Hello. My name is Catherine Smith. I am a clinical pharmacist in the Surgical Critical Care Unit at Maine Medical Center in Portland, Maine, and I thank you for joining me in today's presentation on Opioid Use Disorder and Opioid Stewardship, A Lot to Gain Without Pain, a Guide to Managing Opioid Use Disorder in the Intensive Care Unit. Of note, I have no financial relationships to disclose. Our learning objectives for today are to describe the pathophysiology and associated clinical complications of opioid use disorder, discuss the management of acute pain in critically ill patients with opioid use disorder, or those on concurrent medications for opioid use disorder, and finally, to design a treatment plan for critically ill patients requiring analgesia in the setting of opioid use disorder. As of April 2023, the CDC predicted that over 110,000 deaths were due to drug overdose. 75%, or 84,000, of these deaths were secondary to opioids, as represented by the black line in this graph. Synthetic opioids excluding methadone, which is represented by the brown line in the graph, made up 92% of these opioid deaths. As you can see, synthetic opioid overdose excluding methadone has increased nearly tenfold from 2015 to 2023. This sharp rise correlates with the pandemic. Overdose deaths during early pandemic were driven primarily by out-of-hospital deaths associated with fentanyl. Echoing national data of opioid overdose, admissions for opioid overdose to the ICU are prevalent and rising. Stephens and colleagues published opioid overdose data over a seven-year period from 2009 to 2015 from 162 hospitals. The graphs here demonstrate the rise in ICU admissions by one-third over the seven-year time frame, from 44 per 10,000 to 59 per 10,000 ICU admissions for overdose. ICU mortality also increased 3% in this time frame, from 7% to 10%. Similar themes have been demonstrated in other studies evaluating large national databases over similar time frames. While this data is now nearly a decade old, these trends are likely continuing based on recent national trends, and I think we can all agree we are seeing these increases in our clinical practice. As with rising overdose rates and admissions, illicit drug use amongst U.S. population is also rising. In the Substance Abuse and Mental Health Services Administration, or SAMHSA, National Survey of 2021, 61 million people aged 12 or older reported using illicit drugs, with 9.2 million misusing opioids. Of these, 1.1 million, or 0.4%, used heroin. This use was highest amongst age 26 or older than compared to younger adults. 8.7 million, or 3.1%, reported pain reliever misuse. This was highest amongst young adults 18 to 25 and adults age 26 and older. It is important to point out that illicitly manufactured fentanyl from clandestine labs is not captured in this data, only prescription fentanyl misuse. Once again, referring to the SAMHSA report from 2021, of the 9.2 million people misusing opioids, 5.6 million people, or 2% of the U.S. population, had an opioid use disorder in the previous year. 1.2 million people received treatment for their misuse of opioids, regardless of whether they had an opioid use disorder diagnosis. Of these, 73%, or 887,000 people, had opioid use disorder and received medications for opioid use disorder. Although the focus of the opioid crisis is often fatal overdoses, the misuse of opioids and opioid use disorder may also lead to death, disease, and suffering with devastating medical, social, and economic consequences. This highlights the importance of increasing our knowledge as pharmacists to manage these patients when they are admitted to our ICUs. Let's briefly review the pathophysiology of opioid use disorder. As you can see in the figure of the brain, mu opioid receptors are densely concentrated in brain regions that regulate pain perception, emotional responses, and brain reward regions, explaining why opioids can produce both analgesia and euphoria. Opioid activation of brain analgesia and reward regions concomitantly creates a learned association between the receipt of the drug and physiological and perceptual effects of the drug. Repeated use strengthens these learned associations, which over time results in the craving for the drug's effect. Repeated administration also results in the development of tolerance and physical dependence, creating a negative reinforcement mechanism that contributes to continued use to prevent withdrawal. The brain's reward circuitry in the basal ganglia is driven by the release of certain neurotransmitters, particularly dopamine, but also endogenous opioids, GABA, serotonin, and acetylcholine. This results in positive reinforcement and the probability of using again. While reward acts as a positive reinforcer in the beginning phases of drug taking and the development of OUD, negative emotional experiences, such as withdrawal, craving, and stress drive continued use. These negative emotional experiences are caused by disruptions in the reward neurotransmitters and an increase in stress-related neurotransmitters, such as corticotropin releasing factor, norepinephrine, glutamate, and dynorphin, which are recruited in the extended amygdala. Finally, impairments in executive function and self-control within the prefrontal cortex can contribute to the development of opioid use disorder. Many of the neurotransmitters mentioned, such as dopamine and glutamate, mediate the impaired executive function, resulting in disruptions to decision-making, self-regulation, inhibitory control, and working memory. Opioid use disorder develops only in a minority of individuals exposed to opioids. Contributing factors include genetics, brain development, and social determinants. Certain genes have been identified that appear to contribute to OUD risk or relate to the risk factors, such as personality traits or brain regions implicated in the circuitry of addiction. Early drug use in the adolescent years, as well as social stressors, especially at a young age, can increase vulnerability to the development of OUD. The American Psychiatric Association publishes the DSM-5 Criteria for Diagnosis of Opioid Use Disorder. This criteria reflects the reward, negative emotional, and impaired executive function that defines the pathophysiology of opioid use disorder. The criteria establishes OUD as a problematic pattern of opioid use, leading to clinically significant impairment or distress as manifested by at least two of the following criteria listed below, occurring within a 12-month period. This criteria relates to the amount and efforts required to use opioids, a disruption in social obligations and relationships, use in hazardous conditions, and persistent use despite the desire to reduce use and knowledge of physical or psychological problems. The criteria also reflects the physical dependence resulting from a current opioid use, including tolerance, defined as the need for markedly increased amounts of opioids to achieve the same effect, or a markedly diminished effect with continued use of the same amount of an opioid, and withdrawal, as manifested by either the characteristic opioid withdrawal