The Opioid Epidemic and the Role of the ICU

by Kunal Karamchandani, MD, FCCP
Assistant Professor of Anesthesiology and Critical Care, Co-Director, Surgical Anesthesia ICU, Penn State Milton S. Hershey Medical Center, Hershey, PA

Volume 28 | Issue 3 | Fall 2017

The use of opioids has increased many times over in the last decade across the United States and has now reached epidemic proportions. After alcohol intoxication, opioids are now the most common cause of poisoning in the United States¹ with an estimated incidence of 177.7/100,000 annual ED admissions related to opioid overdose.² Although effective pain relief is a vital component of modern health care, the public health effects of opioid addiction have escalated sharply. Opioid overdose deaths increased 156% from 21,088 in 2010 to 33,091 in 2015, resulting in decreased life expectancy among users.³ There has been a concurrent dramatic increase in the number of opioid prescriptions over the last few decades, from 76 million in 1991 to 219 million in 2011⁴.

The number of patients presenting to the ICU with acute opioid overdose has increased significantly throughout the opioid epidemic and has put an additional burden on the country’s already overextended critical care infrastructure. A recent study found a 34% increase in ICU admissions related to opioid overdose across 162 hospitals in 44 states.⁵ The mortality rate of such patients has previously averaged 7% but increased to 10% in 2015.⁵ These trends are concerning and suggest the need for a national approach to enhancing delivery of critical care services to such patients, providing additional resources in the hospital for patients and families, and to help survivors upon discharge.

Supportive measures and naloxone remain the mainstay of therapy for managing patients admitted to the ICU for acute opioid overdose. Many patients require mechanical ventilation for respiratory support and the use of inotropic drugs and vasopressors is often needed to counter the cardiodepressant and vasodilatory effects of opioids. Naloxone, the antidote for opioid overdose, is a competitive µ opioid–receptor antagonist that reverses all the effects of opioid intoxication. It is active via the parenteral, intranasal, or pulmonary route of administration but has negligible bioavailability after oral administration because of extensive first-pass metabolism.⁶ The effective dose of naloxone depends on the amount of opioid analgesic the patient has taken, the relative affinity of naloxone for the µ opioid receptor and the opioid to be displaced, the patient's weight, and the degree of penetrance of the opioid analgesic into the central nervous system.^7,8 Frequently this information is not available and clinicians have to use empiric dosing. The suggested initial dose of naloxone for adults is 0.04 mg and the dose is increased every 2-3 minutes in a step wise manner to achieve a target respiratory rate of more than 12 breaths/minute to a maximum of 15 mg.⁹ If there is no reversal of respiratory depression after the administration of 15 mg of naloxone, it is unlikely that the cause of the depression is opioid overdose.^10,11 Since the half-life of naloxone is extremely short as compared to most of the opioid analgesics, in patients with overdose, the reversal of opioid toxicity after the administration of single doses of naloxone is often transient. Recurrent respiratory depression is often an indication for a continuous infusion of naloxone along with the necessity to protect the airway via orotracheal intubation. 

Similarly, the number of opioid tolerant patients being admitted to the ICU has increased significantly. The FDA defines a patient as opioid tolerant if for at least 1 week he or she has been receiving oral morphine 60 mg/day; transdermal fentanyl 25 mcg/hour; oral oxycodone 30 mg/day; oral hydromorphone 8 mg/day; oral oxymorphone 25 mg/day; or an equianalgesic dose of any other opioid.¹²These patients present additional challenge as managing analgesia and sedation requires a comprehensive multi-modal treatment regimen which may still fall short. They may have varying degrees of experience with opioids; some may have a history of opioid use disorder (OUD) who are not currently using opioids, and some may have a history of OUD and are being maintained on methadone or buprenorphine.

