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Pain Management in Trauma Patients Affected by The Opioid Epidemic: A

Narrative Review
Article in Journal of Trauma and Acute Care Surgery · April 2019

DOI: 10.1097/TA.0000000000002292
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Journal of Trauma and Acute Care Surgery, Publish Ahead of Print
DOI: 10.1097/TA.0000000000002292
Pain Management in Trauma Patients Affected by The Opioid Epidemic: A
Narrative Review
Kunal Karamchandani MD, FCCP1, John C. Klick MD, FCCP, FASE, FCCM1,
Downloaded from https://journals.lww.com/jtrauma by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3toxqoobVJlY7QxzbwcW58lEx82IvsAg18ccq7+R+k2A= on 04/05/2019
Melissa Linskey Dougherty MD2, Anthony Bonavia MD1, Steven R. Allen MD, FACS2,
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Zyad J. Carr MD, FASA1
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1
Department of Anesthesiology & Perioperative Medicine, Penn State Health Milton S. Hershey
Medical Center, Hershey, PA, USA.

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2
Department of Surgery, Penn State Health Milton S. Hershey Medical Center, Hershey, PA,
USA.
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John C. Klick: jklick@pennstatehealth.psu.edu
Melissa Linskey Dougherty: mlinskey@pennstatehealth.psu.edu

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Anthony Bonavia: abonavia@pennstatehealth.psu.edu
Steven R. Allen: sallen4@pennstatehealth.psu.edu

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Zyad J. Carr: zcarr@pennstatehealth.psu.edu
Corresponding Author:
Kunal Karamchandani, MD, FCCP
Department of Anesthesiology & Perioperative Medicine, H187
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Penn State Health Milton S. Hershey Medical Center
500 University Dr., Hershey, PA, USA 17033
Email: kkaramchandani@pennstatehealth.psu.edu
Phone: (717)-531-5457
Financial Disclosure: None
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Conflicts of Interest: None
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Abstract
Acute and chronic pain in trauma patients remains a challenging entity, particularly in the setting
of the escalating opioid epidemic. It has been reported that chronic opioid use increases the
likelihood of hospital admissions as a result of traumatic injuries. Furthermore, patients admitted
with traumatic injuries have a greater than average risk of developing opioid use disorder after
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discharge. Practitioners providing care to these patients will encounter the issue of balancing
analgesic goals and acute opioid withdrawal with the challenge of reducing post-discharge
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persistent opioid use. Additionally, the practitioner is faced with the worrisome prospect that
inadequate treatment of acute pain may lead to the development of chronic pain and over-
treatment may result in opioid dependence. It is therefore imperative to understand and execute
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alternative non-opioid strategies to maximize the benefits and reduce the risks of analgesic
regimens in this patient population. This narrative review will analyze the current literature on
pain management in trauma patients and highlight the application of the multimodal approach in
potentially reducing the risks of both short and long-term opioid use.
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Study type: Narrative review

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Level of evidence: Moderate to High

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Keywords: Pain management, Opioid epidemic, Multimodal analgesia, Critical illness

Introduction
Opioid abuse has increased significantly over the past two decades and has resulted in a nation-
wide crisis. After alcohol, opioid abuse constitutes the most common cause of intoxication in the
United States(1) and more than 115 people die from opioid overdoses every day.(2) Although
effective pain relief is a vital component of modern health care, recognizing the detrimental
public health consequences of inappropriate emphasis on opioid-centric pain management is
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equally important. Up to a third of patients prescribed opioids for chronic pain misuse them,(3)
and, of those patients, an estimated 4% to 6% transition to heroin abuse.(4) As the incidence of
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opioid abuse and dependence increases, traumatologists will be tasked with managing patients
with a varied spectrum of opioid dependence. The rate of pre-existing opioid use is significantly
higher among trauma patients compared to the general population, (5) and inadequate pain relief
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may lead to the development of chronic pain, and transition to chronic opioid dependence.(6, 7)
In this narrative review, we discuss the impact of the opioid crisis on patients with traumatic
injuries. We highlight the challenges associated with the assessment and management of pain in
these patients, especially those that are critically ill and explore multimodal treatment options.
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Furthermore, we briefly bring to light the emerging concerns of chronic pain related to
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inadequate pain treatment and its potential transition to chronic intensive care-related pain
(CIRP).
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Pre-injury opioid use
Pre-injury opioid use is common among trauma patients with rates varying between 16 and
20%.(8, 9) Of the patients with a positive urine toxicology screen, the detection of an illicitly
administered opiate has been reported to be as high as 50%.(10) In addition, the use of opioids
for chronic pain management increases the risk of traumatic injury. For example, Gomes and
colleagues reported that truck drivers suffering from chronic pain, who take 20 Morphine