syndrome, or opioids are used to relieve or avoid potential withdrawal symptoms. The DSM-5 criteria defines opioid use disorder as mild if there's a presence of two to three symptoms, moderate with the presence of four to five symptoms, or severe when six or more symptoms are present. There are many clinical complications of opioid use disorder, but most relevant to our talk today are overdose, polysubstance use, opioid withdrawal, and undertreated pain. We have already highlighted the increasing prevalence of opioid overdose at a national level earlier in this talk. The typical overdose toxidrome includes meiotic pupils, CNS depression, and hypoventilation. Opioid overdose is complicated today by the formulation of fentanyl to target the younger population, and the contamination of the drug supply with other substances such as xylosine, a potent veterinary alpha-2 agonist sedative related to clonidine. The co-use of fentanyl and xylosine may result in prolonged CNS depression that is not responsive to naloxone alone. Additionally, fentanyl is increasingly being mixed with stimulants such as cocaine or methamphetamines, which also alter the overdose symptomatology we are managing in the ICU, especially when considering cardiac complications. The opioid crisis was declared a nationwide public health emergency in 2017. The opioid crisis has been described as occurring in waves. The first wave began in the early 2000s with the widespread use of prescription opioids. Wave two began around 2010 with a rise in heroin use. Wave three involved the increased use of fentanyl starting in 2013. We have since entered the fourth wave of the opioid crisis with the co-use of fentanyl and stimulants. Since 2010, overdoses involving both stimulants and fentanyl have increased 50-fold and now account for a third of U.S. overdoses in 2021 and nearly 35,000 deaths, according to a study published in the journal Addiction. Individuals report mixing stimulants into injected fentanyl dose prolongs the onset of withdrawal symptoms, increases euphoria, reduces overdose risk, and improves their energy to collect funds for the next drug purchase. This map displays the increased prevalence of stimulant involvement in fentanyl overdose nationwide, with cocaine being most common in the Northeast and methamphetamines more common in other regions of the United States. Comorbid substance use disorder is common in patients with OUD. Aside from the overdose risk as outlined by previous slides, comorbid substance use disorders are associated with numerous other negative health consequences and increased healthcare utilization. A study published in Addiction in 2020 evaluated VA patients to describe the prevalence of specific comorbid substance use disorders. They found that more than 57% of adults with opioid use disorder have additional comorbid substance use disorders, with 36% having two or more other substance use disorders. This study highlights the frequent co-use of opioids and stimulants as previously discussed. However, alcohol use was the most common substance use disorder reported in 41% of the overall cohort. Despite the frequent co-use of opioids and alcohol, there is limited data on the co-management of these two conditions. A study published in JAMA Network Open in 2021 reported 56% of patients treated with medications for opioid use disorder had alcohol-related events requiring emergency department or hospital admission. There is concern for increased respiratory and CNS depression with concomitant medications for opioid use disorder, such as buprenorphine or methadone, and treatment for alcohol withdrawal syndrome with benzodiazepines and phenobarbital. Mahmoud and colleagues published a retrospective cohort of 16 patients who presented to the emergency department with opioid withdrawal, which was treated with buprenorphine, and alcohol withdrawal, which was treated with lorazepam or phenobarbital. They excluded patients receiving methadone because they solely wanted to describe the interaction with buprenorphine. An equal number of patients received lorazepam and phenobarbital with the doses listed here. Buprenorphine was most commonly given sublingually at a median dose of 12 milligrams. The specific aim of their study was to evaluate adverse drug events related to intoxication or ovacization with co-prescription of buprenorphine and benzodiazepines or phenobarbital. While 50% of patients required admission, only one patient required intubation, which was attributed to progressive pneumonia. Interestingly, the study did not evaluate the risk of worsening opioid withdrawal induced by the drug interaction between phenobarbital and buprenorphine. A study published in Addiction in 2023 reported 83 patient admissions over a one-year period at a single center in which phenobarbital was co-prescribed with medications for opioid use disorder. This highlights the frequent co-administration of buprenorphine or methadone and phenobarbital. As you may know, buprenorphine is metabolized by cytochrome P450 3A4 and methadone is metabolized by 2B6 and 3A4. Phenobarbital is a potent inducer of both of these enzymes, which may reduce therapeutic concentrations of these drugs and increase the risk of precipitating opioid withdrawal. Given phenobarbital's prolonged half-life of nearly 80 hours, opioid withdrawal and relapse could occur after hospital discharge. It is important to use caution when co-prescribing these agents, perhaps favoring benzodiazepines if possible. As pharmacists, if phenobarbital is deemed necessary, it is important to educate both providers and patients about this important drug interaction. Another clinical complication of opioid use disorder is opioid withdrawal. One of the most powerful drivers of drug-seeking behavior is the desire to avoid opioid withdrawal. The severity of withdrawal is influenced by the amount, duration, and type of opioid used. As you can see, withdrawal symptoms will begin more quickly, within 6 to 12 hours with short-acting opioids such as heroin, but may be more prolonged with long-acting opioids such as methadone. The duration of symptoms can last 7 to 14 days depending on the half-life of the drug. Early symptoms typically involve drug craving, agitation and anxiety, insomnia, muscle aches, tearing and runny nose, diaphoresis, pupil dilation, and yawning. Later symptoms of withdrawal include hemodynamic changes like tachycardia and hypertension, goosebumps, chills, anorexia, and GI symptoms like nausea, vomiting, and diarrhea. Opioid withdrawal symptoms are uncomfortable but are not considered life-threatening. That said, if a patient is experiencing withdrawal symptoms in the hospital, they may choose to leave AMA, which could place their health and safety at risk. It is important to manage their withdrawal adequately to prevent unplanned discharges. Opioid withdrawal is frequently monitored using the Clinical Opioid Withdrawal Scale, or CALS, an 11-point scale that can be completed in two minutes. It involves one purely subjective item, anxiety, six objective symptoms such as tremor, goose flesh, pupil size, and pulse, and four subjective