Managing such patients in the ICU can be difficult. It is probably safe to assume that continuing their methadone and buprenorphine while in the ICU can help prevent precipitate an acute withdrawal. Agents such as clonidine and dexmetedomidine might also be helpful in preventing acute opioid withdrawal. They are both alpha-2 adrenergic agonists with sedative and analgesic properties. Clonidine administered via transdermal or oral routes can decrease metabolic, respiratory, and hemodynamic demands associated with opioid withdrawal.¹³ Dexmedetomidine, a more selective alpha-2 agonist, causes sedation, analgesia, and anxiolysis with minimal respiratory depression. In a recent case report, dexmetedomidine infusion was successfully used to control heroin withdrawal-related psychotomimetic symptoms in a critically ill patient.¹⁴ 

Another class of drugs that can be useful in ICU patients who have developed opioid dependence and tolerance are the N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine and magnesium that can provide analgesia as well as prevent withdrawal. NMDA and opioid receptors both reside on the spinal cord dorsal horn neurons that process nociceptive information.¹⁵ NMDA receptor antagonists block prolonged depolarization of these neurons and prevent hyperalgesia which is often seen with opioid tolerance/dependence. In a recent study looking at opioid requirements in trauma patients who presented to the ICU with a positive urine drug screen, the authors found a trend towards greater ketamine use in such patients.¹⁶ Ketamine administration may reduce perioperative opioid requirements and sensitize opioid receptors, making it an attractive adjunct in trauma and surgical ICU patients.^17-20 The biggest disadvantage with the use of ketamine in the ICU is its association with psychotomimetic effects such as nightmares, hallucinations, and development of delirium. Well-designed studies comparing ketamine with other commonly used agents like propofol and dexmetedomidine are urgently needed to help evaluate the potential of ketamine as an ICU sedative and analgesic. Multimodal analgesia techniques including NMDA receptor antagonists and alpha-2 agonists are potentially of great value in managing opioid tolerance and dependence and preventing withdrawal in the ICU.²¹  

The other part of the relationship between the ICU and the opioid epidemic lies in what has been aptly described as the clinical conundrum.²¹ Untreated acute pain in the ICU, which can  then transition to chronic pain, and the development of opioid tolerance, opioid dependence and acute withdrawal in patients who receive significant does of opioids in the ICU constitute even bigger challenges for ICU providers. Patients in the ICU experience significant amount of pain irrespective of the admission diagnosis. Pain is also one of the most common memory that patients have of their ICU stay.²² Despite the awareness of the need for analgesia in patients admitted to the ICU, a significant number of patients remain untreated or undertreated.²³ Although acute pain is protective, warning patients and clinicians of impending or actual tissue injury, it can transition to chronic pain in certain susceptible patients.²¹ In three recent studies, patients were asked about ongoing pain lasting at least 6 months from their stay in the ICU and whether the pain was new since ICU admission.^24-26 The 6-month post-ICU chronic pain prevalence rates were 12% in post-cardiac surgery patients²⁶ and ranged from 33% to 44% in the mixed med-surgical patient populations.^24,25 About 45% of these patients considered their ongoing pain to be moderate to severe in intensity.²⁵ Although these numbers are relatively modest, they are significant considering the thousands of patients with multiple diagnoses that are admitted to ICUs each year.

Uncontrolled pain, pain of high intensity, and pain of longer duration are all risk factors for transition from acute to chronic pain and hence every effort should be made to treat pain appropriately in the ICU. Pain in the ICU can be divided into two broad categories: constant background pain and intermittent pain. Background pain includes postoperative pain related to incisions, drains, and dressings; pre-existing pain in patients with arthritis, migraine and other forms of chronic pain; and pain related to trauma (amputations, fractures, pressure sores, soft tissue injuries etc.). Intermittent pain, on the other hand, includes pain associated with commonly performed invasive procedures (central/arterial line placement, intubation, nasogastric and nasoduodenal tube insertion, foley catheter insertion, venous lab draws), as well as routine daily care such as position changes, physiotherapy, tracheal suctioning, and dressing changes. In a large multi-center study,²⁷ the authors found that all of the commonly performed procedures in the ICU were associated with significant increase in pain intensity compared to baseline. Chest tube removal, wound drain removal and arterial line insertion were the procedures associated with the most pain.

