism of Action and Metabolism

Oxycodone has been in use since 1917 and is derived from Thebaine. It is a semi-synthetic opioid analgesic that works by binding to mu-opioid receptors in the central nervous system. It primarily acts as an agonist, producing analgesic effects by inhibiting the transmission of pain signals (Altman, Clark, Huddart, & Klein, 2018).

Oxycodone is primarily metabolized in the liver by CYP3A4/5. It is metabolized in the liver to noroxycodone and oxymorphone.  The metabolite oxymorphone also has an analgesic effect and does not inhibit CYP3A4/5. Because of this metabolite, oxycodone is more potent than morphine, with fewer side effects and less drug interactions. Approximately 72% of oxycodone is excreted in urine (Altman, Clark, Huddart, & Klein, 2018).

Available Forms

Oxycodone can be administered orally, rectally, intravenously, and as an epidural. For this sake, we will focus on immediate-release and extended-release oral formulations.

• Immediate-release (IR) tablets
• IR capsules
• IR oral solutions
• Extended-release (ER) tablets

Dosing and Monitoring

The dosing of oxycodone should be individualized based on the patient's pain severity, previous opioid exposure, and response. Initial dosages for opioid naïve patients range from 5-15 mg for immediate-release formulations, while extended-release formulations are usually initiated at 10-20 mg. Dosage adjustments may be necessary based on the patient's response, but caution should be exercised. IR and ER formulations reach a steady state at 24 hours and titrating before 24 hours may lead to overdose.

Regular monitoring is essential to assess the patient's response to treatment, including pain relief, side effects, and signs of opioid misuse or addiction. Monitoring should include periodic reassessment of pain intensity, functional status, and adverse effects (Altman, Clark, Huddart, & Klein, 2018).

Side Effects and Contraindications

Common side effects of oxycodone include:

• constipation
• nausea
• sedation
• dizziness
• respiratory depression
• respiratory arrest
• hypotension
• fatal overdose

Oxycodone is contraindicated in patients with known hypersensitivity to opioids, severe respiratory depression, paralytic ileus, or acute or severe bronchial asthma. It should be used cautiously in patients with a history of substance abuse, respiratory conditions, liver or kidney impairment, and those taking other medications that may interact with opioids, such as alcohol (4).

It is also contraindicated with the following medications and classes:

• Antifungal agents
• Antibiotics
• Rifampin
• Carbamazepine
• Fluoxetine
• Paroxetine

Considerations

• Nurse practitioners should consider the variations in the mechanism of action for the following:
• Metabolism differs between males and females: females have been shown to have less concentration of oxymorphone and more CYP3A4/5 metabolites.
• Infants have reduced clearance of oxycodone, increasing side effects.
• Pediatrics have 20-40% increased clearance over adults.
• Reduced clearance with age increases the half-life of oxycodone.
• Pregnant women have a greater clearance and reduced half-life.
• Impairment of the liver reduces clearance.
• Cancer patients with cachexia have increased exposure to oxycodone and its metabolite.
• Maternal and neonate concentrations are similar, indicating placenta crossing (4)

Morphine

Mechanism of Action and Metabolism

Morphine is a naturally occurring opioid alkaloid extracted from the opium poppy. It was isolated in 1805 and is the opioid against which all others are compared. Morphine binds to mu-opioid receptors in the brain and spinal cord, inhibiting the transmission of pain signals and producing analgesia. It is a first-line choice of opioid for moderate to severe acute, postoperative, and cancer-related pain (8).

Morphine undergoes first-pass metabolism in the liver and gut. It is well absorbed and distributed throughout the body. Its main metabolites are morphine-3-glucuronide and morphine-6-glucuronide. Its mean plasma elimination half-life after intravenous administration is about 2 hours. Approximately 90% of morphine is excreted in the urine within 24 hours (8).

Available Forms

Morphine is available in various forms, including.

• immediate-release tablets
• extended release tablets
• oral IR solutions
• injectable solutions
• transdermal patches

Dosing and Monitoring

Morphine is hydrophilic and, as such, has a slow onset time. The advantage of this is that it is unlikely to cause acute respiratory depression even when injected. However, because of the slow onset time, there is more likelihood of morphine overdose due to the ability to “stack” doses in patients experiencing severe pain (Bistas, Lopez-Ojeda, & Ramos-Matos, 2023).

The dosing of morphine depends on the patient's pain severity, previous opioid exposure, and other factors. It is usually initiated at a low dose and titrated upwards as needed. Monitoring pain relief, adverse effects, and signs of opioid toxicity is crucial. Reevaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy or of dose escalation. General recommendations for initiating morphine (Bistas, Lopez-Ojeda, & Ramos-Matos, 2023).

Prescribe IR opioids instead of ER opioids.

Prescribe the lowest effective dosage, below 50 Morphine Milligram Equivalents (MME) /day.

Side Effects and Contraindications

Because morphine binds to opioid receptors in the brain and spinal cord, is metabolized in the liver and gut, and has a slow onset, the following side effects are common:

• Constipation
• Nausea
• Vomiting
• Sedation
• Dizziness
• Respiratory depression
• Pruritis
• Sweating
• Dysphoria/Euphoria
• Dry mouth
• Anorexia
• Spasms of urinary and biliary tract

Contraindications of morphine are:

• Known hypersensitivity or allergy to morphine.
• Bronchial asthma or upper airway obstruction
• Respiratory depression in the absence of resuscitative equipment
• Paralytic ileus
• Risk of choking in patients with dysphagia, including infants, children, and the elderly (8)

Concurrent use with other sedating medications: Amitriptyline, diazepam, haloperidol, chlorpromazine

Morphine interacts with the following medications:

• Ciprofloxacin
• Metoclopramide
• Ritonavir

Considerations for Nurse Practitioners

Assess for medical conditions that may pose serious and life-threatening risks with opioid use, such as the following:

• Sleep-disordered breathing, such as sleep apnea.
• Pregnancy
• Renal or hepatic insufficiency
• Age >= 65
• Certain mental health conditions
• Substance use disorder
• Previous nonfatal overdose

Fentanyl

Mechanism of Action and Metabolism

Fentanyl is a synthetic opioid more potent than morphine and was approved in 1968. Fentanyl is an agonist that works by binding to the mu-opioid receptors in the central nervous system. This binding inhibits the transmission of pain signals, resulting in analgesia. Fentanyl is often used for severe pain management, particularly in the perioperative and palliative care settings, or for severe pain in patients with Hepatic failure (8).

It is a mu-selective opioid agonist. However, it can activate other opioid receptors in the body, such as the delta and kappa receptors, producing analgesia. It also activates the Dopamine center of the brain, stimulating relaxation and exhilaration, which is responsible for its high potential for addiction (8).

Indications for fentanyl are as follows:

• Preoperative analgesia
• Anesthesia adjunct
• Regional anesthesia adjunct
• General anesthesia
• Postoperative pain control
• Moderate to severe acute pain (off-label)

Available Forms

• Fentanyl is available in various forms, including:
• transdermal patches
• injectable solutions
• lozenges
• nasal sprays
• oral tablets (8)

Dosing and Monitoring

Fentanyl is metabolized via the CYP3A4 enzyme in the liver. It has a half-life of 3 to 7 hours, and 75% of Fentanyl is excreted in the urine and 9% in feces.

The dosing of fentanyl depends on the route of administration and the patient's needs. For example, transdermal patches are typically applied every 72 hours, while injectable solutions are titrated to achieve the desired analgesic effect. Monitoring should include assessing pain levels, respiratory rate, blood pressure, and sedation scores (8).

Fentanyl is most dosed as follows:

• Post-operative pain control
• 50 to 100 mcg IV/IM every 1 to 2 hours as needed; alternately 0.5 to 1.5 mcg/kg/hour IV as needed. Consider lower dosing in patients 65 and older.

PCA (patient-controlled analgesia): 10 to 20 mcg IV every 6 to 20 minutes as needed; start at the lowest effective dose for the shortest effective duration - refer to institutional protocols (8).

Moderate to severe acute pain (off-label) 1 to 2 mcg/kg/dose intranasally each hour as needed; the maximum dose is 100 mcg. Use the lowest effective dose for the shortest effective duration (8).

Side Effects and Contraindications

Common side effects of fentanyl include:

• respiratory depression
• sedation
• constipation
• nausea
• vomiting
• euphoria
• confusion
• respiratory depression/arrest
• visual disturbances
• dyskinesia
• hallucinations
• delirium
• narcotic ileus
• muscle rigidity
• addiction
• loss of consciousness
• hypotension
• coma
• death (8).

The use of fentanyl is contraindicated in patients in the following situations:

• After operative interventions in the biliary tract, these may slow hepatic elimination of the drug.
• With respiratory depression or obstructive airway diseases (i.e., asthma, COPD, obstructive sleep apnea, obesity hyperventilation, also known as Pickwickian syndrome)
• With liver failure
• With known intolerance to fentanyl or other morphine-like drugs, including codeine or any components in the formulation.
• With known hypersensitivity (i.e., anaphylaxis) or any common drug delivery excipients (i.e., sodium chloride, sodium hydroxide) (8).

Considerations for Nurse Practitioners

Nurse practitioners prescribing fentanyl should thoroughly assess the patient's pain, medical history, and potential risk factors for opioid misuse. They should also educate patients about the proper use, storage, and disposal of fentanyl. It should be used cautiously in patients with respiratory disorders, liver or kidney impairment, or a history of substance abuse. Fentanyl is contraindicated in patients with known hypersensitivity to opioids and those without exposure to opioids.

Alcohol and other drugs, legal or illegal, can exacerbate fentanyl's side effects, creating multi-layered clinical scenarios that can be complex to manage. These substances, taken together, generate undesirable conditions that complicate the patient's prognosis (8).

Hydromorphone

Mechanism of Action and Metabolism

Hydromorphone is a semi-synthetic opioid derived from morphine. It binds to the mu-opioid receptors in the central nervous system. It primarily exerts its analgesic effects by inhibiting the release of neurotransmitters involved in pain transmission, thereby reducing pain perception. Hydromorphone also exerts its effects centrally at the medulla level, leading to respiratory depression and cough suppression (1).

Hydromorphone is indicated for:

• moderate to severe acute pain
• severe chronic pain
• refractory cough suppression (off-label) (1)

Available Forms

Hydromorphone is available in various forms, depending on the patient’s needs and severity of pain.

• immediate-release tablet
• extended release tablets
• oral liquid
• injectable solution
• rectal suppositories

Dosing and Monitoring

The immediate-release oral formulations of hydromorphone have an onset of action within 15 to 30 minutes. Peak levels are typically between 30 and 60 minutes with a half-life of 2 to 3 hours. Hydromorphone is primarily excreted through the urine.

The dosing of hydromorphone should be individualized based on the patient's pain intensity, initiated at the lowest effective dose, and adjusted gradually as needed. Close monitoring of pain relief, adverse effects, and signs of opioid toxicity is essential. Patients should be assessed regularly to ensure they receive adequate pain control without experiencing excessive sedation or respiratory depression.

The following are standard dosages that should only be administered when other opioid and non-opioid options fail.