objective items with GI upset, restlessness, sweating, and bone and joint aches. Mild withdrawal is considered a score of 5 to 12, moderate withdrawal 13 to 24, moderately severe 25 to 36, and severe greater than 36, with a maximum score of 47. Despite widespread inpatient use, CALS has not been validated in an inpatient setting. Similar to the CWAS score for alcohol withdrawal, it is designed for adult patients able to verbally communicate their symptoms in the outpatient setting. Its usefulness in the ICU setting remains unclear. Initial opioid binding to the mu-opioid receptor inhibits the production of downstream cyclic AMP. Cyclic AMP production will recover with chronic opioid use and is further increased in withdrawal, leading to excessive norepinephrine discharge from noradrenergic neurons in the locus serialis. Treatment of opioid withdrawal involves either attenuating the cyclic AMP pathway through mu-opioid receptor agonism with drugs such as buprenorphine or methadone, or by inhibiting excess norepinephrine discharge from locus serialis neurons through presynaptic alpha-2 receptor agonism with clonidine or lofexidine. Other medications may be utilized to help target the symptoms of withdrawal. Benzodiazepines and SSRIs can help with anxiety and restlessness. NSAIDs will help with bone and joint aches. Antihistamines may be used to treat runny nose. Antiemetics and antidiarrheals may help with GI upset. And muscle relaxants can help with the tremor associated with opioid withdrawal. The last complication of OUD we will discuss today is undertreated pain. Consequences of mismanagement of opioid use disorder and undertreatment of acute pain include unplanned hospital discharges, potentially avoidable hospital readmissions, worsened medical conditions, and accidental overdoses. It is important to recognize these risks and treat patients' pain promptly and effectively. Contributors to undertreated pain include tolerance, hyperalgesia, and stigma. As we discussed on the previous slide, when an opioid binds to the mu-receptor, there is an initial reduction in cyclic AMP levels. This reduces excitability and nociception and results in analgesic effects. With chronic use, the mu-receptor becomes phosphorylated by G protein-coupled receptor kinase, which recruits the beta-arrestin protein and can lead to receptor internalization. The result is desensitization or decreased signaling state of the mu-receptor and subsequent tolerance and insufficient analgesia. Mu-receptors will recover over time once opioid stimulus is withdrawn. Long-term opioid use leads to exaggerated opioid tolerance, resulting in escalating dose requirements to maintain analgesia and subsequently contributes to opioid-induced hyperalgesia. Hyperalgesia is a state of heightened pain sensitivity. It can be a cause of undertreated pain as well as a consequence of undertreated pain, and it can lead to inappropriate increases in opioid doses, which will further exacerbate rather than relieve the pain. Hyperalgesia is a result of that increased cyclic AMP levels, the activation of the NMDA receptor, and downregulation of glutamate receptors, which results in increased glutamate levels. This causes an imbalance in pro-nociceptive and anti-nociceptive pathways. The figure on the right of the slide pictorially demonstrates the increase in dose and reduced tolerance to pain seen with long-term opioid treatment resulting in hyperalgesia. Strategies to mitigate opioid tolerance or hyperalgesia involve the appropriate use of opioids, favoring intermittent boluses rather than continuous infusions when possible. Opioid rotation, such as switching from fentanyl to hydromorphone, may also be helpful. Avoiding excessive dose escalation of opioids with the introduction of non-opioid analgesia or regional analgesia, if applicable, is desirable. While we will discuss non-opioid analgesia in detail later, ketamine may be especially helpful as the NMDA receptor plays a central role in the development of tolerance and hyperalgesia. Finally, it is imperative to taper the opioid dose once the patient's pain score is at goal to prevent further contribution to hyperalgesia. Stigma is also a significant contributor to undertreated pain. As discussed earlier, patients have physiologic and neuropsychological reasons for development of OUD, yet stigma often dictates that it is a person's choice or bad decision. Thoughts such as the patient's are drug-seeking and not actually in pain can have detrimental effects. This mentality has an impact at not only the individual level, but also the structural level. Individual effects include a reduction in treatment seeking and engagement with care, worsening quality of care, and exacerbation of patient mistrust. This highlighted text shares the experience of a patient who felt their pain was not adequately controlled while in the hospital and left in order to self-medicate, potentially increasing this patient's risk of morbidity and mortality. At a structural level, discriminatory policies and reduced investment in systems that support people with OUD can affect stigma. Prior to June of 2023, a special waiver called the DATA waiver, along with other restrictions and patient limits, was required to prescribe buprenorphine for the treatment of opioid use disorder. This federal requirement has since been repealed and providers may prescribe buprenorphine with an active DEA license and either eight hours of opioid or substance use disorder training or board certification in addiction medicine. This is a positive step toward reducing stigma and allowing more providers to prescribe buprenorphine in the management of OUD. A limited evidence base exists for stigma reduction strategies. A recent publication in 2022 enrolled a large national sample of health care providers to assess the impact of two message framing strategies communicated via a visual campaign with and without accompanying written narrative vignettes from a perspective of a patient with opioid use disorder who felt dehumanized by phrasing such as addict and drug abuser, a clinician who became more intentional with their language using more respectful words when interacting with patients, or a health care system administrator who instituted policies with more clinically appropriate language and realizing that we can be role models to changing stigmatizing words and regulations in our health care practice. The Words Matter website is a helpful source to learn which words induced stigma such as addict and learning alternative phrasing to minimize stigma such as a person with substance use disorder. Now that we grasp the scope of the opioid crisis and its impact on critical care, how can we manage these patients preventing opioid withdrawal and effectively treating pain? We will move on to our second objective in which we will discuss the management of acute pain in patients with opioid use disorder or those who are receiving medications for opioid use disorder. In 2019, Reicheld and colleagues published a study of survey results evaluating the presence of sedative and analgesic guidelines for the general ICU population, patients