Recognition and assessment of pain in ICU patients is the first step towards management.  Assessing pain in the ICU is not easy as verbal reporting is not always possible and physiological changes, such as hypertension and tachycardia, that usually correlate with pain, can be masked or caused by various other factors in the ICU setting (e.g. sepsis, inotropic and vasopressor therapy, beta blockade, arrhythmias, and other pharmacologic interventions). Less than 50% of intensive care professionals actually assess pain, and even when done, it is not done frequently.²⁸ In patients that can self-report, numerical rating scale (NRS) and visual analogue scales (VAS) are the gold standard, however in patients that are unable to self-report but have intact motor function and observable behaviors pain scales such as Behavioral Pain Scale (BPS) and Critical Care Pain Observation Tool (CPOT) have been found to be effective.²⁹ Once pain has been appropriately assessed, multimodal analgesia techniques that include non-opioids and/or non- pharmacological interventions are recommended to reduce opioid requirements, prevent adverse effects of large doses of opioids, and enhance pain relief.^29,30

Opioids are still the first line drugs for managing pain in the ICU and many ICU patients, particularly those receiving mechanical ventilation, receive continuous infusions of opioids, not only to prevent pain but to improve ventilator synchrony and minimize agitation. In the aftermath of the introduction and validation of “analgosedation” by the Society of Critical Care Medicine (SCCM),²⁹ there has been a greater focus on recognition and management of pain in the ICU which has potentially led to a greater usage of opioids. Long-term use of opioids can cause opioid tolerance and physical dependence, and there is always a concern that the patients who have received significant doses of narcotics in the ICU might develop tolerance.   Extensive use of opioids for analgosedation could also lead to iatrogenically induced opioid withdrawal during opioid weaning. A small retrospective study looked at the incidence of acute withdrawal syndrome (AWS) in mechanically ventilated trauma patients found that almost 32% of these patients developed AWS.³¹ The key to preventing AWS in critically ill patients is to use a multimodal pain regimen including non-opioid analgesics as well as loco-regional analgesia. When using opioids, periodically assessing pain and titrating the medications per individual patient needs is important. An ideal regimen in patients with constant background pain could include a small bolus of IV fentanyl followed by an infusion with the dose increased by 15-20% at a time titrated to a BPS or CPOT score with a slow wean when applicable with a reduction in rate by about 25% each time. 

In conclusion, the opioid epidemic has had a significant impact across the country leading to a substantial increase in mortality in the last decade. The critical care community has not only been affected by the significant increase in acute opioid overdose related admissions and the associated morbidity and mortality but also the massive increase in the number of opioid dependent and opioid tolerant patients being treated in the ICUs across the country for myriad of other reasons. The implications of such a change are hard to quantify but the onus remains on the critical care community to provide a holistic, multi-modal and pragmatic approach when caring for these patients. Effectively assessing and treating pain in the ICU is essential to promote comfort and rehabilitation to the patients as well as preventing the transition from acute to chronic pain. Yet, providing large, continuous doses of opioid analgesics may put patients at risk for opioid dependence and withdrawal during drug tapering. Further research is required to examine how to promote optimal pain management while avoiding opioid withdrawal and thus minimize post-intensive care morbidity.