Equivalents (MEQ) or greater on a daily basis have a 21% to 42% increased risk of experiencing
a motor vehicle accident.(11) In addition, elderly patients on chronic opioid regimens are also at
an increased risk of falls and bone fractures.(12) In trauma patients, prior use of opioids
contributes to prolonged hospital as well as ICU length of stay and an increased requirement for
mechanical ventilation.(8, 10) Higher rates of operative interventions and mortality have been
observed in patients with pre-injury use of controlled substances including opiates.(10)
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Pain in the critically ill trauma patient
A majority of patients in the ICU experience moderate to severe pain, and pain is one of the most
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commonly recalled memories of their ICU stay.(13) The prevalence of moderate to severe pain
in critically ill patients with severe trauma has been reported to be as high as 80%.(14) In
addition to trauma-related pain, these patients may experience pain from procedures routinely
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performed in the ICU.(15) Pain in the ICU can be broadly divided into two categories; constant
background pain and intermittent pain (Table 1). Patients suffering traumatic injuries are
commonly exposed to both types of pain during their ICU stay, thus making adequate pain
management challenging.
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Approximately 75% of multi-trauma patients in the ICU report inadequate pain control, rating
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their pain intensity between moderate to severe.(16) It is well understood that uncontrolled pain
can lead to significant neurological and psychiatric consequences. Physiologically, inadequate

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pain control is the progenitor of a potent inflammatory response and tends to affect all major
organ systems (Figure 1). In addition, inadequate pain relief has been associated with increased
morbidity, hospital length of stay and cost.(16-18) Patients also frequently report despair,
isolation, anxiety, sleep deprivation and the development of post-traumatic stress disorder
(PTSD).(19) The stress response after traumatic injury and its downstream effects are
intrinsically linked to deleterious psychiatric and neurological outcomes culminating in severe,

often debilitating, chronic pain conditions.(20, 21) Though not fully understood, persistent pain
conditions, nerve injury and persistent inflammation may generate uncontrolled negative
nociceptive feedback loops via peripheral and central nerve sensitization, resulting in the
generation of a chronic pain state. (6, 7) At this time, there are no definitive treatment strategies
that effectively cure this condition and attempts to minimize its development should be
emphasized. Despite evidence highlighting the detrimental effects of uncontrolled pain,
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physicians remain reluctant to aggressively treat it.(16) Although the reasons behind inadequate
pain control in trauma patients are incompletely understood, misinterpretation of pain intensity,
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concern for narcotic-related hemodynamic instability, narcotic-related respiratory depression,
prioritization of neurological exams, concern for inadequate gastric motility, and fear of potential
post-ICU opioid dependence may all play a role.(20)

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Assessment of Pain
Timely recognition and appropriate assessment of pain are critical for adequate pain
management. Reproducible pain assessments should be performed, and patients monitored over
time to determine the adequacy of therapeutic interventions to treat pain. To maintain

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consistency and reliability, intensive care nurses should be tasked with this assessment.
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Assessment of pain in critically ill patients is challenging, as verbal reporting is not always
possible and physiological indicators of pain are nonspecific. Pain-related physiological

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derangement can be masked by sepsis, inotrope/vasopressor therapy, arrhythmias, and
pharmacologic interventions. As a result, less than 50% of ICU providers accurately assess
analgesic requirements. (22) Self-reporting of pain by patients is considered the gold standard
and providers should try and rate patient’s self-reported pain whenever possible using objective
pain scales, such as the numerical rating (NRS) and visual analogue scales (VAS) (23) However,
patient-reported measures of pain can be limited by discordance between the perceived severity