with OUD, and patients receiving medications for opioid use disorder or MOUD. There were 54 survey respondents. As you can see, nearly 75% of respondents reported having guidelines for the general ICU population, but less than 10% reported having sedative or analgesic guidelines for patients with OUD, and even fewer reported guidelines for patients receiving MOUD. Before we begin discussing acute pain management in this population, I wanted to highlight that these survey results reflect the lack of available evidence for management of OUD in the ICU. The recommendations offered in this presentation are mostly extrapolated from expert opinion and the perioperative literature. If addiction medicine is available at your hospital, it is helpful to involve them in devising guidelines for the management of patients with OUD and in individual patient care. The principles we will discuss today of acute pain management in patients with OUD include the prevention of opioid use disorder and the treatment of acute pain management in patients with OUD include the prevention of opioid withdrawal, continuation of medications for opioid use disorder if a patient is receiving them prior to admission, pain assessment, and multimodal pain management, including non-opioid analgesia. We will review each of the FDA-approved treatment options for opioid use disorder. This table includes these options, their mechanisms of action, route, dosing, and half-life. Opioid drugs with longer half-lives, slower clearance rates, and slower brain uptake are favored for the treatment of opioid use disorder. Let's begin with reviewing buprenorphine. Buprenorphine is approved for the treatment of opioid use disorder alone with the availability of a sublingual tablet or a subcutaneous injection or in combination with naloxone, which is minimally systemically absorbed, as sublingual formulation. As you can see, the dosing is daily with sublingual formulations, as the half-life is 24 to 48 hours, and weekly or monthly with sub-Q formulations, with the half-lives ranging from 3 to 5 days for the weekly formulation up to 20 to 60 days for our monthly injections. Let's use a patient case to guide us through the management of opioid use disorder with buprenorphine in an ICU patient. JG is a 57-year-old male who is admitted to the ICU for septic shock due to right lower extremity skin and soft tissue infection and a septic hip joint. His past medical history includes multiple sclerosis, neuropathic pain, tobacco abuse, polysubstance use, and opioid use disorder. His home medications include acetaminophen, baclofen, buprenorphine at 16 milligrams sublingually daily, dalfambridine, ergocalciferol, and gabapentin. He is currently on norepinephrine at 0.05 mics per kilo per minute for hemodynamic support. He is on room air. He is complaining of 10 out of 10 right hip pain. How do we manage JG's buprenorphine for opioid use disorder? Buprenorphine is a partial mu-opioid receptor agonist and a kappa-opioid receptor antagonist. It is effective for management of cravings due to its high mu-receptor affinity and slow release. Due to its partial agonism and long receptor half-life, this reduces the potential for euphoria. Its partial agonism may also offer a ceiling effect, lowering the risk of respiratory depression. The kappa-opioid receptor antagonism may help oppose hyperalgesia, which could be a benefit. As mentioned earlier, buprenorphine is made in combination with naloxone as an injection deterrent. Naloxone undergoes tremendous first-past hepatic metabolism, resulting in very low bioavailability when taken as intended. The table on the left of the slide highlights the high affinity of buprenorphine for the mu-receptor. The high buprenorphine affinity can cause a full agonist, such as morphine or fentanyl, to displace from the receptor when given concomitantly with buprenorphine. Historically, buprenorphine has been held in the setting of acute pain due to this propensity to knock full agonists off of the mu-receptor. The table on the right demonstrates that the degree of receptor occupancy is dose-dependent. As a result, at doses of 8 to 16 milligrams, the typical daily dosing regimen for buprenorphine for the management of OUD, 20 to 35 percent of mu-receptors remain available for full agonist binding. Arguably, this should allow for adequate pain control while continuing buprenorphine for the patient's underlying opioid use disorder. Buprenorphine is available in many different formulations with a wide range of bioavailability. While not all formulations are FDA approved for treatment of OUD, intravenous, subcutaneous, transdermal, buccal films, and sublingual tablets may be available for use in the inpatient setting. When continuing buprenorphine in the ICU, I frequently am asked by nurses if buprenorphine can be given via the feeding tube. However, the oral bioavailability of buprenorphine is very low at only 10 to 15 percent, so it is not to be administered orally or entirely. Its bioavailability is as low as 15 percent for transdermal and as high as 100 percent for IV formulations. Most buccal and sublingual formulations have a bioavailability of about 30 to 60 percent with buccal films typically having the higher bioavailability. It is important to assess if dose conversions are necessary. For example, if a patient is receiving subsolve and you do not have this formulation on formulary, you may need to determine the dose conversion to suboxone. Dosing approximations for conversions between products do exist but should be used with caution. Your use of buprenorphine formulations will typically be driven by what is available on your hospital formulary. This table provides guidance for converting from a transdermal patch, buccal film, and long-acting subcu injections to sublingual tablet equivalency. It is important to note much of this guidance is based on pharmacokinetic modeling and not clinical data, but it can be a helpful resource as a place to start when this question arises. The pharmacokinetic parameters of buprenorphine can be altered in the critically ill. Absorption of certain formulations such as transdermal, sublingual, and buccal formulations may be reduced in the setting of shock due to redistribution of blood flow with lower perfusion to peripheral tissues. Also, it is unknown how well sublingual or buccal products are absorbed in the setting of dry mouth associated with mechanical ventilation. Buprenorphine has a high lipophilicity and large volume of distribution and also high protein binding, which may be altered in the setting of critical illness. As mentioned earlier when discussing drug interactions with phenobarbital, buprenorphine is metabolized by 3A4 to an active metabolite norbuprenorphine. Potent 3A4 inhibitors and inducers administered in the ICU may impact metabolism and doses may need to be reduced in the setting of severe hepatic impairment. Buprenorphine is eliminated one-third in the urine and two-third in the feces and fortunately does not require adjustment in the setting of renal dysfunction. Now that we have more knowledge of buprenorphine's pharmacology and