By Elaine Chen, MD

Assistant Professor, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Section of Palliative Medicine, Rush University Medical Center, Chicago

Dr. Chen reports no financial relationships relevant to this field of study.

She started using opioids as a teenager after a painful sports injury. She had been traveling, working, and using heroin, but had recently returned to her family’s home at age 21. She was hoping to stay clean, with plans to look for a job and go back to school. She had created a series of inspiration boards to help her focus. After going out with friends one evening, she injected heroin again. After she vomited and remained unresponsive, her friends called 911. She was resuscitated and brought to a local ED, then transferred to our tertiary care ICU. Over the next several days, despite maximal medical measures, she progressed to brain death.

He was 67 years old, living in a senior building. He presented with sepsis from a decubitus ulcer that had progressed to osteomyelitis. He had been addicted to heroin for decades, continuing to use it to numb the pain from his wound and escape the difficulties of his life. He required debridement for his infection and high doses of opioid medications to control his pain. He reported that he did not anticipate abstaining from heroin after he was discharged. Every critical care clinician has cared for patients with complications related to opioid use. The spectrum of conditions is broad. There are the heartbreaking overdose cases such as described above. There are patients who have survived many years of opioid use, misuse, and abuse, who may or may not have overcome their addiction, and who now live with complications of prior drug ingestion, inhalation, or injection. The long list includes complicating conditions such as COPD, chronic hypercapnia, dyspnea, debilitating joint pain, chronic kidney disease, hepatitis C and chronic liver disease, HIV infection, local site infections, and systemic infections such as endocarditis, malnutrition, and pressure ulcers.

WHAT ARE OPIOIDS?

Opioids are medications that attach to and activate opioid receptor proteins. In the brain and spinal cord, they can reduce the intensity of pain signal perception, affect areas that control emotion, and activate reward regions that cause euphoria. Centrally, opioids also can induce respiratory depression, cough suppression, drowsiness, and confusion. Peripherally, opioids can affect receptors in the gastrointestinal tract, slow motility, and lead to nausea and constipation.1

Opium, cultivated from poppy seeds, has been described since ancient times. It has been used for relieving grief, for healing the sick, as a euphoriant in religious rituals, and for preventing excessive crying of children. Its use and abuse have been described in many cultures spanning several centuries. Morphine first was isolated in 1806 and began to be used for perioperative pain in the 1850s. Because opium and morphine were found to have significant abuse potential, efforts to develop a safer opioid led to the development of heroin, a semi-synthetic opioid, in 1898. Heroin was touted as a more potent and less addictive opiate than morphine, but its addictive potential soon was realized. Meperidine, an opioid with a structure different from morphine, first was synthesized in 1939 but is less commonly used today because of its side effect profile. Methadone, also structurally unrelated but with some similar pharmacologic properties, was synthesized first in 1946 and remains frequently prescribed for management of both pain and addiction.2 More recently, opioid use began to increase rapidly in the 1990s when pharmaceutical companies marketed new formulations of prescription opioids as safe and effective analgesia without addiction potential. Over the subsequent two decades, diversion and misuse have increased as people realized that these medications are addictive.3

Opioids can be classified into prescription or nonprescription (illegal) forms, enteral or parenteral, or full or partial agonists. Prescription opioids include immediate-release and extended-release oral formulations, as well as transmucosal and transdermal fentanyl formulations. Opioids can be combined with nonopioid analgesics for synergistic effect. Occasionally, opioids can be combined with nonabsorbable opioid antagonists to deter abuse. Commonly prescribed enteral formulations include codeine cough syrups, hydrocodone combination analgesics, tramadol, morphine, oxycodone, and hydromorphone. Commonly available parenteral forms include morphine, fentanyl, and hydromorphone. Sufentanil and remifentanil are ultra fast-acting fentanyl analogues used more frequently for anesthesia purposes. Buprenorphine is a weak partial opioid agonist used for both chronic pain management and treatment of addiction.1

For many years, heroin has been the most commonly abused illicit opioid. Today, because of its high potentcy, fentanyl often is used to adulterate heroin and other street opioids.4 Desomorphine, commonly known as krokodil, is cooked by combining codeine with household acid (which can include hydrochloric acid, gasoline, and paint thinner) similarly to methamphetamine. Developed in Russia, krokodil was created as a cheaper and more available alternative to heroin, so named because of the skin necrosis that develops at injection sites.5