of pain and the verbalized score. Furthermore, these scores may not be as reliable in patients
previously exposed to opioids, or with a history of prior substance abuse. For patients unable to
communicate, such as those with encephalopathy, TBI or those that are intubated, pain scales
such as the Behavioral Pain Scale (BPS) and Critical Care Pain Observation Tool (CPOT) have
been found to be effective tools to guide analgesic regimens.(24) These scales use facial
expressions, body movements, muscle tension, and compliance with the ventilator to assess pain.
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Although the behavioral scales are unable to assess the severity or intensity of pain, they can still
be used to broadly determine the presence or absence of pain.(25)
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Pain Management in the Trauma Intensive Care Unit
Analgesia should be titrated to individualized and patient-centered goals. This is essential when
one considers the multiple physiological derangements faced by critically ill patients. Substantial
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derangements in the pharmacodynamics and pharmacokinetics will present a significant
challenge for providers caring for critically ill patients (Table 2). In addition, dynamic
physiological derangements necessitate frequent reassessments to ensure that adverse events are
averted. Complex processes mediate the transmission, interpretation and physiological effects of
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both acute and chronic pain. The simultaneous use of different classes of analgesic medications
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and regional anesthesia techniques (the multimodal approach), is efficacious in the treatment of
both acute and chronic pain. The overarching goal is minimizing adverse effects and maximizing
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the synergistic analgesic properties of the selected agents. The clinician should also be aware of
the development of paradoxical hypersensitivity, or opioid-induced hyperalgesia (OIH), a
syndrome where opioid administration paradoxically worsens pain. (26) OIH is a complex
physiological process that may complicate opioid-based pain regimens, it predisposes patients
with chronic opioid exposure to hyperalgesia and such patients are identified by worsening pain
relief with increasing opioid doses. The multimodal approach may be more effective than using

systemic opioid based analgesia alone in patients who have sustained traumatic injuries, with the
potential to prevent OIH.(27, 28) We discuss these interventions in detail below.
Opioid analgesics
Opioids are the cornerstone of pain management in the ICU, and most current guidelines still
recommend the use of intravenous opiates as the first-line agents in the treatment of non-
neuropathic pain in critically ill patients.(23) Continuous opioid infusions remain the mainstay in
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mechanically ventilated patients to prevent pain, minimize patient-ventilator dyssynchrony, and
reduce agitation. However, inadequately titrated continuous infusions rapidly lead to drug
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accumulation, ileus, and depressed cognition. In addition, opioids are associated with both
short- and long-term systemic effects especially in patients with traumatic injury. Over-sedation,
respiratory depression, nausea, constipation, ileus, urinary retention, and pruritus are the most
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commonly reported short-term adverse effects of opioids. In addition, long-term adverse effects
include B and T cell-mediated immune dysfunction, OIH, and the potential for physiological and
psychological addiction.(29) OIH has been reported following both short and long-term use of
opioids.(30) The commonly used opioids in the ICU and their properties are listed in Table 3.
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An ideal opioid should have a rapid onset and offset, should be titratable, have a predictable dose
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response and a high therapeutic index. It should ideally have no interactions and should have
limited accumulation in organ dysfunction. Although such an opioid does not exist,
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understanding the pharmacokinetics and dynamics of individual opioids and choosing an agent
tailored to patient needs is ideal. Fentanyl, a synthetic opioid with a potency 100 times greater
than intravenous morphine, has a short half-life for intermittent bolus dosing (30-60 min) and
does not have any active metabolites. Given its minimal vasodilatory and cardiac depressant
effects, it has been recommended as the analgesic of choice in critically ill patients with
hemodynamic instability. (31, 32) It does have a long context-sensitive half-life and long

duration continuous infusions can lead to drug accumulation and prolong sedation without
careful titration. Remifentanil is an attractive option for providing continuous infusions because
of its very short context-sensitive half-life, however, the risk of OIH limits its routine
administration in patients with traumatic injuries.
The central tenet of opioid based pain management approach is tailoring the regimen to the
individual patient based on physiological derangements, comorbid conditions and type of injury.
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Acknowledging the well-known risk of delirium associated with excessive use of sedative-
hypnotics, a regimen based on continuous fentanyl infusion should be considered for
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mechanically ventilated patients. These infusions should be assessed daily and titrated to
maintain the minimal dosage to preserve ventilator synchrony and patient comfort. Daily
sedation holidays should be routinely performed in most patients. Patients with adequate enteral
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access should be actively assessed for transition to oral oxycodone formulations using morphine
equivalent unit calculations. Intravenous intermittent dosed hydromorphone is a useful adjunct to
wean continuous opioid infusions in patients without adequate enteral access. Intravenous
patient-controlled analgesia using hydromorphone or morphine can be a viable alternative in

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patients that are awake and alert.

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Non-opioid analgesics
Non-opioid analgesics are an essential component of the multimodal approach and can reduce
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the risk of opioid-related side effects. The use of non-narcotic analgesics can improve subjective
pain scores and decrease total opioid consumption.(33) Commonly used non-opioid analgesics
include acetaminophen, ketorolac, ibuprofen, gabapentinoids, ketamine, alpha -2 agonists
(clonidine and dexmedetomidine) and lidocaine.