• Immediate-release oral solutions dosage: 1 mg/1 mLoral tablets are available in 2 mg, 4 mg, and 8 mg.
• Extended-release oral tablets are available in dosages of 8 mg, 12 mg, 16 mg, and 32 mg.
• Injection solutions are available in concentrations of 1 mg/mL, 2 mg/mL, 4 mg/mL, and 10 mg/mL.
• Intravenous solutions are available in strengths of 2 mg/1 mL, 2500 mg/250 mL, ten mg/1 mL, and 500 mg/50 mL.
• Suppositories are formulated at a strength of 3 mg (1).

Side Effects and Contraindications

Hydromorphone has potential adverse effects on several organ systems, including the integumentary, gastrointestinal, neurologic, cardiovascular, endocrine, and respiratory.

Common side effects of hydromorphone include:

• Constipation
• Nausea
• Vomiting
• Dizziness
• Sedation
• respiratory depression
• pruritus
• headache
• Somnolence
• Severe adverse effects of hydromorphone include:
• Hypotension
• Syncope
• adrenal insufficiency
• coma
• raised intracranial pressure.
• seizure
• suicidal thoughts
• apnea
• respiratory depression or arrest
• drug dependence or withdrawal
• neonatal drug withdrawal syndrome
• Hydromorphone is contraindicated in patients with:
• known allergies to the drug, sulfites, or other components of the formulation.
• known hypersensitivity to opioids.
• severe respiratory depression
• paralytic ileus
• acute or severe bronchial asthma (1).

Caution should be exercised in patients with:

• respiratory insufficiency
• head injuries
• increased intracranial pressure.
• liver or kidney impairment.

Considerations for Nurse Practitioners

As nurse practitioners, it is crucial to assess the patient's pain intensity and overall health status before initiating Hydromorphone. Start with the lowest effective dose and titrate carefully for optimal pain control. Regular monitoring for adverse effects, signs of opioid toxicity, and therapeutic response is essential. Educate patients about the potential side effects, proper dosing, and the importance of not exceeding prescribed doses. Additionally, nurse practitioners should be familiar with local regulations and guidelines regarding opioid prescribing and follow appropriate documentation and monitoring practices.

Additional Considerations

In terminal cancer patients, clinicians should not restrain opioid therapy even if signs of respiratory depression become apparent.

Hydromorphone requires careful administration in cases of concurrent psychiatric illness.

Specific Patient Considerations:

• Hepatic impairment and Renal Impairment: Initiate hydromorphone treatment at one-fourth to one-half of the standard starting dosage, depending on the degree of impairment.
• Pregnancy considerations: Hydromorphone can traverse the placental barrier and induce NOWS.
• Breastfeeding considerations: Nonopioid analgesic agents are preferable for breastfeeding women.
• Older patients: hydromorphone is categorized as a potentially inappropriate medication for older adults (1).

Tramadol

Mechanism of Action and Metabolism

Tramadol is a Schedule IV opioid medication with a higher potential for dependency and misuse than non-opioid medications. It binds to opioid receptors in the central nervous system, inhibiting the reuptake of norepinephrine and serotonin. It also has weak mu-opioid receptor agonist activity.

The liver metabolizes tramadol mediated by the cytochrome P450 pathways (particularly CYP2D6) and is mainly excreted through the kidneys.

Tramadol is used for moderate to severe pain.

Available Forms of Tramadol include:

• Immediate-release-typically used for acute pain management.
• Extended-release-used for chronic pain.

Dosing and Monitoring

Tramadol has an oral bioavailability of 68% after a single dose and 90–100% after multiple doses and reaches peak concentrations within 2 hours. Approximately 75% of an oral dose is absorbed, and the half-life of tramadol is 9 hours (18).

Tramadol dosing should be individualized based on the patient's pain severity and response.

The initial dose for adults is usually 50-100 mg orally every 4-6 hours for pain relief. The maximum daily dose is 400 mg for immediate-release formulations and 300 mg for extended-release formulations (18).

It is essential to monitor the patient's pain intensity, response to treatment, and any adverse effects. Regular reassessment and adjustment of the dosage may be necessary.

Side Effects and Contraindications

Tramadol is responsible for severe intoxications leading to consciousness disorder (30%), seizures (15%), agitation (10%), and respiratory depression (5%). The reactions to Tramadol suggest that the decision to prescribe should be carefully considered.

Common Side Effects of Tramadol Include:

• Nausea
• Vomiting
• Dizziness
• Constipation
• Sedation
• Headache
• CNS depression
• Seizure
• Agitation
• Tachycardia
• Hypertension
• reduced appetite
• pruritus and rash
• gastric irritation

Serious side effects include:

• respiratory depression
• serotonin syndrome
• seizures

Contraindications

Tramadol is contraindicated in patients with:

• history of hypersensitivity to opioids
• acute intoxication with alcohol
• opioids, or other psychoactive substances
• Patients who have recently received monoamine oxidase inhibitors (MAOIs)

Additionally, the following can be observed in tramadol intoxication:

• miosis
• respiratory depression
• decreased level of consciousness
• hypertension
• tremor
• irritability
• increased deep tendon reflexes

Poisoning leads to:

• multiple organ failure
• coma
• cardiopulmonary arrest
• death

Considerations for Nurse Practitioners

Tramadol has been increasingly misused with intentional overdoses or intoxications. Suicide attempts were the most common cause of intoxication (52–80%), followed by abuse (18–31%), and unintentional intoxication (1–11%). Chronic tramadol or opioid abuse was reported in 20% of tramadol poisoning cases. Fatal tramadol intoxications are uncommon except when ingested concurrent with depressants, most commonly benzodiazepines and alcohol (18).

Tramadol poisoning can affect multiple organ systems:

• gastrointestinal
• central nervous system: seizure, CNS depression, low-grade coma, anxiety, and over time anoxic brain damage
• Cardiovascular system: palpitation, mild hypertension to life-threatening complications such as cardiopulmonary arrest
• respiratory system
• renal system: renal failure with higher doses of tramadol intoxication
• musculoskeletal system: rhabdomyolysis
• endocrine system: hypoglycemia, serotonin syndrome (18)

Cannabis

Mechanism of Action and Metabolism

Cannabis is classified as a Schedule I status. It contains various cannabinoids, with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most studied. THC primarily acts on cannabinoid receptors in the brain, producing psychoactive effects, while CBD has more diverse effects on the nervous system. These cannabinoids interact with the endocannabinoid system, modulating neurotransmitter release and influencing various physiological processes (32).

Similar to opioids, cannabinoids are synthesized and released in the body by synapses that act on the cannabinoid receptors present in presynaptic endings (32). They perform the following actions related to analgesia:

• Decrease the release of neurotransmitters.
• Activate descending inhibitory pain pathways.
• Reduce postsynaptic sensitivity and alleviate neural inflammation.
• Modulate CB1 receptors within central nociception processing areas and the spinal cord, resulting in analgesic effects.
• Attenuate inflammation by activating CB2 receptors (32).
• Emerging research shows cannabis is indicated for:
• Migraines
• chronic pain
• back pain
• arthritic pain
• pain associated with cancer and surgery.
• neuropathic pain
• diabetic neuropathic pain when administered early in the disease progression.
• sickle cell disease
• cancer
• inflammatory bowel disease (32)

Available Forms

Cannabis refers to products sourced from the Cannabis sativa plant. There are differences between cannabis, cannabinoids, and cannabidiol (CBD). Cannabinoids are extracted from the cannabis plants. Cannabinoid-based treatments, such as dronabinol and CBD, are typically approved medical interventions for specific indications. THC (9-tetrahydrocannabinol) is the psychoactive component of the cannabis plant. CBD is a non-psychoactive component (32).

Cannabis can be consumed in different forms, each with a different onset and duration. Patients may have individual preferences, including:

• smoking/vaporizing dried flowers.
• consuming edibles
• tinctures or oils
• applying topicals (32)

Dosing and Monitoring

Inhaling marijuana via the lungs by smoking or vaping causes maximum plasma concentration within minutes. Psychiatric effects begin within seconds to a few minutes after inhalation and peak after 15 to 30 minutes. The effect diminishes throughout 2 to 3 hours (32).

Oral ingestion of marijuana causes psychiatric effects that typically occur between 30 and 90 minutes and reach maximum effect after 2 to 3 hours. Ingested marijuana effects last about 4 to 12 hours (32).

Dosing cannabis is challenging due to variations in potency and individual responses. Start with low doses and titrate slowly to achieve the desired effect while minimizing side effects. Regular monitoring is crucial, including assessing symptom relief, adverse effects, and potential drug interactions. Encourage patients to keep a diary to track their cannabis use and its effects (32).

Side Effects and Contraindications

Cannabis can exacerbate mental health conditions such as anxiety and psychosis. Common side effects of cannabis include (32):

• Dizziness
• dry mouth
• increased heart rate
• impaired memory
• psychoactive effects

Contraindications include:

• Pregnancy
• Breastfeeding
• heart disease
• respiratory conditions
• history of substance abuse
• mental health disorders

Case Study

Mary is agreeable to trying an increased dose of Gabapentin. Mary would also like to see a counselor to discuss her past and get help with her anxiety. You made an appointment for Mary to see a Licensed Clinical Social Worker in your clinic.

You read the side effects and warnings for Gabapentin, and it is unsafe to use Gabapentin and Tramadol together since they are both depressants. You order a non-steroidal drug for Mary's somatic knee pain and make a consult for imaging studies on her left knee. You also make a referral to Orthopedics.

You educated Mary about the side effects of Gabapentin and scheduled a follow-up appointment. The day after Mary began her treatment with the increased Gabapentin, you called Mary to follow up on its effect. Mary still has pain, but she is not having any untoward side effects. Gabapentin may not work immediately so you will schedule a follow-up call in 3 days.

Opioid Use, the Opioid Epidemic, and Statistics

The use and misuse of opioids has become a pressing public health concern, leading to a global epidemic. The history of opioid use, the opioid epidemic, and associated statistics provide essential context for healthcare professionals in addressing this public health crisis. More importantly, it is estimated that 1 in 4 patients receiving prescription opioids in primary care settings will misuse them. In addition, 50% of opioid prescriptions are written by primary care providers, including nurse practitioners (22). Understanding the factors contributing to the epidemic and the magnitude of its impact is crucial for effective prevention, intervention, and treatment strategies.

History of Opioid Use

Opioids have a long history of medicinal use, dating back to ancient civilizations. They have been a drug of choice for pain relief for thousands of years. The introduction of synthetic opioids in the 19^th century, such as morphine and later heroin, revolutionized pain management. However, their potential for addiction and misuse soon became apparent (16).

The Opioid Epidemic

The opioid epidemic refers to the surge in opioid misuse, addiction, and overdose deaths. The epidemic gained momentum in the late 1990s with increased prescribing of opioids for chronic pain (43).

No doubt, increased prescribing put opioids in the hands of consumers, but increased prescribing resulted from a multifactorial influence. One of the main influences was aggressive marketing by pharmaceutical companies, which has been well publicized. However, due to the long history of underprescribing pain medications for fear of misuse and addiction, the medical community was primed to expand its opioid prescribing practices (31).