pharmacokinetic considerations, how are we managing it in the inpatient setting? Data published from a large national database indicates a two-fold increase in buprenorphine prescribing from 2009 to 2018. Despite this rising outpatient prescribing, a recent study evaluating sepsis and opioid-related hospitalizations over a similar timeframe echoed the previously discussed increasing opioid-related hospitalizations. However, it did not demonstrate a rise in buprenorphine use in the inpatient setting. There is a sparsity of data on buprenorphine prescribing for opioid use disorder in the ICU. A single-center retrospective study over a four and a half year period was published last year and evaluated the continuation of buprenorphine during critical illness. They included adults who are maintained on buprenorphine for at least three months prior to admission and reported 44% of these patients were continued on treatment during their ICU stay at an average dose of eight milligrams per day. It is notable that the dose of buprenorphine continued in the ICU was lower than the reported pre-admission dose of 16 milligrams a day. This study found that continuation of buprenorphine every day appears to result in lower non-buprenorphine opioid use and significantly lower fentanyl equivalents compared to no buprenorphine use. The odds of receiving non-buprenorphine opioids was six times higher on days when buprenorphine was not administered in the ICU compared to when it was administered. This data supports continuation of buprenorphine in the ICU setting, but it is not without limitations, including a small sample size, single-center practice, and the presence of provider bias where providers may not have been using full mu-agonists with buprenorphine. Given the aforementioned limited data in the ICU, we turn to national guidelines for guidance. The American Society of Addiction Medicine and Perioperative Guidelines recommend continuation of buprenorphine in moderate to severe pain. Thinking back to the receptor availability table in our pharmacology slide, doses greater than 16 milligrams per day may result in inadequate pain control due to less mu-receptor availability for full agonist binding. If your patient is experiencing inadequate pain control with buprenorphine continuation, possible strategies to improve pain control are to reduce that daily dose to 16 milligrams or less, or to divide the dosing every six to eight hours with the goal of avoiding discontinuation if at all possible. Returning to our patient, JG, who is admitted to the ICU with septic shock and takes buprenorphine pre-admission, and is currently complaining of pain 10 out of 10 in his right hip. How do you manage the buprenorphine for OUD? First, it is important to complete a medication history. You can check your state prescribing monitoring program, confirm with the patient, especially as our patient here is awake and not intubated, call the pharmacy, or contact the prescriber. It may be beneficial to recommend continuing the home buprenorphine dose of 16 milligrams a day, and if he experiences inadequate pain control, consider dividing that dose every six to eight hours. Let's move on to methadone, the next FDA approved treatment that is frequently prescribed like buprenorphine. The oral formulation of methadone is approved for opioid use disorder. Methadone has a long but variable half-life, which allows it to be dosed once daily. Once again, we will use a patient case to apply our knowledge of methadone. KB is a 43-year-old male with multiple traumatic injuries following a motor vehicle crash. His injuries include bilateral rib fractures, a sternal fracture, open pelvic fracture, tibia fracture, and a rectal injury. He has status post exploratory laparotomy and diverting colostomy and irrigation and debridement of his left knee. His past medical history includes recent incarceration, IV drug use, and opioid use disorder. His medications prior to admission were methadone, 213 milligrams oral daily. His sister reports he illicitly uses benzodiazepines and gabapentin. He is admitted to the intensive care unit post-operatively, intubated, and receiving hydromorphone continuous infusion at 4 milligrams per hour for analgesia and propofol continuous infusion, 20 mics per kilo per minute for sedation. How do you manage KB's methadone for opioid use disorder? Methadone is a synthetic full mu, delta, and kappa opioid agonist. Activation of the presynaptic opioid receptors prevents release of substance P, preventing its binding postsynaptically and inhibiting nociception. Methadone is also a weak NMDA receptor antagonist, which opposes glutamate and disrupts transmission of pain signals to the peripheral and central nervous system. This mechanism of action may also be helpful in preventing hyperalgesia. Methadone is a serotonin and norepinephrine reuptake inhibitor, which may elevate mood and inhibit pain perception. When used for opioid use disorder, maintenance doses are typically 80 to 100 milligrams once daily. Methadone's long half-life, high lipophilicity, and large volume of distribution make it effective as a once-daily treatment for stabilizing opioid cravings and preventing withdrawal symptoms. Methadone has good oral bioavailability of 70 to 80 percent, but it is available as an IV formulation if a patient is strictly NPO. Historically, the IV to PO conversion was considered to be 1 to 2, but a more recent systematic review defined an IV to PO conversion of 1 to 1.3 based on clinical data. Once again, we must consider alterations to methadone pharmacokinetics in the critically ill patient. Oral and enteral absorption may be reduced if there is decreased perfusion to the GI tract or reduced GI motility. The intravenous formulation can replace the oral formulation, but it does have a faster onset, so one must monitor for euphoria. Like buprenorphine, methadone has a large volume of distribution and high protein binding that may be altered in the setting of critical illness. Methadone is primarily metabolized by 2b6 and to a lesser extent by other CYP enzymes, such as 3a4. Drug interactions related to its metabolism, serotonergic activity, and QTC prolongation must be considered closely in the ICU. Finally, methadone is eliminated mostly in the feces with no adjustment required for renal dysfunction. While there is some evidence available for use of methadone in preventing iatrogenic withdrawal in the ICU, there is a lack of data evaluating methadone continuation for opioid disorder in the ICU. When continuing methadone in the ICU, it is imperative to verify the patient's methadone dose with the opioid treatment program or methadone clinic. Unlike buprenorphine, most state-maintained prescription monitoring programs do not provide information on methadone. It is recommended to continue methadone at the prescribed dose, but the dose may be divided every 8 to 12 hours to optimize its analgesic effects, or the dose may be temporarily increased for the management of acute pain. Importantly, if a patient has not received methadone in the prior 72 hours, dose reduction is recommended. When continuing