Resources

1. Nelson LS, Juurlink DN, Perrone J. Addressing the Opioid Epidemic. JAMA. 2015;314(14):1453-1454.
2. Audrey J. Weiss PD, Anne Elixhauser, Ph.D., Marguerite L. Barrett, M.S., Claudia A. Steiner, M.D., M.P.H., Molly K. Bailey, and Lauren O'Malley Opioid-Related Inpatient Stays and Emergency Department Visits by State, 2009-2014. Healthcare Cost and Utilization Project: Agency for Healthcare Research and Quality;2017.
3. Gostin LO, Hodge JG, Jr., Noe SA. Reframing the Opioid Epidemic as a National Emergency. JAMA. 2017.
4. IMS’s National Prescription Audit (NPA) & Vector One ®: National (VONA).
5. Stevens JP, Wall MJ, Novack L, Marshall J, Hsu DJ, Howell MD. The Critical Care Crisis of Opioid Overdoses in the United States. Ann Am Thorac Soc. 2017.
6. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9(1):1-25.
7. Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet. 1976;1(3):219-230.
8. Tenenbein M. Continuous naloxone infusion for opiate poisoning in infancy. J Pediatr. 1984;105(4):645-648.
9. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146-155.
10. Prosser JM, Jones BE, Nelson L. Complications of oral exposure to fentanyl transdermal delivery system patches. J Med Toxicol. 2010;6(4):443-447.
11. Schumann H, Erickson T, Thompson TM, Zautcke JL, Denton JS. Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol (Phila). 2008;46(6):501-506.
12. FDA. Extended-release (ER) and long-acting (LA) opioid analgesics Risk Evaluation and Mitigation Strategy (REMS). .  www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm311290.pdf.
13. Liatsi D, Tsapas B, Pampori S, Tsagourias M, Pneumatikos I, Matamis D. Respiratory, metabolic and hemodynamic effects of clonidine in ventilated patients presenting with withdrawal syndrome. Intensive Care Med. 2009;35(2):275-281.
14. Upadhyay SP, Mallick PN, Elmatite WM, Jagia M, Taqi S. Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse. Indian J Palliat Care. 2011;17(3):251-254.
15. Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage. 2000;19(1 Suppl):S7-11.
16. Kram B, Kram SJ, Sharpe ML, James ML, Kuchibhatla M, Shapiro ML. Analgesia and Sedation Requirements in Mechanically Ventilated Trauma Patients With Acute, Preinjury Use of Cocaine and/or Amphetamines. Anesth Analg. 2017;124(3):782-788.
17. Gupta A, Devi LA, Gomes I. Potentiation of mu-opioid receptor-mediated signaling by ketamine. J Neurochem. 2011;119(2):294-302.
18. Kissin I, Bright CA, Bradley EL, Jr. The effect of ketamine on opioid-induced acute tolerance: can it explain reduction of opioid consumption with ketamine-opioid analgesic combinations? Anesth Analg. 2000;91(6):1483-1488.
19. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293-299.
20. Zakine J, Samarcq D, Lorne E, et al. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg. 2008;106(6):1856-1861.
21. Puntillo KA, Naidu R. Chronic pain disorders after critical illness and ICU-acquired opioid dependence: two clinical conundra. Curr Opin Crit Care. 2016;22(5):506-512.
22. Stein-Parbury J, McKinley S. Patients' experiences of being in an intensive care unit: a select literature review. Am J Crit Care. 2000;9(1):20-27.
23. Bertolini G, Minelli C, Latronico N, et al. The use of analgesic drugs in postoperative patients: the neglected problem of pain control in intensive care units. An observational, prospective, multicenter study in 128 Italian intensive care units. Eur J Clin Pharmacol. 2002;58(1):73-77.
24. Battle CE, Lovett S, Hutchings H. Chronic pain in survivors of critical illness: a retrospective analysis of incidence and risk factors. Crit Care. 2013;17(3):R101.
25. Baumbach P, Gotz T, Gunther A, Weiss T, Meissner W. Prevalence and Characteristics of Chronic Intensive Care-Related Pain: The Role of Severe Sepsis and Septic Shock. Crit Care Med. 2016;44(6):1129-1137.
26. Choiniere M, Watt-Watson J, Victor JC, et al. Prevalence of and risk factors for persistent postoperative nonanginal pain after cardiac surgery: a 2-year prospective multicentre study. CMAJ. 2014;186(7):E213-223.
27. Puntillo KA, Max A, Timsit JF, et al. Determinants of procedural pain intensity in the intensive care unit. The Europain(R) study. Am J Respir Crit Care Med. 2014;189(1):39-47.
28. Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study. Anesthesiology. 2007;106(4):687-695; quiz 891-682.
29. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306.
30. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49(10):1405-1428.
31. Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients. Crit Care Med. 1998;26(4):676-684.