A historical event that increased comfort with prescribing opioids, in the writer's opinion, was the introduction of the Medicare Hospice Benefit in 1986. Medical directors must be contracted or employed by hospices, and these medical directors had or soon gained pain management expertise. To further promote hospice and effective pain management, the hospice medical directors, with newly acquired skills, provided education throughout medical communities about pain management and specifically to decrease the fear of using opioids. Pharmacies and attending physicians grew accustomed to giving opioids for home use. Hospice care is for terminally ill patients, defined as a life expectancy of 6 months or less. Still, the reality is that hospice discharges 12 to 40% of patients for ineligibility and other reasons.

A more prominent factor in increasing opioid prescribing was the 1996 American Pain Society's introduction of pain as "the 5^th Vital sign." Soon after, The Joint Commission promoted pain as "the 5^th Vital Sign" and began compliance surveys in healthcare organizations requiring pain assessment details to be as prominent as blood pressure and heart rate. The Joint Commission cited a quote from 1968 by a nurse from the University of California Los Angeles, Margo McCaffrey, who defined pain as "…Whatever the experiencing person says it is, existing whenever s/he says it does." The Joint Commission accreditation programs pursued pain management as part of the accreditation process throughout its healthcare accreditation programs, including hospice accreditation by 1989 per TJC Timeline (48).

The National Institute of Health published an article about the Joint Commission's role in the opioid epidemic, particularly regarding the definition of pain, "This definition emphasizes that pain is a subjective experience with no objective measures. It also stresses that the patient, not the clinician, is the authority on the pain and that their self-report is the most reliable indicator of pain. This set the tone for clinicians: Patients are always to be trusted to report pain accurately” (45).

Statistics on the Opioid Epidemic

In the United States alone, over 500,000 people died from opioid overdoses between 1999 and 2017. The number of opioid-related overdose deaths continues to increase, with synthetic opioids, mainly illicitly manufactured Fentanyl, playing a significant role in recent years (46). Fentanyl-laced drugs, such as marijuana, are increasingly sold knowing and unknowingly to introduce medications with a high addiction rate, thus creating new consumers. This practice can potentially increase deaths due to the imprecise nature of manufacturing (16).

Opioid-related hospitalizations have also risen substantially. In 2014, there were approximately 1.27 million hospitalizations related to opioids in the United States. These hospitalizations not only place a burden on healthcare systems but also reflect the severe consequences of opioid misuse (3).

Federal Regulations on Opioid Prescribing

The history of substance use disorder prevention that promotes opioid recovery and treatment for patients and communities can be traced back to the early 20^th century. However, the current approach to addressing opioid addiction and promoting healing has evolved significantly in recent times (36).

In the early 1900s, health professionals treated opioid addiction with punitive measures, including incarceration and moralistic approaches. The focus was on punishing individuals rather than providing effective treatment. This approach persisted for several decades until the mid-20^th century when the medical community started recognizing addiction as a medical condition rather than a moral failing (36).

The Controlled Substances Act (CSA), introduced in 1970, was a response to increasing drug abuse and illicit drug trafficking in the United States. The CSA is a federal law regulating the manufacture, possession, distribution, and use of certain substances, including drugs and medications, that can potentially cause abuse and dependence. Its primary purpose is to combat drug abuse, reduce drug-related crimes, and protect public health and safety. The Drug Enforcement Agency (DEA) plays a crucial role in enforcing the CSA by monitoring and controlling controlled substance production, distribution, and use (31).

In the 1990s, the significant increase in opioid prescribing, leading to a surge in opioid addiction and overdose deaths, prompted a shift in focus toward prevention. Efforts were made to educate healthcare providers about the risks of overprescribing opioids and to implement prescription drug monitoring programs to track and prevent abuse (36).

The Comprehensive Addiction and Recovery Act (CARA) was signed into law in 2016 to expand access to treatment and recovery services for opioid addiction. This legislation allocated funding for prevention, treatment, recovery, and support services while promoting evidence-based practices and programs (36).

The Centers for Disease Control and Prevention (CDC) published guidelines in 2016 for prescribing opioids for chronic pain, which was updated in 2022. These guidelines emphasize the importance of non-opioid alternatives, using the lowest effective dose for the shortest duration, and assessing the benefits and risks of continued opioid therapy (13).

Furthermore, the Substance Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT) was signed into law in 2018, providing additional resources to address the opioid crisis. This legislation expanded access to medication-assisted treatment (MAT), increased the availability of naloxone, a medication used to reverse opioid overdose, and enhanced support for recovery housing (36).

In recent years, there has been a growing recognition of the importance of a comprehensive approach to opioid addiction, including harm reduction strategies, increased access to naloxone, and the integration of mental health services. Communities and organizations have been working together to address the underlying issues contributing to addiction, such as poverty, trauma, and social determinants of health (50).

Overall, the history of substance use disorder prevention that promotes opioid recovery and treatment has evolved from a punitive approach to a more compassionate and evidence-based model. Efforts are now focused on prevention, early intervention, and expanding access to comprehensive treatment and support services for individuals and communities affected by opioid addiction (36).

The most current federal regulations on opioid prescribing for healthcare providers are the amendments to the CSA in 2018, which added new rules to limit the quantity and duration of opioid prescriptions for acute pain to seven days. In 2022, the CDC updated recommendations to the Clinical Practice Guidelines for Prescribing Opioids for Pain.

The 2022 CDC guidelines are summarized below (13):

1. Non-opioid therapies should be considered the first-line treatment for chronic pain.
2. Establish clear treatment goals with patients, including realistic pain management and functional improvement expectations.
3. Conduct a thorough risk assessment for potential harms before initiating opioid therapy.
4. When opioids are used, start with the lowest effective dose and consider immediate-release opioids instead of extended-release or long-acting opioids.
5. Prescribe the lowest effective dose for the shortest duration possible, typically three days or less and rarely exceeding seven days.
6. Reassess benefits and risks within one day after prescribing opioids, including checking the prescription drug monitoring database.
7. Avoid prescribing opioids and benzodiazepines concurrently whenever possible due to the increased risk of overdose and death.
8. Offer naloxone to patients at increased risk of opioid overdose, including those with a history of overdose, substance use disorder, or concurrent benzodiazepine use.
9. When opioids are no longer needed, taper the dose gradually to minimize withdrawal symptoms.
10. Arrange an evidence-based treatment for patients with opioid use disorder, including medication-assisted treatment (Naltrexone, Buprenorphine, or Methadone).

Safe Prescribing and Prescription Monitoring Program

Prescription Drug Monitoring Programs (PDMP) are state-run electronic databases that track.

the prescribing and dispensing of controlled substances. PDMPs are designed to improve patients.

care and safety by giving clinicians access to patients' prescription histories, allowing them to make informed decisions when prescribing controlled substances. PDMPs help identify patients at risk of substance misuse or prescription drug overdose. They also enable clinicians to identify potential drug interactions and prevent opioid diversion (14).

PDMPs collect and store data from pharmacies and prescribers in a centralized database. Clinicians can access this database to review a patient's prescription history, including the types of medications prescribed, the prescribers involved, and the dispensing pharmacies (14).

In many states, PDMP use is mandated by law, and nurse practitioners may be required to register and use the system. It is essential to understand state-specific laws and regulations regarding PDMP use.

PDMPs have some limitations, such as incomplete data or delays in reporting. The CDC emphasizes that clinicians should use PDMP data for their clinical assessment and other relevant information to make informed decisions about prescribing controlled substances. Still, PDMP cannot be used as the sole basis for denying or providing treatment (14).

Case Study

After five days on Gabapentin, Mary was doing well, and her neuropathic pain had decreased to 3/10. However, Mary suffered a fall after her knee "gave out" and injured her knee and back. She was in severe pain, and her family drove her to the ER. The ER doctors saw Mary, and orthopedics were consulted. Mary has surgery scheduled for a knee replacement a week from now.

Mary was prescribed Vicodin because she was in excruciating pain, but her prescription only allowed enough medication for two days. Mary has made an appointment with you to renew her prescription.

You evaluate Mary because you know that concomitant use of Gabapentin and opioids puts Mary at risk for respiratory depression and possible side effects, including accidental overdose.

Mary stated she has been more alert the past 24 hours and is afraid her functional status will continue to decline if she does not have more Vicodin because the pain in her back and knee makes it difficult to stand. You assess Mary. Mary stated she occasionally drinks alcohol but has not had a drink since she moved. She has no familial history of substance abuse or mental health disorders.

Mary's mother stayed at her house to help her for the first 24 hours after Mary's return from the ER, but Mary is providing her care now.

You check the PDMP database and see that Mary was prescribed eight pills she has taken over the last 48 hours.

Since the Vicodin has been effective without untoward side effects, and Mary's function is improving, you decide to refill the prescription of Vicodin. You will taper the dose to three Vicodin daily for two days and two for one day. Mary will be near her appointment for a knee replacement as well.

Preventing Opioid Use Disorder

As previously discussed, opioid addiction is a growing concern worldwide, affecting individuals from all walks of life. According to the CDC, "Anyone who takes prescription opioids can become addicted to them" (14).

As frontline healthcare professionals, nurse practitioners must recognize the signs of opioid addiction to provide timely intervention and support. This section will outline the key indicators of opioid addiction.

Physical Symptoms

Physical symptoms are often the first noticeable signs of opioid addiction. These symptoms may include constricted pupils, drowsiness, slurred speech, impaired coordination, and increased sensitivity to pain. Additionally, individuals struggling with opioid addiction may exhibit frequent flu-like symptoms, such as a runny nose, sweating, itching, or gastrointestinal issues.

Behavioral Changes

Opioid addiction can significantly impact an individual's behavior. These may include increased secrecy, frequent requests for early prescription refills, doctor shopping (seeking prescriptions from multiple healthcare providers), neglecting personal hygiene, and experiencing financial difficulties due to excessive spending on opioids (37).

Social Isolation

Opioid addiction often leads to social withdrawal and isolation. Individuals struggling with opioid addiction may distance themselves from family, friends, and social activities they once enjoyed. They may exhibit erratic mood swings, become defensive or hostile when confronted about their drug use, and display a general lack of interest in previously important activities (30).

Psychological Changes

The psychological impact of opioid addiction is significant. Individuals with opioid addiction may exhibit increased anxiety, depression, irritability, and restlessness. They may also experience cognitive impairments, memory lapses, and difficulties in decision-making. Healthcare professionals should be attentive to these changes, as they can indicate opioid addiction (51).

Tolerance and Withdrawal Symptoms

The development of tolerance and withdrawal symptoms are critical signs of opioid addiction. Individuals may require increased dosages of opioids to achieve the desired effect, indicating a growing tolerance. Furthermore, withdrawal symptoms such as muscle aches, nausea, vomiting, insomnia, and intense cravings for opioids may occur when the drug is discontinued or reduced abruptly (51).

Opioid Overdose

The management of opioid overdose, withdrawal, and addiction requires a comprehensive approach that combines pharmacological interventions with psychosocial support. Naloxone remains a vital tool for reversing opioid overdose, while medications such as Methadone, buprenorphine, and naltrexone play crucial roles in withdrawal and addiction treatment (National Institute of Health, 2023). Nurse practitioners must stay vigilant and informed about the evolving landscape of medications. This section aims to provide a comprehensive review of medications and treatment strategies for opioid overdose, withdrawal, and addiction and is excerpted from the NIH (40).