methadone, monitor your patient for signs of opioid withdrawal, QTC prolongation, and drug interactions, as mentioned previously. Returning to our patient case of KB with multiple traumatic injuries on methadone prior to admission, how are we going to manage his opioid use disorder? We are going to verify his dose with the methadone clinic and continue methadone, and given he has reasons for acute pain with many fractures, we can consider dividing the dose entrally 70 milligrams every 8 hours so he still maintains his total daily dose of 210 milligrams daily. We will monitor his QTC and review his medication list for drug interactions to avoid multiple serotonergic agents, QTC prolongers, or potent 3A4 inducers. The final FDA-approved treatment option for OUD that will be discussed is naltrexone. It is approved as an intramuscular injection that is given monthly, and like the other agents, naltrexone has a long half-life of 5 to 10 days. While naltrexone is the least commonly encountered of the three options, there are many important considerations in the ICU patient. Naltrexone is a mu-opioid receptor antagonist that has a very high binding affinity for the mu-receptor, with a binding affinity of about 0.11 that is stronger than even buprenorphine, thereby preventing other opioids from binding and leading to euphoria. Naltrexone is not associated with the development of opioid tolerance or dependence due to its antagonistic properties. While naltrexone is available as a tablet, oral naltrexone is not used to treat OUD due to the lack of efficacy. The long-acting intramuscular injection maintains opioid abstinence, prevents relapse, prevents relapse, and improves treatment retention. Opioid receptor upregulation may occur with prolonged naltrexone antagonism. This may increase the risk of overdose if full agonists are used toward the end of a dosing interval. Naltrexone intramuscular depot injection has an initial peak concentration at approximately 2 hours, which is then followed by a second peak 2 to 3 days later. Concentrations slowly decline around day 14. Naltrexone has low protein binding and no CYP-mediated metabolism, minimizing the risk for drug interactions. It is metabolized in the liver to an active metabolite 6-beta-naltrexone. So when we think about our critically ill patients, naltrexone effect may be prolonged in acute liver dysfunction. Naltrexone is eliminated in the urine and has a half-life of five to 10 days, which may also be prolonged in the setting of renal impairment in the ICU. When managing patients on naltrexone in the ICU, it is important to confirm the last dose of naltrexone received. This can be confirmed through discussion with the patient, if possible, patient's friends or family, an outpatient provider, or review of medical records. Some labs do offer naltrexone urine testing. Because of its antagonistic properties, naltrexone should be held if acute pain is anticipated. And then once that acute pain has resolved, you will need to wait seven days from the last dose of full opioid agonist to resume naltrexone due to the risk for precipitated withdrawal. Because of its high binding affinity, you will anticipate high doses of opioids, especially earlier in the dosing interval. And therefore, it is important to maximize non-opioid analgesia. And as discussed, that up-regulation of opioid receptors may pose an issue for adverse offense or overdose toward the end of a dosing interval when full opioid agonists are utilized. We have reviewed how to manage patients on various forms of MOUD, but how do we manage a patient who is not receiving MOUD? GC is a 25-year-old male admitted with multiple complex facial fractures as a result of being hit by a side mirror of a vehicle traveling 75 miles per hour. He has a past medical history of IV drug use, opioid use disorder, sedative use disorder, tobacco use, chronic hepatitis C, anxiety, depression, and ADHD. He reports injecting fentanyl three grams daily using methamphetamines and illicit use of clonazepam, four to six milligrams daily. He arrives to the surgical ICU with severe agitation, receiving a continuous infusion of hydromorphone four milligrams per hour, midazolam at eight milligrams per hour, propofol infusion at 40 mics per kilo per minute, and phenobarbital receiving a 7.5 mg per kg load followed by 91 milligrams IV every eight hours. How do we manage his opioid use disorder? We have a few options for preventing withdrawal in patients not on MOUD. First is methadone. Methadone can be initiated at 10 to 30 milligrams per day and titrated every three to five days by 10 to 15 milligram per day increments. It is not recommended to go above 40 milligrams of methadone daily unless your patient can be connected with an opioid treatment program on discharge. Another option is to provide full MU agonists such as fentanyl or hydromorphone in a scheduled continuous infusion or patient-controlled analgesia or PCA format. The reason for giving it as scheduled or continuous is to limit the intermittent dosing that could place your patient at risk of withdrawal. Finally, low-dose buprenorphine injection may be a good option Low-dose buprenorphine injection may be an option. It could be done sublingually with small doses of 0.2 to two milligrams per day to start, transdermally or intravenously with small doses every six hours. It is important to recognize that the data evaluating these strategies is not in the ICU, but primarily comes from non-ICU hospitalized patients or the ED setting. It may be most optimal to use this strategy in a patient who is awake and alert and able to monitor their withdrawal symptoms. We sometimes encounter patients who would like to transition their MOUD therapies during their ICU stay. For example, I've had patients request to switch from buprenorphine to methadone during their stay. These same strategies could be employed in those patients as well. In our particular patient case of GC, we decided to initiate methadone at a dose of 10 milligrams Q8 or 30 milligrams daily. Less than 20 to 40% of patients with opioid use disorder are receiving medications for opioid use disorder. When patients are hospitalized and recovering from critical illness, this may be the optimal time to conduct a screening, brief intervention and referral to treatment or SBIRT, engaging the patient in their treatment. This may be an opportunity in which we can work with addiction medicine and social work and initiate medication for opioid use disorder and referral for ongoing therapy. While SBIRT is not purely a pharmacist role, I would be remiss to not mention this important aspect of their care. Additionally, the CDC recommends co-prescribing naloxone for patients on prescription opioids who are at increased risk of overdose. This includes patients with a history of overdose or substance use disorder, a higher opioid dosage greater than 50 milligrams of morphine male equivalents per day, and patients using concurrent benzodiazepines. Survivors of opioid overdose and patients with active opioid use disorder may also benefit from co-prescribing of naloxone. At this point in the presentation, I hope