THE OPIOID CRISIS IN THE UNITED STATES

The White House has declared the opioid crisis a public health emergency. A national commission and a panel of state governors have issued recommendations for action. According to the CDC, more than 115 people die per day of opioid overdose in the United States. More than 350,000 people died from an overdose related to any opioid from 1999-2016.3 Prescription opioid misuse is estimated to cost the United States $78.5 billion per year. In 2015, it was estimated that 2 million people suffer from prescription opioid misuse disorders, and 591,000 suffer from heroin use disorder.6 In other reports, in 2016, more than 11 million Americans misused prescription opioids. Opioid overdose-related deaths have skyrocketed, tripling between 2002 and 2015, and more than quadrupling since 1999.3,7

Despite the rapid increases in overdoses and deaths, Americans may not recognize the severity of the crisis. Blendon et al compiled data from seven national polls conducted in 2016 and 2017. They found that Americans consider opioids a “second-tier” priority for the government, sixth on a 15-item priority list, and place most of the blame on prescribers (33%) and those who sell prescription painkillers illegally (28%).8 The public is uncertain about the effectiveness of treatment for opioid use disorder and ambivalent about whether it should be covered by insurance. However, most of those surveyed believe that anyone who is found to possess prescription opioids without a prescription should be treated rather than incarcerated. Even physicians and clinicians may not clearly understand the scope and details of the opioid crisis, thus highlighting the need for education.

The language sometimes can be confusing, with some reports using the term “opioid-related” to refer to prescription drugs, while other reports use the term to refer to prescription opioids, heroin, and other illicits. Drug dependence occurs when constant exposure to a drug leads to changes in the body. Rapid cessation or removal of the drug can lead to physiologic withdrawal symptoms. Misuse refers to any use of a prescription drug differently than it is prescribed or intended (e.g., using another person’s medication or using a medication for a different reason, at a different dose, or more often than it was prescribed). Abuse refers to use of a drug to experience feelings associated with the drug, such as euphoria or relaxation. Addiction is considered a more serious condition. Now reclassified as a “drug use disorder,” addiction is when ongoing drug use leads to changes in the brain and body. An individual compulsively seeks and uses drugs despite significant negative health and social consequences.1,2

Opioid use patterns have seen some shifts over time, but ongoing increase in use remains consistent. Over the past 50 years, the demographics of heroin use has changed substantially. This shift from an inner-city minority population to an affluent white suburban and rural population, attributed to the increase in availability of prescription opioids, has been reported frequently in mainstream media and corroborated by research. A mixed-methods retrospective data analysis study using surveys and statistics from substance use treatment programs showed that people who began using heroin in the 1960s were primarily young men (83% male; mean age, 16.5 years) whose first opioid of abuse was heroin (80%), with equal numbers of whites and non-whites. However, of those who began use in the 2000s, nearly 90% were white, with equal numbers of men and women (mean age, 22.9 years), and 75% of them were introduced to opioids through prescription drugs.9

From 2002-2010, opioid prescriptions increased substantially, then decreased from 2011-2013. Hypotheses for potential causes for this decrease include formulation changes in extended-release drugs, which decreased their desirability for abuse and injection, as well as improved programs for increasing the safety of opioid prescribing. When prescriptions decreased, abuse and diversion followed an associated decrease. However, there was a coincident increase in abuse (and overdose) of heroin in the United States.10 These findings suggest that as prescription opioid use has waned, there have been significant increases in the numbers of people who concurrently abuse heroin with prescription opioids. In a qualitative online survey, of 126 respondents who reported abusing prescription opioids prior to heroin use, 73% primarily cited practical factors, such as accessibility and cost, when explaining their transition to heroin.11

One recent report by Jones et al described the recent significant rise in synthetic opioid involvement in the opioid crisis. This is primarily illicit fentanyl, which is found mixed with other illicit drug supplies frequently. In 2016, there were 42,249 opioid-related overdose deaths. Of those, 19,413 involved synthetic opioids, 17,087 involved prescription opioids, and 15,469 involved heroin. Synthetic opioid involvement in these deaths increased significantly from 14% in 2010 to 46% in 2016 (P for trend < 0.01), and now it is the most common drug involved. Among synthetic opioid-related overdose deaths in 2016, 80% involved alcohol or another drug, most commonly another opioid or heroin. Because illicit synthetic opioid potency, variability, adulteration, and availability is poorly understood, and users often are unaware, its use poses significant risks to individuals and the public.12

CRITICAL CARE COMPLEXITIES IN THE OPIOID EPIDEMIC

Given the breadth of clinical presentations, the total effect of the opioid crisis on the ICU is complex and not well-characterized. To better understand the effect of overdoses on ICUs, Stevens et al used a large national database of hospital admissions to study the epidemiology of opioid overdose admissions to ICUs.13 Administrative data from 2009-2015 showed a near doubling in monthly opioid overdose deaths in the ICU over that period. Throughout that time, there were 21,705 overdose admissions to the ICU, with an average of 52.4 overdoses per 10,000 ICU admissions. Overdose admissions increased steadily at an average rate of 0.6% per month, with more admissions in summer months. Overall mortality increased during this period from 7.3% to 9.8%. Months with higher heroin overdose admissions were associated with higher mortality compared to months with higher prescription opioid overdose admissions. Additionally, admitted patients received significantly more intensive care in 2015 compared to 2009. This study was the first to describe the immense effect of the opioid crisis on the critical care community, showing significantly increased critical care use due to increasing opioid overdoses. The authors proposed that most, if not all, opioid overdose admissions to the ICU are preventable with upstream interventions and called for expanded primary prevention strategies and frontline responders.