Naloxone

Mechanism of Action and Metabolism

Naloxone is an opioid receptor antagonist. It works by binding to opioid receptors and displacing any opioids present, thereby reversing the effects of opioid overdose. It has a higher affinity for opioid receptors than most opioids, effectively blocking their action.

Naloxone is indicated for emergency intervention of opioid overdose. It effectively reverses respiratory depression and other life-threatening effects. Studies suggest the potential benefits of combining naloxone with other medications, such as buprenorphine (see below), to improve outcomes. Initiatives promoting community-based naloxone distribution programs have shown promising results in reducing opioid-related deaths.

Available Forms

Naloxone is available in various formulations:

• Intranasal
• Intramuscular
• Intravenous
• auto-injectors.

The most used form is the intranasal spray, which is easy to administer and requires no specialized training. Intranasal naloxone formulations have gained popularity due to their ease of use and increased availability. A recent study showed that the non-FDA-approved compound spray was far less effective than either FDA compound (15).

Dosing and Monitoring

The recommended initial dose of naloxone for opioid overdose is 2mg intranasally or 0.4mg to 2mg intramuscularly or intravenously. If the patient does not respond within 23- minutes, additional doses may be administered every 2-3 minutes. Continuous monitoring of the patient's respiratory status is essential, as repeat doses may be required due to the short half-life of naloxone.

Side Effects and Contraindications

Naloxone has been shown not to affect individuals without opioids in their system.

Common side effects of naloxone include

• Withdrawal symptoms: increased heart rate, sweating, and agitation
• nausea
• vomiting
• headache

Contraindications include known hypersensitivity to naloxone and situations where the use of naloxone may be unsafe or not feasible.

Considerations for Nurse Practitioners

Fentanyl and other opioids have a rapid onset, and the need to act quickly is paramount. As mentioned previously, the ease of use and higher plasma concentrations using the FDA-approved 4-mg FDANxSpray device compared with the locally compounded nasal sprays should be considered when ordering Naloxone (15).

Fentanyl and other potent synthetic opioids may require multiple administrations of naloxone to achieve reversal of an overdose (Chiang, Gyaw, & Krieter, 2019). As a nurse practitioner prescribing naloxone, it is crucial to assess the patient's risk factors for opioid overdose, such as a history of substance use disorder or chronic pain management. Education regarding the proper administration of naloxone should be provided to the patients and their caregivers. Additionally, it is essential to provide resources for follow-up care, including addiction treatment and ongoing support.

Methadone

Mechanism of Action and Metabolism

Methadone is a long-acting opioid agonist that effectively suppresses withdrawal symptoms and reduces cravings. It binds to the same opioid receptors in the brain as other opioids. It relieves withdrawal symptoms and reduces cravings by blocking the euphoric effects of opioids, thus helping individuals with opioid dependence to achieve stability (33).

Available Forms

Methadone is available in oral tablets and liquid formulations. The oral tablet is the most used form and is typically administered once daily (33).

Dosing and Monitoring

Methadone dosing is individualized based on the patient's response and needs. Initially, the dose often started low and gradually increased until the patient reached a stable dose. Dosing may need to be adjusted based on the patient's response, adherence, and any changes in their overall health. Regularly monitoring the patient's vital signs, urine drug screens, and assessment of their withdrawal symptoms and cravings is essential.

Side Effects and Contraindications

Common side effects of methadone include:

• Constipation
• dry mouth
• drowsiness
• sweating
• weight gain
• respiratory depression

Contraindications include:

• known hypersensitivity to methadone
• severe asthma
• respiratory depression
• certain heart conditions (33).

Considerations for Nurse Practitioners

As a nurse practitioner prescribing methadone, conducting a comprehensive assessment of the patient's medical history, current medications, and substance use history is crucial. Opioid treatment programs or specialized clinics are often involved in methadone treatment, so collaboration and coordination of care with these programs are essential. Regularly monitoring the patient's progress, adherence, and potential side effects or drug interactions is essential. Additionally, providing education on the risks and benefits of methadone and the importance of adherence to the prescribed regimen is crucial for successful treatment outcomes.

Buprenorphine

Mechanism of Action and Metabolism

Buprenorphine is a partial opioid agonist with a ceiling effect that minimizes the risk of overdose while reducing withdrawal symptoms. Buprenorphine is a partial opioid agonist that binds to the same receptors as other opioids but produces a weaker response. It has a high affinity for the mu-opioid receptors, which helps reduce cravings and withdrawal symptoms in individuals with opioid dependence.

Available Forms

Buprenorphine is available in different formulations, including sublingual tablets, buccal films, and extended-release injections. The sublingual tablets have different strengths, such as 2mg, 4mg, 8mg, and 12mg. Buprenorphine is taken as a daily tablet or weekly or monthly injection.

Dosing and Monitoring

The dosing of buprenorphine varies depending on the individual's opioid dependence severity and treatment phase. Initially, a low dose (e.g., 2-4mg) is given, and it may gradually increase to a maintenance dose of 8-24 mg daily. Regular monitoring is essential to assess the patient's response, adherence, and potential side effects.

Side Effects and Contraindications

Common side effects of buprenorphine include:

• Constipation
• Nausea
• Headache
• Insomnia
• Sweating

Serious side effects are rare but can include:

• Respiratory depression
• Allergic reactions

Buprenorphine is contraindicated in individuals with:

• Severe respiratory insufficiency
• Acute intoxication with opioids
• Known hypersensitivity

Considerations for Nurse Practitioners

Nurse practitioners can prescribe buprenorphine for opioid dependence treatment under the Drug Addiction Treatment Act (DATA). To become eligible, they must complete specific training requirements and obtain a waiver from the Substance Abuse and Mental Health Services Administration (SAMHSA). Nurse practitioners should assess patients thoroughly, including their opioid use history, comorbidities, and medication compatibility, while ensuring appropriate counseling and referral for comprehensive treatment (40).

Clonidine + Lofexidine

Mechanism of Action and Metabolism:

Both Clonidine and Lofexidine are alpha-2 adrenergic agonists. They work by stimulating alpha-2 receptors in the brain, which reduces sympathetic outflow and norepinephrine release. This results in decreased sympathetic activity, leading to various effects such as reduced blood pressure, decreased heart rate, and alleviated withdrawal symptoms (28).

Available Forms

Clonidine is available in oral tablets and patches. Lofexidine is available in oral tablets and is taken as needed (40).

Dosing and Monitoring

For opioid withdrawal, the Clonidine dose ranges from 0.1-0.3 mg every 4-6 hours. Lofexidine is usually initiated at 0.53 mg three times daily, and the dose can be increased to 2.88 mg daily. Monitoring blood pressure and heart rate is essential during treatment (40).

Side Effects and Contraindications:

Common side effects of both medications include:

• dry mouth
• sedation
• dizziness
• constipation
• orthostatic hypotension (40).

Both medications are contraindicated in patients with:

• Hypotension
• Bradycardia
• heart block
• history of hypersensitivity to the drugs (40).

Considerations for Nurse Practitioners:

An early study of lofexidine vs. clonidine for withdrawal symptoms showed that treatment with lofexidine resulted in lower withdrawal symptoms, fewer mood problems, less sedation, and hypotension. There were no significant differences in craving levels, morphine metabolites in urine, or dropout rates when both were compared.

Lofexidine can be a safe option for outpatient treatment as it does not lead to hypotension. However, nurse practitioners must closely monitor patients' blood pressure and heart rate during treatment and educate them about possible side effects. If patients experience any concerning symptoms, they should inform their nurse practitioner immediately.

Gradual dose reduction of Clonidine is crucial to prevent rebound hypertension. Before prescribing either medication, nurse practitioners should assess for any contraindications or potential drug interactions (19).

Emerging Therapies for Withdrawal

Extended-release naltrexone: Naltrexone is an opioid receptor antagonist that blocks the effects of opioids, reducing the risk of relapse. It is taken as a monthly injection.

Alpha-2 adrenergic agonists: Emerging evidence suggests the potential use of dexmedetomidine and guanfacine for managing opioid withdrawal symptoms.

Medication-Assisted Treatment (MAT):

Methadone was introduced in the 1960s and marked a significant turning point in opioid addiction treatment or MAT. Along with counseling and behavioral therapies, MAT became the cornerstone of opioid addiction recovery.

Examples of medications used:

• Methadone
• Buprenorphine:
• Naltrexone:

Adjunctive Pharmacotherapies:

Antidepressants: Selective serotonin reuptake inhibitors and tricyclic antidepressants may help manage co-occurring depression and anxiety.

Anticonvulsants:

Medications like Gabapentin and pregabalin show promise in reducing opioid cravings and improving treatment outcomes.

Other Substance Use Disorders

Patients in pain may struggle with Substance Use Disorders other than Opioid Use Disorder. Substance use disorders may often occur with mental health conditions such as anxiety, depression, and bipolar disorder. In addition, many individuals engage in polydrug use. Understanding the most common Substance Use Disorders aids in a comprehensive assessment of the patient and the development of appropriate treatment plans (28).

Alcohol Use Disorder (AUD):

The prevalence of AUD worldwide was estimated to be 9.8% in men and 5.5% in women in 2016 (28).

Cannabis Use Disorder (CUD):

the prevalence of CUD in the United States increased from 2.18% in 2001-2002 to 2.89% in 2012-2013. (28).

Cocaine Use Disorder:

According to the National Survey on Drug Use and Health (NSDUH), in 2019, approximately 1.9 million Americans aged 12 or older had cocaine use disorder in the past year (44).

Methamphetamine Use Disorder:

A study published in Drug and Alcohol Dependence reported that the prevalence of methamphetamine use disorder in the United States was estimated to be 0.2% in 2015-2016 (6).

Drug Diversion and Illegal opioids

Misuse of opioids is facilitated by diversion and is defined as "the transfer of drugs from lawful to unlawful use" (24). Most commonly, this occurs when family and friends share prescribed opioids with other family and friends. Opioids and other controlled drugs are also diverted from healthcare facilities. Statistics show that healthcare facility diversion has increased since 2015 (24)

Diversion affects patients, healthcare workers, healthcare facilities, and public health. Patients experience substandard care due to ineffective pain management and impaired healthcare workers. In addition, affected patients are at risk of infections from compromised syringes (24).

Healthcare employees who divert are at risk of overdose and death. If caught, they face criminal prosecution and malpractice suits. Healthcare facilities also bear the cost of diverted drugs via internal investigations, follow-up care for affected patients, regulatory fines for inadequate safeguards, and declining public trust (24).

Despite the enormous consequences of drug diversion, healthcare facilities have implemented few processes to detect and deter the diversion of controlled substances (24).

Patient Teachings and Considerations

Opioids have significant side effects and carry a risk of addiction and overdose. Nurse practitioners can decrease the risks of misuse and addiction by educating patients on appropriate disposal, safe storage, and potential signs of addiction. Taking additional time to provide teaching nurse practitioners can promote patient safety, informed decision-making, and responsible opioid use.

Safe Storage and Disposal:

• Teach patients to store opioids securely, out of reach of children, pets, visitors, and non-caregiver family members, to prevent accidental ingestion or misuse (13). Only the caregiver, if applicable, or the patient should have access to pain medications.
• Instruct patients on proper disposal methods, such as using drug take-back programs or mixing opioids with undesirable substances (e.g., coffee grounds) before throwing them away (11) (13).