that you feel that we have adequately covered the first two principles of acute pain management in patients with OUD, including the prevention of opioid withdrawal and the continuation of medications for opioid use disorder. Let's now move on to the last two principles of pain assessment and multimodal pain management, including non-opioid analgesia. It is important that we treat patients with opioid use disorder It is important that we treat patients with opioid use disorder just as those without opioid use disorder. Pain assessment should be taken regularly to assess the adequacy of analgesia. We can expect that our patients with OUD will have higher pain scores, a slower resolution of pain, and an unpredictable response to medications in patients with opioid tolerance. As with the SCCM pain, agitation, delirium, immobility, and sleep guidelines, it is recommended that our patients self-report using the numeric rating scale if possible. And if they are unable to self-report their pain, utilizing behavioral pain assessment tools with either the behavioral pain score or the critical care pain observation tool as included here. While these are not specifically validated in the opioid use disorder or opioid tolerant population, this is what would be recommended at this time. Short-acting full mu-receptor agonists are considered first line for acute pain in the critically ill patient. And the same principle applies to patients with opioid use disorder. Short-acting agonists can be used in addition to continuing their baseline medications for opioid use disorder or meeting their baseline opioid requirements with the strategies we have already discussed. While opioids remain the mainstay of pain management, the 2018 PADIS guidelines recommend a multimodal approach with the use of adjunctive non-opioid pain medications and non-pharmacologic treatments with the goal of minimizing opioid-related side effects and augmenting pain control. We will review the non-opioid adjuncts listed here in more detail, but non-pharmacologic maneuvers such as music therapy and massage may also be helpful adjuncts to alleviating pain. Starting with opioids, short-acting full agonist opioids should be added if the patient is experiencing severe acute pain. Looking at the bottom figure, if providing medication for opioid use disorder with methadone or buprenorphine, we already have a long-acting agent on board. A PCA may be quite useful in providing patient control over pain if the patient is alert, oriented, and extubated. Otherwise, it would be recommended to schedule full agonists to avoid interruptions in pain control and to maintain a basal level of pain control. If scheduling agents, enteral administration is preferred, as highlighted in the top figure. Enteral agents will maximize analgesia while minimizing CNS side effects, such as euphoria. As mentioned earlier, we must anticipate higher doses within patients without opioid use disorder to optimize pain control and consider use of higher affinity agents like hydromorphone, especially in patients receiving buprenorphine. Opioid rotation may also be useful as discussed with hyperalgesia. Finally, we must consider organ function and avoid agents with active metabolites in the setting of renal dysfunction, such as morphine, or an acute liver failure, such as agents that require phase one metabolism, like fentanyl. Additionally, if patients are on high doses of methadone, we may want to avoid fentanyl given the increased risk of serotonin syndrome. Overall, there is limited literature evaluating non-opioid adjunctive analgesia in ICU. Perioperative and emergency medicine literature have demonstrated non-opioid adjuncts may reduce pain scores, reduce opioid requirements, and minimize opioid-related side effects, GI dysfunction with constipation and ileus, as well as respiratory depression. The 2018 PATAS guidelines provide conditional recommendations encouraging the use of certain medications, such as acetaminophen for all critically ill patients and ketamine for post-surgical ICU patients. Wheeler and colleagues conducted a systematic review and meta-analysis in 2020 to evaluate the evidence for non-opioid adjuncts in adult ICU patients. They included 34 studies and the population primarily represented surgical ICU, with the majority of medications being dexmedetomidine in 11 studies, acetaminophen in seven studies, or NSAIDs in six studies. This may limit the generalizability of these results. They found that the use of any adjuvant reduced pain scores at 24 hours, but when evaluating independent medications, only adjunctive acetaminophen was significant compared to opioids alone. 24-hour opioid consumption was also reduced with the use of any adjuvant non-opioid analgesic, as demonstrated in the forest plot on the right. When evaluating individual medications, the use of NSAIDs and acetaminophen, as demonstrated here, and dexmedetomidine and ketamine demonstrated reductions in opioid use. However, you may notice that there was significant heterogeneity of the studies and the overall quality of evidence was low, which does limit interpretations of this data. In addition to the limitations just described, patients with preexisting opioid use or patients with opioid use disorder are often underrepresented in ICU trials, with many excluding these patients or enrolling small numbers, such as less than 10 to 20% of the study population. Revisiting the small single-center retrospective study evaluating buprenorphine continuation in the ICU, non-opioid analgesia utilization was overall low in the study. Acetaminophen was not surprisingly the most frequently prescribed non-opioid adjunct in 68% of patients. Gabapentin was co-prescribed in 40%, but only 12% received an epidural or patient-controlled analgesia. No other non-opioid adjuncts were reported in this study. I have taken the liberty of classifying the non-opioid analgesic adjuncts into three groups. The first group is those agents to consider in most or all patients with opioid use disorder in the ICU. Acetaminophen is a relatively benign, yet effective analgesic. Patients with opioid use disorder may have co-occurring hepatitis C or cirrhosis, and it is recommended to limit the dose to less than three grams per day, if this is the case, to lower the risk of hepatotoxicity. As discussed earlier in this presentation, ketamine's NMDA antagonism may be helpful for patients with opioid tolerance and hyperalgesia. One of the most common side effects we worry about is its psychomymatic effects, with one ICU study showing a signal toward more antipsychotic utilization in patients receiving ketamine. Ketamine should be avoided in certain situations, such as pregnancy, due to the potential to affect neurocognitive development of the fetus. Ketamine may exacerbate hypotension with negative inotropic effects in patients with catecholamine-depleted states, such as heart failure. Ketamine dosing for pain is considered sub-anesthetic and is listed on the slide. Alpha-2 agonists, such as dexmedetomidine and clonidine, may be beneficial to spare opioids and reduce opioid-induced hyperalgesia. These