Opioid intoxication and withdrawal also are important considerations in the ICU. It is vital to screen all confused, injured, or otherwise high-risk critical care patients with urine toxicology at the time of admission to assess for possible intoxication or withdrawal syndromes. While opioid withdrawal does not include the potential life-threatening complications of alcohol withdrawal syndrome, the withdrawal symptoms of diarrhea, vomiting, insomnia, muscle and joint pain, thermoregulation disturbances, tachycardia, and hypertension can affect management significantly. It is important to remember that opioid withdrawal symptoms can occur in patients maintained on opioids for the treatment of chronic pain. In patients with opioid dependence and tolerance, it may be difficult to achieve adequate analgesia and sedation. Medications such as methadone, buprenorphine, and alpha-agonists may be considered in the ICU for management of opioid dependence. However, treatment of the opioid use disorder and addiction may be better reserved for starting after the critical illness has resolved. Treatment of acute pain in patients maintained on buprenorphine may be especially challenging. Buprenorphine, with its partial agonist properties, has a very high affinity for mu-opioid receptors, rendering opioid analgesia less effective.14

As intensivists, it is our role to treat and support our patients who have been affected by opioids the best we can. This means best practice ICU care for all, managing pain and symptoms with possibly higher-than-expected doses of opioids. Consultative assistance of addiction support teams should be sought prior to transfer out of the ICU, if possible. For overdose survivors, the ICU stay may be a good time to engage their families and communities with future abstinence efforts.7 Prescription of intranasal naloxone to those with opioid use disorder (so that first responders may have an option for treatment) has been increasing.1 This has been shown to reduce death rates; paradoxically, this increase in naloxone use may be leading to increased ICU admissions, given that those overdoses now are surviving to hospitalization.7 Advocacy, education, addiction treatment programs, and mental health services are important components in fighting the opioid crisis. The opioid crisis is complex, multidimensional, and must be approached not only at an individual, family, and community level, but also through healthcare institutions and public policy.

REFERENCES

  1. National Institute on Drug Abuse. Misuse of prescription drugs. Available at: https://bit.ly/2rd6odi. Accessed Aug. 7, 2018.
  2. Brownstein MJ. A brief history of opiates, opioid peptides, and opioid receptors. Proc Natl Acad Sci USA 1993;90:5391-5393.
  3. National Institute on Drug Abuse. Opioid overdose crisis. Available at: https://bit.ly/2j6YEE1. Accessed Aug. 7, 2018.
  4. National Institute on Drug Abuse. Opioids. Available at: https://bit.ly/1RkAYHr. Accessed Aug. 7, 2018.
  5. Haskin A, Kim N, Aguh C. A new drug with a nasty bite: A case of krokodil-induced skin necrosis in an intravenous drug user. JAAD Case Rep 2016;2:174-176.
  6. Florence CS, Zhou C, Luo F, Xu L. The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care 2016;54:901-906.
  7. Mehta AB, Weinstein Z, Walkey AJ. The untold toll of the opioid crisis on intensive care units in the United States. Ann Am Thorac Soc 2017;14:1763-1765.
  8. Blendon RJ, Benson JM. The public and the opioid-abuse epidemic. N Engl J Med 2018;378:407-411.
  9. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: A retrospective analysis of the past 50 years. JAMA Psychiatry 2014;71:821-826.
  10. Dart RC, Surratt HL, Cicero TJ, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med 2015;372:241-248.
  11. Cicero TJ, Ellis MS, Harney J. Shifting patterns of prescription opioid and heroin abuse in the United States. N Engl J Med 2015;373:1789-1790.
  12. Jones CM, Einstein EB, Compton WM. Changes in synthetic opioid involvement in drug overdose deaths in the United States, 2010-2016. JAMA 2018;319:1819-1821.
  13. Stevens JP, Wall MJ, Novack L, et al. The critical care crisis of opioid overdoses in the United States. Ann Am Thorac Soc 2017;14:1803-1809.
  14. Tetrault JM, O’Connor PG. Substance abuse and withdrawal in the critical care setting. Crit Care Clin 2008;24:767-788.