Medication Adherence:

• Emphasize the importance of taking opioids as prescribed, at the correct dose and frequency, to achieve optimal pain relief.
• Encourage patients to notify their healthcare provider if they experience inadequate pain control or side effects (35).

Potential Side Effects:

• Educate patients about common side effects of opioids, including constipation, nausea, sedation, and respiratory depression.
• Discuss strategies to manage side effects, such as maintaining adequate hydration, consuming a fiber-rich diet, and using over-the-counter laxatives as needed (11).

Risk of Dependence and Addiction:

• Explain the potential for opioid dependence and addiction, especially with long-term use or a history of substance abuse.
• Encourage patients to promptly report signs of opioid misuse, such as craving, loss of control, or continued use despite negative consequences (51).

Avoiding Alcohol and Other Central Nervous System Depressants:

• Instruct patients to avoid consuming alcohol or other medications that can enhance the sedative effects of opioids, increasing the risk of respiratory depression.
• Advise patients to contact the Nurse Practitioner before starting new medications, including over-the-counter drugs or herbal supplements (2).

Driving and Operating Machinery:

• Inform patients about the potential impairment caused by opioids, including reduced alertness, reaction time, and coordination.
• Advise patients to avoid driving or operating heavy machinery while taking opioids until they know how the medication affects them (14).

Case Study

You take some extra time with Mary to educate her on the taper dose of Vicodin, the potential for harm, and the risk of opioids, especially when used concomitantly with Gabapentin. You let Mary know it is unsafe to use alcohol, not only with Vicodin but also with Gabapentin. You let Mary know that Vicodin has a risk of dependency and misuse and, therefore, she will be monitored carefully. You also educate that Mary should store the Vicodin away from visibility by anyone but herself since she can self-administer her medication. You let Mary know that Vicodin can cause constipation and that she should increase her water intake and take a stool softener.

You ask Mary to call you if her pain is not adequately relieved or if her medications run out before the three days.  

You let Mary know that if she does stop taking the Vicodin before she has completed all the medication, she should dispose of it by mixing the pills with liquid and coffee grounds to make them unpalatable to animals and others.

Mary complied with your education, completed her course of Vicodin, and was scheduled for surgery. Mary's social worker helped her communicate with her new employer and delayed her start date until after her recovery.

During her recovery, Mary received physical therapy and a short course of pain medication managed by her orthopedist.

Mary returned to the clinic for a follow-up visit after completing her therapy and before starting work. Mary's pain level in her knee is 3/10, and she already feels like she can walk further than pre-surgery. Gabapentin has continued to help Mary's neuropathic pain in her back, and she reports 2/10. Mary looks forward to beginning her new job and is optimistic about the future.

Conclusion

Pain management is the leading cause of primary care appointments and chronic pain is the leading cause of disability. Yet, prescribing opioids for primary care patients is also a factor in drug misuse and the opioid epidemic. Nurse practitioners are challenged to appropriately treat pain and effectively control diversion, addiction, and death from overdose.

It is imperative that nurse practitioners use evidence-based practices to assess, appropriately intervene, and educate about the benefits and potential harm caused by treatment with opioids. Nurse practitioners must stay up to date with the current federal regulations regarding PDMPs, clinical prescribing guidelines, and emerging treatments for pain and opioid abuse disorders.

Medication Assisted Treatment (MAT)

Introduction   

Medication Assisted Treatment (MAT) is a treatment modality for substance use disorders. It combines counseling and behavioral therapies for addiction with medications used carefully to reduce the physical symptoms of cravings and withdrawal and assist clients in the recovery process. With half of people 12 and older reporting use of an illicit substance at least once and 21 million Americans experiencing addiction, this is an important and relevant topic (4).

Historically, an intense stigma is attached to both addiction and some of the medications used to treat addiction. A thorough understanding of substance use disorders, available MAT therapies, and care of affecting clients are essential topics for nurses to be familiar with, particularly those working in psychiatry, pain management, or addiction medicine.

Overview of Addiction and Substance Abuse:

Drug and alcohol abuse and addiction are chronic, complicated issues involving persistent changes to the brain. There is a stigma or misunderstanding that people with substance abuse disorders can stop any time they want to or lack the willpower or moral fortitude to stop using. This is entirely untrue, and even people who are "recovering" and have not had any drugs or alcohol in years can easily relapse into addiction once those brain changes have occurred (5).

When a person uses drugs or alcohol, the brain's reward center is flooded with dopamine. This provides a "buzz" or pleasurable sensation that may create the desire to use more of the same substance. Over time, and with regular use of the substance, the brain becomes accustomed to the flooding of dopamine and reduces the reward response, a process known as tolerance.

It will now take the same person a more significant amount of the substance to achieve the same "buzz" or "high" they used to feel. This process can also dull the pleasure response to activities not involving substance use, such as food, socialization, or sexual activity. Over time, the chemical changes in the brain can progress to include decreased functioning of learning, decision-making, judgment, response to stress, memory, and behavior (5).

To understand substance abuse disorders, it is first essential to understand some basic definitions. These terms are sometimes used interchangeably, but they mean different things and represent different stages of disease.

Definitions

Substance Use: Substance use is any consumption of drugs or alcohol, regardless of frequency or amount. An occasional glass of wine or taking an edible at a party is an example of substance use. Substance use does not cause problems or dependency in many people (5).

Substance Abuse: Substance abuse is the continued use of drugs or alcohol, even when they do cause problems. Conflict or problems at home, school, work, or legal issues related to the use of drugs or alcohol are signs of abuse. For example, being sent home from school for smoking in the bathroom or failing a drug test at work (5).

Substance Dependence or Addiction: Dependence and addiction can be used interchangeably or is sometimes called substance use disorder. Addiction occurs when a person cannot stop drinking or using drugs despite creating problems in their life. People who are addicted may experience cravings until they use a specific substance, or they may experience uncomfortable physical symptoms, known as withdrawal if they do stop (5).

The American Psychiatric Association (APA) utilizes the following criteria to diagnose clients who suffer from addiction. The more criteria a client answers yes to, the greater their problem with substance use.

Six or more positive criteria are indicative of addiction.

1. Using substance in more significant amounts or for more extended periods than intended
2. Trying to stop using but being unable to
3. Increased amounts of time getting, using, or recovering from use of the substance
4. Experiencing cravings or urges to use.
5. Continuing to use the substance despite problems with relationships or social situations.
6. Missing work, social, or recreational obligations or activities because of substance use
7. Participating in risky behavior because of substance use
8. Continuing to use the substance despite psychological or physical health problems.
9. Needing to use more substance over time to achieve the desired effect.
10. Experiencing withdrawal symptoms when stopping the substance (1).

Substance Abuse Statistics

Many factors go into gathering data on substance abuse disorders, from underreporting, the nuance between use, abuse, and addiction, and the large variety of substances available, with the legality of some substances varying by state or age.

The statistics below from 2020 are not meant to be an exhaustive list of substance use disorders in this country but rather an overview of some of the more prevalent addiction-related issues.

• 50% of people 12 years and older have used an illicit substance at least once.
• 5% of Americans 12 years and older have used drugs within the last month.
• This is a 3.8% increase from the previous year.
• About 50% of Americans 12 and over drink alcohol
• 4% of those people have an alcohol use disorder.
• About 20% of Americans use tobacco products or vape
• 18% of Americans over 18 used marijuana in the last 12 months
• 30% of those have some level of misuse or addiction.
• Marijuana is commonly involved in polysubstance use, paired with alcohol or other drugs.
• 7% of Americans over 12 misused opioids in the last 12 months
• 96% of those used prescription pain relievers
• Opioid prescriptions peaked in 2012, with 81.3 prescriptions per 100 people.
• The rate has declined recently due to increased attention to this crisis.
• In 2018, the rate was down to 51 prescriptions for every 100 people
• Fentanyl is now rising as a new and deadly concern.
• 5 million prescriptions were written for fentanyl in 2015.
• Fentanyl is involved in 53% of overdose deaths.
• 7% of all Americans misuse a prescription drug.
• 1% of those misuse stimulants
• 2% of those misuse sedatives
• 5% misuse painkillers
• Over 70,000 drug overdose deaths occur annually in the United States (4)

Risk Factors

A combination of factors is involved in the risk of addiction, and no one factor can determine if someone will develop addiction or after how many uses this will occur.

The addiction process does occur more easily or progresses more rapidly for people with certain risk factors, including:

Genetics

There is a strong genetic correlation with addiction, indicating that biology plays a significant role in the disorder. Family history of addiction, gender, ethnicity, and comorbid mental health conditions can all influence the risk of addiction. (5)

• Children of addicts are eight times more likely to develop an addiction at some point.
• In 2020, among those using illicit or misusing prescription drugs, 22% were male and 17% female.
• Only 20% of users in drug treatment programs are women.
• 9% of people with substance abuse disorders also have at least one mental health disorder (4)

Environment/Non-Genetic Demographics

The attitudes about drugs and alcohol from those in a person's network and life experiences play a role in the risk of addiction. Substance use among friends, family, or coworkers increases the risk that a person will also use substances. Exposure to substance use from a young age relaxed parental attitudes about substance use, and peer pressure from friends can increase the risk. Certain stressful life circumstances such as veteran status, history of sexual or physical assault, or being part of the LGBTQ community can also increase risk. (5)

• 20% of people in urban areas used illegal drugs in 2020 compared to 5% in rural locations.
• 51% of Americans with an illegal pain relief medication obtained it from a friend or relative.
• 7% of LGBTQ Americans abuse illicit drugs.
• 2% of LGBTQ Americans abuse alcohol.
• 7% of Veterans abuse illicit drugs.
• 80% of Veterans abuse alcohol (4)

Developmental Stage

Substance use at any age can lead to addiction, but children and teens are at particular risk due to their underdeveloped brains. The parts of the brain responsible for decision-making, risk assessment, and self-control do not fully develop until the early 20's, putting teenagers at increased risk of dangerous behaviors. In addition, the effects of drugs and alcohol on the developing brain may mean that those parts of the brain never fully develop at all for teens with substance abuse disorders. (5)

• 70% of users who try an illegal substance before age 13 will develop a substance use disorder within the next seven years.
• This is for only 27% of people who first try an illegal substance after age 17.
• 47% of youths report trying an illegal substance by the time they graduate high school (4)

Overview of Medication Assisted Treatment (MAT)

Treatment of substance abuse disorders is a complex and often tumultuous process. The nature of the brain changes that occur during addiction means that a person is never entirely "cured" but will always be considered "recovering" as the risk for relapse is always present. Effective treatment must be multifaceted and often involves removing triggers (such as people, places, and stressors) that may prompt a person to use again behavioral therapy, and medications to curb withdrawal symptoms and reduce cravings.

Medication Assisted Treatment (MAT) is a treatment that involves FDA-approved medications, in combination with behavioral therapy, in the recovery process for substance abuse disorders. Several medications are available for MAT, and evidence continues to emerge that the treatment is highly effective if used correctly.

However, it is a vastly underused and understudied treatment modality. MAT has been available in some form for over 50 years but is just starting to gain traction among the medical community (and policymakers) in recent years, with the federal government calling for more research and increased accessibility for the treatment (8).