Acetaminophen
Acetaminophen is a weak analgesic and exerts its effects at central COX-3 receptors.
Acetaminophen use has been observed to reduce opioid and sedative consumption and decrease
nausea when used in doses up to 4000 mg/day. (34, 35) Oral formulations of acetaminophen
may be limited by enteral access or the presence of ileus. Intravenous formulations may improve
onset time to pain control due to earlier and higher plasma levels compared to equivalent doses
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of oral acetaminophen, although the findings are equivocal. (36) Data regarding the safety profile
of intravenous formulations is limited but it appears safe for administration in critically ill
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patients, although hypotension has occasionally been reported.(37) Scheduled dosing of
intravenous or oral acetaminophen can reduce the requirement of opioids and help provide
multimodal analgesia.
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Nonsteroidal Anti-inflammatory drugs (NSAIDs)
NSAIDs work by inhibition of the COX-1 and COX-2 enzymes, decreasing tissue production of
prostaglandins and thromboxane and consequently reducing inflammation-mediated pain, in
addition to their anti-pyretic properties. Traditional non-selective NSAIDs (ibuprofen, ketolorac)

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predominately exert their analgesic effects on peripheral tissues. In contrast, the selective COX-
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2 drugs (e.g. Celecoxib, Rofecoxib) exert their effects both in peripheral tissues and in the central
nervous system.(38) Unfortunately, their widespread adoption has been limited by dose-
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dependent adverse effects such as platelet dysfunction, gastritis, renal impairment, and impaired
bone healing. The efficacy of NSAIDs have not been well studied in critically ill patients. Some
promising data suggests that their potential benefits outweigh their risks. In a retrospective
cohort study of patients admitted to ICU after rib fractures, ketorolac use was associated with a
decreased incidence of pneumonia, and increased ventilator-and ICU-free days.(39) Furthermore,
early intravenous ibuprofen therapy in patients with traumatic rib fractures has been found to
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decrease opioid requirements and result in clinically meaningful reductions in hospital length of
stay.(40) NSAIDs should be considered as part of multimodal analgesia regimen in patients with
traumatic rib fractures unless contraindicated.
Gabapentinoids
The anticonvulsants gabapentin and pregabalin are structural analogs of gamma-amino-butyric
acid and exert their effects by binding to the α2δ subunits of voltage-dependent calcium ion
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channels. Their analgesic properties are believed to be related to the reduction of calcium influx,
activation of spinal noradrenergic activity, and downstream attenuation of spinal cord excitatory
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amino acids such as glutamate and aspartate.(41) By interfering with the development of
hyperalgesia, they act as useful adjuncts in the treatment of neuropathic pain and potentially
prevent the transformation of acute pain to chronic pain. Disadvantages to gabapentinoids

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include lack of an intravenous formulation and selective duodenal absorption preventing patients
with distal feeding tubes from adequately absorbing drug. In addition, use is limited secondary to
an extensive list of adverse effects including somnolence, dizziness, visual disturbances,
convulsions, and ataxia.(42) Gabapentin can be added to the analgesic regimen in patients with
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post-thoracotomy and phantom limb pain in whom the benefits might outweigh the risks. (43,
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44)
Ketamine
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Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has demonstrated efficacy as both
an analgesic and as a sedative-hypnotic agent. Ketamine has long played a role in the anesthetic
management of trauma patients due to its hemodynamic stability compared to other anesthetics.
It is increasingly being studied for both postoperative analgesia and acute pain management in
trauma patients.(29) Ketamine has been observed to reduce opioid use in mechanically ventilated
adult trauma patients.(45) At sub-anesthetic infusions, ketamine has effective analgesic
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properties while significantly reducing total opioid requirements.(46) Therapeutic dosing for
postoperative pain control ranges from 0.1 to 0.4 mg/kg/hour. Ketamine has historically been
associated with adverse cardiovascular, pulmonary, neurological and psychiatric effects but new
studies have disputed some of these commonly held perceptions. The psychotomimetic effects
are dose-dependent and may be reduced by the concomitant administration of low-doses of
benzodiazepines or propofol. Secondly, the common assertion that ketamine increases
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intracranial pressure has been challenged by recent evidence suggesting that this is
negligible.(47) In addition, there is evidence to support ketamine’s neuroprotective role in
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patients experiencing traumatic injuries.(48) Thirdly, high doses of ketamine may induce
myocardial depression in catecholamine-depleted patients based on pre-clinical studies.(49)
With smaller dosages in human studies, ketamine demonstrates a sympathomimetic effect