agents can be particularly helpful if there is a concomitant need for sedation, or if a patient is experiencing withdrawal symptoms. There are no specific dosing recommendations for the opioid-sparing or analgesic effects of these agents. Clonidine dosing may vary depending on the indication. If for withdrawal, the recommended dose may be lower at 0.1 milligrams every eight hours, or if a sedative effect is desired, higher doses of 0.2 to 0.4 milligrams every six hours may be recommended. I have included non-steroidal anti-inflammatory drugs and gabapentinoids under the class of drugs to consider with caution. While NSAIDs are an effective option for pain control, their side effects, especially nephrotoxicity and bleeding, limit their use in the ICU. If these agents are utilized, literature stemming from the emergency department have demonstrated an analgesic ceiling, specifically 10 milligrams with Catorlac and 400 milligrams with ibuprofen. Gabapentinoids, such as gabapentin and pregabalin, should be reserved for patients with neuropathic pain. Gabapentin has been studied in a randomized controlled trial fashion for rib fractures without benefit. Of particular concern with these agents are the rising rates of misuse amongst patients with concomitant opioid use and the detection of gabapentin in over 90% of fatal opioid overdoses. Our final category of agents Our final category of non-opioid analgesics are those to consider in select patients. Pre-injury opioid use has been reported in up to 20% of trauma patients, and rib fractures are a common injury in this population. Regional anesthesia has many potential benefits, including improved return of bowel function and reduced ICU length of stay. However, if a patient has coagulopathy, altered mental status, or hemodynamic instability, the use of epidurals would be contraindicated. Methocarbamol, a muscle relaxant, has been studied in a few single-center retrospective studies with positive results in patients with rib fractures. Finally, lidocaine may have antihyperalgesic properties, but its use as an IV infusion is limited by significant dosing heterogeneity in trials, with variable inclusion of bolus of one to two mg per kg versus infusion strategies, usually dosing 0.5 to two mg per kg per hour, and variable durations. Its narrow therapeutic index and significant toxicity are a cause for concern in our ICU population with multi-organ failure. Topically, lidocaine may reduce opioid requirements in patients with rib fractures and is considered safe. Let's put everything we have learned about acute pain management in this population together and review our patient cases once more. Returning to our patient, GJG, who takes buprenorphine prior to admission for his OUD, how do we manage his 10 out of 10 hip pain? Luckily, this patient is able to self-report, so we will continue to monitor his pain with the numerical rating scale. Given the high affinity of buprenorphine to the mu receptor, we elected to start hydromorphone at a higher dose of six milligrams every three hours as needed, along with IV for breakthrough pain. From a non-opioid perspective, we resumed his home acetaminophen, his gabapentin for neuropathic pain, and baclofen. For our patient, KB, who has multi-trauma and was taking methadone prior to admission and is currently receiving hydromorphone at four milligrams an hour per continuous infusion, how do we manage his acute pain? We already talked about resuming his methadone in divided dosing, and because of his intubated status, we will continue to monitor his pain using a behavioral pain score. We will continue his hydromorphone infusion while intubated given his frequent trips to the OR. This provides him a nice basal rate of analgesia. And eventually, once he's able to take enteral medications, we can consider scheduling hydromorphone via his NG tube. For non-opioid adjuncts, he has no contraindications to acetaminophen. We started ketamine given his high opioid requirements and potential hyperalgesia. Lidocaine patches and methylcarbamol may be helpful for management of his rib fractures. And finally, we could transition his propofol to dexmedetomidine infusion given his concomitant sedation needs and potential for opioid sparing effects. Lastly, let's return to our patient, GC, who was not on medications for opioid use disorder prior to admission, but had reported illicit use of fentanyl, methamphetamines, and clonizepam. As you remember, he had significant requirements for analgesia with hydromorphone at four milligrams an hour, as well as sedation requirements with midazolam, propofol, and phenobarbital. How did we manage his acute pain? As discussed earlier, we started methadone in divided dosing 10 milligrams every eight hours. We stopped phenobarbital due to the drug interaction with methadone and encouraged weaning from midazolam infusion as a stimulant metabolism allowed. As his agitation improved, we were able to transition from propofol to dexmedetomidine for its opioid sparing effects, and continued to assess his pain using a behavioral pain score with his intubated status. We continued his hydromorphone infusion and eventually transitioned that over to enteral hydromorphone to allow us to wean the continuous infusion. And once extubated, we used a PCA to allow him more control over his pain. For non-opioids, we started methamphetamine, acetaminophen, and ibuprofen. And finally, due to his polysubstance use, we wanted to avoid withdrawal from other agents. Therefore, we started clonizepam and weaned that over the course of his admission, as well as mirtazapine to treat his stimulant withdrawal. In conclusion, it is helpful to devise a standardized approach to manage patients with opioid use disorder, whether they are treated with MOUD or yet to be treated, and also to manage their acute pain in the ICU. Here is an example of an approach we employ at our institution, which compiles all of what we discussed today. For patients receiving MOUD, it is imperative to verify their dosing. And for methadone and buprenorphine, to continue their total daily dose, potentially as divided dosing, if they're experiencing acute pain. We would want to hold naltrexone during their ICU stay and acknowledge that there will be higher doses of short-acting opioids in order to overcome their effect. For those patients who are not yet on MOUD, one could consider providing full agonists or methadone or even buprenorphine at low doses in order to prevent withdrawal. Finally, for acute pain, we will follow the principles that were discussed today in terms of frequent pain assessment, provision of supplemental short-acting opioids, and maximizing non-opioid analgesia. I hope this presentation has provided you with the knowledge and tools to manage your critically ill patients with opioid use disorder. Thank you once again for joining me in this presentation. I am honored for the opportunity to discuss this important topic with you.

Opioid Use Disorder

Opioid Stewardship

ICU

acute pain management

pathophysiology

opioid-related deaths

DSM-5 criteria

medication options

buprenorphine

non-opioid analgesia