The height of the opioid crisis in the last several years has highlighted the magnitude of drug addiction and deaths in the United States, bringing renewed attention to MAT as a treatment option. So, how does MAT work? Prescription medication is given to both stimulate the receptors seeking the abused substance and block the drug's euphoric effects.

Over time, this normalizes brain chemistry and helps the person break the habit of using without the discomfort of cravings and withdrawal symptoms. Gradually, the prescription medication dosage is reduced, all the while in conjunction with behavioral therapy and lifestyle changes, and eventually, the client should be able to stop the medication altogether, often within 1-3 months (8).

MAT does require close supervision by a trained medical professional and an appropriate facility for treatment. It can be done on an inpatient, partial inpatient, or outpatient basis. There may be side effects to the medication, and there is a risk of misusing or developing addiction to the new drug, though the successful outcomes often outweigh this risk. Clients must also participate in behavioral therapy for a comprehensive and effective treatment plan. As with any treatment regimen, careful consideration of the client's history and circumstances is essential (8).

Pharmacokinetics

Currently, there are three medications with FDA approval for MAT: buprenorphine, methadone, and naltrexone. Each will be discussed in depth below.

Buprenorphine

Mechanism of Action and Metabolism

Buprenorphine is an opioid partial agonist, acting on the same receptors as other opioids but with weaker effects. It can be used for the treatment of misuse of opioids, including:

• Heroin
• Fentanyl
• Oxycodone
• Hydrocodone
• Morphine
• Methadone (3)

Opiate receptors are G-protein coupled receptors (GPCRs) with four major types: Mu, Delta, Kappa, and opioid receptor like-1 (ORL1). Stimulation of these receptors results in varying levels of the following effects:

• Euphoria
• Relaxation
• Pain relief
• Sleepiness
• Sweating
• Constipation
• Impaired concentration
• Reduced sex drive (3)

Buprenorphine has a high affinity to the Mu-opioid receptor and is a partial agonist at this site, causing reduced opioid effects with a plateau or ceiling at higher doses. This limits dangerous effects and makes overdose unlikely. It also has slow dissociation from the site, allowing milder and more easily tolerated withdrawal effects compared to full agonists like morphine and fentanyl. Buprenorphine is also a weak kappa receptor antagonist and delta receptor agonist, reducing the craving sensation and improving tolerance to stress (3).

Buprenorphine has poor bioavailability when given orally due to the first-pass effect, where most of the drug is broken down in the liver and intestines. Because of this, sublingual or buccal are the preferred routes of administration and the most common forms in which the drug is manufactured. Transdermal patches and IV and IM forms exist, though not for use in MAT (3).

CYP34A enzymes break down buprenorphine, so other drugs, such as ketoconazole, may inhibit metabolism and increase available levels of buprenorphine. CYP34A inducers such as carbamazepine, topiramate, phenytoin, and barbiturates may speed metabolism and lower available levels. Once broken down, the med takes the form of norbuprenorphine and is excreted in the feces (3).

Available Forms

Buprenorphine is available by itself and with naloxone (in a 4 to 1 ratio). However, in oral form, naloxone is not readily absorbed, and buprenorphine is the only genuinely active ingredient. This combination is beneficial should clients try to inject their buprenorphine to get high; naloxone is a fast-acting opioid antagonist that is active when used intravenously and would block the opioid effect of buprenorphine, rendering it useless for recreational use and ensuring it has no street value.

The currently available preparations of buprenorphine for MAT include:

• Generic Buprenorphine/naloxone sublingual tablets
• Subutex - Buprenorphine sublingual tablets
• Suboxone - Buprenorphine/naloxone sublingual films
• Zubsolv - Buprenorphine/naloxone sublingual tablets
• Bunavail - Buprenorphine/naloxone buccal film (3)

Sublingual products dissolve within 2-10 minutes. Bloodstream absorption begins quickly, bypassing the first pass effect. Buprenorphine has a slow onset of action, peaking about 3-4 hours later. Metabolism is also slow, with the half-life lasting anywhere from 25 to 70 hours (an average of about 38 hours). This long half-life means the drug can be spaced out to every other day administration once weaning begins (3).

Dosing and Monitoring

Clients prescribed buprenorphine must stop using opioids for at least 12 to 24 hours before the first dose; this varies depending on which opioid they are stopping. For short-acting opioids like heroin and oxycodone, buprenorphine may be started 6-12 hours after the last dose. With longer-acting opioids such as morphine or extended-release preparations of oxycodone, buprenorphine should be delayed for about 24 hours. For the longest action opioids, fentanyl patch, 48 -72 hours must be between the last dose and buprenorphine initiation (3).

This initiation schedule means clients will be in the early stages of discomfort and withdrawal. Administration of buprenorphine when clients still have opioids in their bloodstream will lead to competition for receptor sites, rapidly replacing the opioid with buprenorphine and causing acute and more severe withdrawal symptoms.

Depending on the severity of a client's addiction, they may complete the first step of abstaining and withdrawal in an inpatient setting. Once the initial withdrawal symptoms have passed and the initial dose of buprenorphine has been given, the client may be discharged home to continue buprenorphine initiation on an outpatient basis (3).

Initial doses are typically 2-4mg, with up to 4mg given to clients used to higher potency or larger doses of opioids. The dose is gradually increased to meet the client's individual needs, with a maximum dosage of 24mg per day. The average client requires 8-12 mg per day and can reach this dose within the first 2-4 days. It is recommended that doses be supervised by a pharmacist at the dispensing pharmacy for the first two months of treatment to ensure compliance and clients are less likely to relapse (3).

The length of treatment with buprenorphine depends on each client's case and, for some, may be indefinite. Clients who do wish to wean off buprenorphine can begin the process once they are stable and experiencing few or no cravings, and a minimum of 8 weeks from treatment initiation. Doses are moved to alternating days and eventually discontinued altogether (3).

Side Effects and Contraindications:

As with any medication, there are potential side effects, including:

Common Side Effects

• Nausea
• Vomiting
• Drowsiness
• Dizziness
• Headache
• Memory loss
• Sweating
• Dry mouth
• Miosis
• Postural hypotension
• Sexual dysfunction
• Urinary retention

Serious side effects

• CNS depression
• QT prolongation
• Reduced seizure threshold
• Potential for abuse or overdose (3)

Buprenorphine is contraindicated for clients with a past hypersensitive reaction to it. It should be used cautiously for clients with respiratory suppression, older adults, or for those with liver pathologies. Regular monitoring of liver enzymes via lab work is essential (3).

It is a Category C medication for pregnancy, and the risks versus benefits should be carefully weighed. Buprenorphine does cross the placenta and increases the risk of withdrawal symptoms and neonatal abstinence syndrome (NAS) after delivery. However, for pregnant clients with the highest risk of relapse and abuse of opioids, evidence does support that continuation of buprenorphine during pregnancy may improve maternal and fetal outcomes (3).

Buprenorphine may be abused by crushing tablets, snorting the powder, or dissolving it into an injectable solution. Safety measures against this include supervised administration by a pharmacist and the addition of naloxone, which blocks the buprenorphine effects. While the effect ceiling of buprenorphine makes overdose difficult, combining the drug with benzodiazepines, alcohol, or other drugs can compound the CNS depressant effects and increase the risk of overdose (3).

Clinicians need to have a comprehensive health history of clients before initiating buprenorphine so that all risks and potential interactions can be addressed appropriately.

Role of the Pharmacist

Pharmacists play a significant role in the success of MAT involving buprenorphine. Outpatient doses are monitored by the dispensing pharmacist daily, with at-home quantities being allowed on a limited basis (such as weekends or travel) and only for the most motivated and compliant clients. Vital signs are collected before each dosage, with careful monitoring for hypotension or bradypnea. The dose may be skipped for clients who experience excessive side effects, and the client can return the next day for their dose.

Clients presenting with signs of overdose (usually to the ED) may receive naloxone, which will reverse overdose symptoms within 1 hour. Overdose symptoms include dizziness, pinpoint pupils, hypotension, bradypnea, hallucinations, seizure, or unconscious state.

If a client misses a dose, does not show up for it, or is experiencing significant side effects from buprenorphine, the prescribing clinician should be notified so that the treatment plan can be revisited and revised if needed (3).

Considerations for the Prescriber

When considering which medication to prescribe for MAT, prescribers should understand that buprenorphine offers advantages over methadone.

• Lower risk of abuse
• Safer, including at higher doses.
• Therapeutic dose achieved quickly.
• Easier to taper.
• Can be obtained from any provider rather than a methadone clinic.
• Less stigma

The cost of a 30-day supply is around $300. Buprenorphine/naloxone combinations are a little more expensive at $400/month. While prior authorization is usually required, most commercial insurance and state Medicaid programs will cover the medication.

Buprenorphine is a Schedule III Controlled Substance; however, recent federal regulations have been aimed at approving access to MAT, and any provider with an active DEA license may prescribe buprenorphine as allowed by state regulations. Specialized clinics are not required (as they are with methadone), and it is dispensed at regular pharmacies.

Prescribers are encouraged to participate in additional training about MAT with buprenorphine, but it is not required. Detailed documentation must be completed, including the reason for prescribing, start and end dates of treatment, the pharmacy used, the credentials of who will supervise administration, and frequency of follow-up and compliance monitoring. The sublingual and buccal routes are the only forms of medication used for MAT; patches, IM, and IV preparations are not routinely used for MAT.

The success of buprenorphine treatment depends on the client's education. Addiction potential, risk of combination with other CNS depressants, and side effects vs. signs of overdose should all be discussed with clients and their support system (3).

Methadone

Mechanism of Action and Metabolism

Methadone is a synthetic opioid and a full agonist of the Mu-receptor site, stimulating the same effects as opioids.

• Euphoria
• Analgesia
• Sedation

It can be used as a potent analgesic for pain not responding to traditional medications, such as in clients with cancer or terminal illness, as well as for MAT and neonatal abstinence syndrome (NAS).

For this course, it will be discussed as a MAT agent, used in treatment for clients addicted to opioids such as:

• Heroin
• Fentanyl
• Oxycodone
• Hydrocodone
• Morphine
• Hydromorphone (2)

Methadone is a full agonist at the Mu-receptor, meaning it is a more potent and more easily addictive medication than partial agonists like buprenorphine. Methadone has a long half-life (8-60 hours), occupying the Mu-receptors and blocking short-acting opioids from making a client high. The longer half-life also leads to less severe cravings and withdrawal symptoms. Methadone is also an antagonist to the N-methyl-d-aspartate (NMDA) receptor, which adds to its pain relief action (2).

It has high oral bioavailability, is active in the bloodstream within 30 minutes of ingestion and remains elevated for around 24 hours. It is broken down via CYP3A4 and CYP2B6 enzymes and metabolized through the liver, making it a good option for clients with renal problems.

Medications such as ciprofloxacin, benzodiazepines, fluconazole, cimetidine, and fluoxetine may slow methadone metabolism, increasing the available drug and the side effects of overdose risk. Other medications may speed metabolism and decrease the effects of methadone, including phenobarbital, phenytoin, rifampin, ritonavir, and carbamazepine (2).

Available Forms

Methadone is available in many forms, including oral, IM, subcutaneous, IV, and intrathecal, though only the oral is typically used for MAT.

• Methadone - tablets
• DISKETS - dispersible/dissolvable tablet
• Methadone HCL Intensol - 10mg/ml suspension
• Methadone - dispersible tablet (2)

Dosing and Monitoring

Oral dosing is initiated at 30-40 mg/day with a slow titration of 10-20 mg/week until the optimal dosage is reached. The optimal dosage varies by client and depends on the drug they are replacing, tolerance to opioids, and side effects experienced. A dosage between 80- 150 mg/day is the typical goal. (2)

If parenteral methadone is given, it is usually 50%-80% of the oral dosage.

Blood sugar, EKG, and methadone blood levels should be checked regularly, every week for higher-risk patients, and every 3-6 months for those in good health and compliance. The target methadone blood level is around 400 ug/ml (2).

Side Effects and Contraindications

Potential side effects are directly related to stimulation of the opioid receptors and include:

• Diaphoresis
• Flushing
• Pruritus
• Nausea
• Dry mouth
• Constipation
• Sedation
• Lethargy
• Respiratory Depression
• QT prolongation
• Hypoglycemia (2)

Methadone should be considered with a comprehensive view of a client's health history and other medications. Clients with CNS-related disease processes (trauma, increased ICP, dementia, or delirium) must be monitored closely or have other medication considered.

Methadone should not be used simultaneously as other opioids, benzodiazepines, alcohol, or antipsychotics due to increased CNS effects. Methadone is a Pregnancy Category C medication, and risks versus benefits should be weighed carefully. Infants exposed to methadone in utero are at increased risk of NAS after delivery (2).

Overdose can occur, and clients and support systems should be educated on signs of overdose.

• Lethargy
• Somnolence
• Stupor
• Coma
• Miosis
• Bradycardia
• Hypotension
• Respiratory sedation
• Cardiac arrest

Naloxone is used to reverse overdose (2).

Considerations for Prescribers and Clinics

Methadone is a Schedule II Controlled Substance, meaning it has a high abuse potential and must be carefully monitored. The Prescription Drug Monitoring Program (PDMP) is an electronic database used nationwide to register the distribution of controlled substances so that clients do not seek care at multiple clinics or pharmacies to obtain more of a controlled substance.

When prescribing methadone, providers should check the PDMP for both methadone and other prescription opioids so that they are fully aware of other medications clients may be receiving from other places. Regular urine drug screening should be performed to make sure clients are not using other substances not obtained by prescription and that they are testing positive for methadone, meaning they are genuinely taking it if administration is not observed (2).

At the beginning of treatment, methadone is given in the office under a nurse's supervision, and then clients are monitored for adverse effects. Some take-home doses (up to 7 in the first two weeks) may be arranged for weekends or during travel, but this possibility is limited during the first few weeks of treatment. As treatment progresses and compliance is demonstrated, clients may self-administer more doses at home (up to 28 doses per month) and go longer between visits to the clinic. The total length of treatment varies but is often 1-2 years and can even be indefinite (7).

There are methadone clinics that work entirely in the scope of addiction management, but primary care providers may prescribe methadone as well. Prescribers must have an active DEA license and comply with state-based controlled substance regulations (2).

Naltrexone

Mechanism of Action and Metabolism

Naltrexone has been in use since the 1960s and is an opioid antagonist. It competes primarily with the mu-receptor but also serves as an antagonist at the kappa and delta receptors. As an antagonist, it competes with agonists such as opioids and alcohol and blocks the effects of agonists at those sites.

• Prevents euphoria.
• Prevents intoxication.
• Reduces tolerance (6)

Naltrexone also acts on the hypothalamic-pituitary-adrenal axis, modifying it to reduce cravings and suppress alcohol consumption.

It is FDA-approved for use in clinical practice for the treatment of:

• Alcohol use disorder
• Opioid use disorder (prescription and non)

Naltrexone is absorbed orally and undergoes extensive metabolism via the first-pass effect. However, this does not affect its potency as naltrexone's active metabolite, 6β-naltrexone, acts as a potent opioid antagonist. The medication's half-life is around 4 hours but can last up to 24 hours. If administered parenterally, it bypasses the first pass and is even longer acting, with a half-life of 5-10 days. Naltrexone is excreted by the kidneys (6).

Available Forms

Naltrexone is available in an oral tablet and IM injection. Available preparations include:

• Generic naltrexone tablets
• Revia (oral tablet)
• Depade (oral tablet)
• Vivitrol (solution for IM injection, extended-release) (6)

Dosing and Monitoring

Since naltrexone will compete for and block all opioid receptor sites, the risk for withdrawal symptoms is high, and clients must stop the use of alcohol or opioids for 7-10 days before beginning treatment to lessen the risk of withdrawal symptoms. A naltrexone challenge is recommended at the start of therapy.

This consists of administering small amounts of naltrexone subcutaneously or via IV and monitoring the client and their vital signs for signs of withdrawal, such as:

• Nausea
• Vomiting
• Diaphoresis
• BP changes
• Tachycardia
• Rhinorrhea
• Agitation
• Tremors
• Abdominal pain
• Pupillary dilation (6)

If a client fails the naltrexone challenge and has not been long enough since their last use of alcohol or opioids, the naltrexone initiation should be delayed, and the test should be repeated in 24 hours. If clients tolerate the naltrexone test and the negative result, they may begin naltrexone treatment (6).

For oral tablets, dosing usually starts at 25 mg for the first dose. Clients are observed for withdrawal symptoms and side effects; an additional 25 mg is given 1 hour later. After that, clients take 50 mg per day. Clients may continue with 50mg daily or take 100 mg every other day or 150 mg every 3rd day (6).

Alternatively, naltrexone may be given via IM injection for more extended action, improving compliance and reducing relapse. Particularly for alcohol or heroin dependence, data indicates that the IM route has much higher success rates than the oral route. If a client receives the IM injection, 380 mg is given to the gluteal muscle every four weeks (6).

Side Effects and Contraindications

Most common side effects of naltrexone include:

• GI irritation
• Diarrhea
• Abdominal cramps
• Nausea
• Vomiting
• Hypertension
• Headache
• Anxiety
• Low energy
• Joint or muscle pain
• Nervousness
• Sleep disruption

Less commonly, clients report:

• Loss of appetite
• Constipation
• Dizziness
• Irritability
• Depression
• Rash
• Chills (6)

Caution should be used for clients with liver function issues and renal impairment. It is Category C for use during pregnancy, and the risks versus benefits of use in pregnancy must be carefully considered. It also crosses into breast milk and must be considered carefully.

There is limited data about the overdose of naltrexone, and there may be very few symptoms if an overdose occurs. Clients should be monitored for signs of liver dysfunction, seizures, depression, and suicidal ideations. No antidote for naltrexone is currently available.

Naltrexone is contraindicated for clients who failed a naltrexone challenge, test positive for opioids or alcohol on drug screening, have a history of seizures, or have experienced a past hypersensitivity reaction to naltrexone.

Clients may switch from buprenorphine or methadone to naltrexone at some point in treatment. Both medications are agonists at the opioid receptor sites, so changing to naltrexone (an antagonist) may increase the risk of withdrawal symptoms for the first two weeks of treatment (6).

Considerations for Prescribers

Because naltrexone does not cause any euphoria or "high," the abuse potential is non-existent. It is not a controlled substance and can be prescribed by any clinician with prescriptive authority. However, its use is typically only by those who work in mental health or addiction medicine. Clients can take the medication at home or go to the clinic for IM injections.

Many considerations for naltrexone use center around monitoring for side effects and treatment compliance. Baseline and periodic drug screening and liver function tests are prudent. Clients' support persons should be educated on compliance and signs of relapse. The IM formulation should be considered for those with poor compliance or most at risk for relapse (6).

Nursing Considerations

Nurses will encounter clients with addiction and even those receiving MAT in a variety of settings, including:

• Outpatient clinics for routine care of any health issues
• ED admission for acute problems not related to addiction.
• Inpatient hospitalization related to other health problems.
• Outpatient setting for participation in MAT or addiction management.
• ED admission for acute problems related to substance abuse or toxicity of MAT medication.
• Inpatient mental health admission for mental health and addiction issues

Regardless of the setting and if the client is being seen for an addiction issue or something else, it is crucial for nurses to be familiar with MAT medications and how they work to provide safe and competent care. Nurses may need to:

• Administer medication.
• Monitor lab results.
• Observe for side effects, toxicity, or withdrawal symptoms.
• Coordinate care within a multidisciplinary team
• Communicate with therapeutic and nonjudgmental techniques.

Case Study

Justin is a 32-year-old male who presents to the ED with nausea, lethargy, and confusion worsening over the last 24 hours. Upon exam, the nurse notes diaphoresis, slurred speech, and pinpoint pupils. His vitals are RR 10, HR 54, BP 82/58, SPO2 97%, Temp 99.0.

He reports taking Wellbutrin 150mg daily for depression and smoking cessation, methadone 100mg daily for history of oxycodone abuse, and was started on ciprofloxacin 250mg BID for a UTI 2 days ago at urgent care.

His labs are significant for a WBC of 15,000 but otherwise regular. He tests positive for methadone, which is expected, but not for other substances. He reports being compliant with MAT and avoiding opioid use for nine months.

It is determined that Justin is experiencing methadone toxicity due to the slowed metabolism of the drug from the combination of methadone and ciprofloxacin. He is given naloxone in the ED, and within an hour, his symptoms have improved significantly, and his vital signs are typical. His antibiotic is switched to cefdinir, and he is discharged home in stable condition with instructions to follow up with his PCP within 1-2 days.

Conclusion

Substance use disorders are a long-standing and dangerous pathology experienced by millions of people each year. At the same time, the stigma of seeking help for such disorders has been eroding in recent years; there has also been a renewed push by the federal government to address the issue in evidence-based and meaningful ways, with access to effective treatment being at the top of the priority list.

Addiction treatment programs utilizing MAT will likely become much more popular in the coming years, and nurses will be on the front lines of this therapy. For nurses to provide competent and comprehensive care to this client population, up-to-date and accurate knowledge is necessary.

Opioid Prescribing for Chronic Pain

Introduction   

Opioids are a class of medications used to treat chronic pain. The Centers for Disease Control and Prevention estimates that above 75% of drug overdose deaths in 2021 were from opioid medications [2]. Thus, healthcare providers must be diligent when prescribing opioids and follow best practice guidelines.  

Understanding the different pharmacokinetics, interactions, and contraindications of opioids is crucial. This course outlines opioid pharmacology and addresses pharmacokinetics, including mechanism of action, side effects, usage, and contraindications. In addition, it reviews considerations for prescribing and upcoming research regarding pain control.  

Definitions 

This section covers the definitions related to opioid medications. 

Chronic Pain: pain lasting three months or more and can be caused by any medical condition, injury, or unknown etiology [1]. 

Opioid: medication that interacts with the body’s receptors to reduce pain [1]. 

Opioid analgesics: referral to as prescription opioids [1]. 

Opioid dependence: the body physically adjusts to using opioids and when the medication is stopped, physical symptoms appear [1]. 

Opioid tolerance: the body has a reduced response to opioid medication, and thus increased dosages are required to control pain [1]. 

Opioid Overview 

This section briefly reviews opioid subclasses and the controlled substance schedules. 

Opioids are used for the treatment of chronic pain, as well as various other medical conditions in both inpatient and outpatient settings. They are divided into two major classes: full opioid agonists and atypical opioids [6]. Opioids can be classified by their mode of synthesis, which includes naturally occurring, semi-synthetic compounds, and synthetic compounds [10].  

Some examples of each are: 

• Naturally-occurring: morphine, codeine 
• Semi-synthetic: oxycodone, buprenorphine 
• Synthetic: fentanyl, methadone [10]. 

The U.S. Drug Enforcement Administration (DEA) defines and classifies mediations by schedules, ranging from I to V. Schedule I controlled substances have no acceptable medical use approved in the United States and have a high potential for abuse. Conversely, Scheduled V controlled substances have a low potential for abuse relative to schedules I through IV.  

Some examples of opioids that fall under Schedule I to III include [17]: 

• Schedule I: heroin 
• Schedule II: methadone, oxycodone 
• Schedule III: buprenorphine [17] 

Healthcare providers must follow licensure and state prescribing rules and regulations as these vary by state and professional level of practice.  

Pharmacokinetics 

This section discusses the pharmacokinetics of each opioid medication class. 

Opioids are agonists that act on specific receptor sites in the brain to control pain [9]. There are three types of opioid receptors in the central nervous system, which are mu, kappa, and delta. Opioids most commonly act on the mu-opioid receptors, but also on the delta and kappa receptors to aid in pain control and analgesia [6, 8].  

Opioid medications can be divided into two different classes, which include full opioid agonists and atypical opioids [6]. 

Full Opioid Agonists 

Full opioid agonists are a subclass of opioid medications used to control chronic pain. Examples of full opioid agonists include morphine, oxycodone, codeine, and fentanyl [6]. Morphine and Oxycodone are approved by the Federal Drug Administration (FDA) for the treatment of moderate to severe acute or chronic pain [12, 15]. Morphine is also used in an emergency setting.  

It’s administered to patients with acute coronary syndrome, as it relieves pain while also reducing the heart’s oxygen demand [12]. Codeine is often prescribed for chronic pain in patients who have cancer or are under palliative care. Off-label and non-FDA-approved indications of codeine are cough, restless leg syndrome, and persistent diarrhea [13].  

Fentanyl, a higher-potency opioid, treats severe pain in patients with advanced cancer. It has other uses, such as preoperative and postoperative analgesia, and can be used as a regional and general adjunct anesthesia [14]. 

Opioids act on both presynaptic and postsynaptic neurons. They block presynaptic calcium channels by inhibiting the release of neurotransmitters, like substance P and glutamate, which cause pain. Opioids open postsynaptic potassium channels, causing cell hyperpolarization, which inhibits cell signaling as well.  

Most full agonist opioids act at the mu receptor but can also act on the delta and kappa receptors [8]. Some opioids also can affect serotonin pathways by inhibiting serotonin reuptake or increasing the release of intrasynaptic serotonin [3]. 

Full opioid agonists are available in many forms, including sublingual, subcutaneous, intravenous (IV), oral, rectal, intramuscular (IM), and topical. Oral routes are available in immediate-release or extended-release forms. The rectal route is typically reserved for individuals who cannot take medications by mouth. Topical forms, usually Fentanyl, are administered via a transdermal patch that is removed and reapplied after a certain amount of time.  

Morphine can also be given via epidural or intrathecally through an implantable spinal pump. Recommended starting dosages of each opioid vary greatly and depend on the route, underlying pain condition being treated, and patient tolerance [3].  

Regardless of route and dosages, opioids can present potential adverse effects including: 

• Sedation 
• Central nervous system (CNS) depression 
• Nausea or vomiting 
• Constipation 
• Respiratory depression 
• Pruritis 
• Bradycardia  

[3, 8] 

Many patients prescribed opioids develop physical dependence, where they develop withdrawal symptoms when the opioid is discontinued. In addition, patients prescribed opioids for chronic pain will potentially develop a tolerance. Thus, they will likely require increased opioid dosages to feel the same effects of pain control [8].  

As some full opioid agonists affect serotonin pathways, these medications increase the likelihood of developing serotonin syndrome [3]. 

Full agonist opioids have several contraindications and therefore, healthcare providers should exercise caution when ordering these medications. Patients who have had a recent head trauma or have increased partial carbon dioxide (pCO2) from hypoventilation, or increased intracranial pressure are at increased risk for respiratory and CNS depression.  

If the patient has reduced liver or kidney function, the healthcare provider should avoid prescribing opioids when able, since they are metabolized through these organs. When prescribing any opioid, healthcare providers must be aware of the potential for opioid overdose and consider prescribing an opioid antagonist for overdose emergencies.  

Lastly, individuals with thyroid or adrenal deficiencies may be more sensitive to opioids and likely require lower dosages [8]. 

Atypical Opioids  

Atypical opioids are another subclass of opioids used to control chronic pain. Some examples of atypical opioids include buprenorphine, tramadol, and methadone [18]. Buprenorphine is FDA-approved to treat acute and chronic pain. It’s also approved to treat opioid dependence, especially for those with a heroin addiction [11].  

Tramadol is used to treat moderate to severe pain and off-label uses include treatment for premature ejaculation and restless leg syndrome [4].  

Lastly, methadone is FDA-approved to treat moderate to severe pain and for detoxification during opioid use disorder treatment. It can be used to treat neonatal abstinence syndrome, where substances were abused during pregnancy. However, this is not approved by the Federal Drug Administration [5]. 

Atypical opioids have varying mechanisms of action based on the medication and differ from full agonist opioids. Buprenorphine is a partial mu receptor agonist and a weak delta and kappa receptor agonist. It’s metabolized by the cytochrome CYP3A4 enzyme [11]. Tramadol is another partial mu receptor agonist that also inhibits the reuptake of serotonin and norepinephrine. It’s metabolized by the CYP2D6 liver enzyme, activating the M1 metabolite, which acts on the mu receptor [4].  

Methadone is a full mu receptor agonist and competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor. This medication has a longer half-life than other opioids and is 8 to 60 hours [5]. 

This subclass of opioids is available in many forms and dosages, which depend on the medication. Buprenorphine is available via transdermal patch or subcutaneous implant and in IV, IM, and sublingual routes. The dosage of buccal films and sublingual tablets starts at 75 mcg and 2mg, respectively [11]. Alternatively, tramadol is available only in oral form and immediate-release dosages start at 50mg [4].  

Methadone is available in many forms, including oral, IM, IV, epidural, and subcutaneous. Dosages depend on the route, the underlying condition being treated, and the opioid tolerance of the individual [5]. However, healthcare providers should always start at the lowest dose possible when prescribing.  

Similar to full opioid agonists, atypical opioids can pose side effects including: 

• Respiratory depression 
• CNS depression 
• Sedation 
• Nausea and vomiting 
• Dry mouth 
• Hypotension  

[4, 5, 11] 

Buprenorphine and methadone are also associated with QT prolongation [5, 11]. Atypical opioids have varying contraindications, but many are the same as full opioid agonists as described above. Buprenorphine is contraindicated in patients with suspected or confirmed gastrointestinal obstruction and has a black box warning of accidental exposure causing overdose [11].  

Healthcare providers must avoid prescribing tramadol to patients under 12 years old or patients under 18 years old who have had a tonsillectomy or adenoidectomy. Prescribing tramadol to patients who are taking monoamine oxidase inhibitors (MAOIs), or tricyclic antidepressants is contraindicated as well [4].  

Methadone has many drug interactions when compared to other atypical opioids. Therefore, healthcare providers must verify the patient’s medication list is up-to-date and accurate [5].  

Considerations for Prescribers 

This section reviews potential considerations when prescribing opioids. 

When prescribing opioids, healthcare providers must consider and review several factors. The route of administration and dosage are determined by the healthcare setting, medical condition, current medications, and patient’s tolerance level. Evidence-based treatment guidelines for prescribing opioids should be followed.  

When assessing a patient’s pain, screening tools like the Visual Analogue Scale or pain scale can help measure a patient’s pain level [8]. For patients with or undergoing opioid withdrawal, the Clinical Opiate Withdrawal (COWS) tool may also be useful. Before prescribing any opioids, healthcare providers should check the patient’s controlled-substance prescription records through the state’s Prescription Drug Monitoring Program (PDMP).  

In addition, a urine drug screen is useful for the initial assessment and monitoring of opioid medication compliance. The healthcare provider should document the necessity for prescribing opioids, medication compliance, and patient behaviors at least every three months. The patient’s age and liver and kidney function are also important factors to review before prescribing opioids [8]. 

Opioids interact with several medications and have varying adverse effects. Therefore, the healthcare provider must ensure the patient’s medication list is accurately updated. Medications like selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), antifungals, and MOAIs are a few common classes of medications that pose serious interactions [3, 5, 8].  

Additionally, healthcare providers should avoid prescribing benzodiazepines to patients who are taking opioids and vice versa. Patients should be educated on the adverse effects of respiratory and CNS depression, and how alcohol can contribute to these effects when combined with opioids.  

As opioids can cause constipation, patients should understand the importance of eating a balanced, high-fiber diet and drinking adequate water when instructed by their provider. The healthcare provider should also consider prescribing stool softeners for constipation prevention [8]. 

Healthcare providers and patients should be knowledgeable about the signs of opioid overdose and withdrawal. Patients should be educated on the signs of opioid overdose, which are altered mental status, respiratory depression, and constricted pupils. When prescribing opioids, healthcare providers must consider concurrently prescribing a nonselective opioid antagonist, like naloxone, to counteract the effects of opioid overdose.  

Patients and family members should be instructed on their use [3, 8]. Alternatively, patients should also be instructed on the effects of abruptly discontinuing the use of chronic pain medications, as these can lead to withdrawal symptoms. Patients should be encouraged to report withdrawal symptoms to their healthcare provider [8]. 

Another important factor when prescribing opioids is considering alternative or adjunct treatment options. Some alternatives to opioids for pain management include nonsteroidal anti-inflammatories (NSAIDs), tricyclic antidepressants, and SNRIs. Adjunct therapies such as cognitive behavioral therapy (CBT), and physical therapy and activity are also helpful in pain control [8]. 

Upcoming Research 

This section reviews ongoing research about opioid medications. 

Over the past several years, there has been much-needed research about alternative pain management modalities to opioids. Some alternatives include those discussed above and other alternatives like nerve and spinal cord stimulators, epidural injections, and transcutaneous electric nerve stimulation [8].  

Synthetic opioids, like fentanyl, were discovered in the 1950s and extremely potent synthetic opioids, like carfentanil, were developed in the 1980s. Carfentanil is 1,000 times stronger than morphine and 50 times more than fentanyl. Therefore, it’s not widely prescribed by healthcare providers due to its high potency and risk of overdose [7].  

Nitazenes, also called benzimidazoles, are another class of opioids that is not approved for use in the United States. However, the Drug Enforcement Administration has seen an uptick in their illegal use over the past several years [16]. 

Conclusion

Opioids are approved to treat chronic pain, as well as various other conditions and off-label uses. Healthcare providers must understand the pharmacokinetics, potential adverse effects, and contraindications when selecting opioids. They should also follow current prescribing guidelines and be diligent about initially and continuously reviewing a patient’s prescription drug monitoring report, urine drug screening, list of current medications, and screening for opioid abuse and addiction. 

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