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without myocardial depression.(50) Further studies are needed to assess the safety of ketamine in
critically ill trauma patients prior to recommending its routine use, none the less, it provides an
attractive option in patients requiring escalating doses of opioids.
Alpha -2 agonists (clonidine and dexmedetomidine)

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Clonidine and dexmedetomidine are alpha-2 agonists that promote both peripheral and central
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analgesia, anxiolysis and sedation. Clonidine is longer acting, differs in its receptor subtype
activation and is traditionally administered via the enteral route or via transdermal patch.
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Dexmedetomidine is indicated for short-term infusion and has a short half-life (distributive half-
life: 6 min; elimination half-life: 2 hours). Both dexmedetomidine and clonidine possess anti-
nociceptive properties via both peripheral and centrally mediated mechanisms, including
activation of post-synaptic α-2 adrenoceptors of descending noradrenergic pathways. Compared
to clonidine, dexmedetomidine has a higher affinity for α-2 receptors and hence, slightly better
hemodynamic profile. Dexmedetomidine has demonstrated limited efficacy in the reduction of
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delirium in critically ill patients and also has an opioid-sparing effect.(51, 52) Adverse effects
with its administration include bradycardia and hypotension due to centrally-mediated
sympatholysis and caution should be exercised in volume-depleted patients. Persistent
bradycardia can often be treated with intermittent low doses of the anticholinergic drug
glycopyrrolate (0.2mg q6h as needed). Dexmedetomidine can be a viable option to provide
sedation as well as analgesia for trauma patients that are in the post-resuscitative phase when the
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risk of hypotension is mitigated. The variability in patient response also limits its routine use and
needs to be explored further.
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Lidocaine
The local anesthetic lidocaine mediates analgesia independent of its direct local anesthetic
properties. When administered intravenously, it has been observed to decrease pain and opioid
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requirements via an unclear mechanism of action, although it is surmised that it exerts these
effects via N-methyl-D-aspartate (NMDA) receptors that populate the dorsal horn of the spinal
cord. Although many studies have validated the effectiveness of lidocaine in the perioperative
setting(53), there are limited studies extrapolating their use to critically ill patients with traumatic
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injuries.(54)
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Regional analgesia
When appropriate, regional analgesia is an excellent opioid sparing modality. Advantageous

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benefits to the use of regional analgesia, epidural analgesia, or continuous peripheral nerve
blocks (CPNB) have been demonstrated in poly-trauma patients.(27, 28) Aggressive methods to
reduce opioid use in eligible patients can lead to fewer opioid-induced adverse effects, decreased
post-traumatic stress disorder symptoms(55) and a lower incidence of post-traumatic chronic
pain.(56) Reduced opioid use can facilitate weaning from mechanical ventilation, hasten the
return of bowel function after gastrointestinal surgery, and reduce the length of ICU stay.(57, 58)
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Use of regional analgesia and its opioid-sparing effects may also help reduce the risk of delirium
in geriatric patients with rib fractures.(59) Regional analgesia can be broadly categorized into
neuraxial blocks (subarachnoid and epidural blocks), peripheral nerve blocks, and fascial plane
blocks.
Neuraxial blocks
Neuraxial blocks have been used extensively in postoperative pain management following
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abdominal, thoracic and vascular surgical procedures.(24, 60) Epidural analgesia is well tolerated
in the ICU setting in post-trauma (14%), after major surgery (42%), and acute pancreatitis (31%)
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patients.(61) In addition, neuraxial blocks have been observed to decrease the risk of venous
thromboembolism and cardiopulmonary complications in postoperative patients.(62, 63) Relative
and absolute contraindications to the use of central neuraxial blockade in the ICU setting include
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coagulopathy, difficulty with patient positioning, the need for aggressive venous
thromboembolic prophylaxis, altered mental status and the potential for hemodynamic instability
associated with sympathetic nervous system blockade. A risk assessment in conjunction with the
anesthesiologist should be performed prior to the execution of neuraxial blocks in patients with
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traumatic injuries.
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Peripheral nerve blocks
Peripheral nerve blocks (PNB) involve the injection of local anesthetics and analgesic adjuncts in
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close proximity to individual nerves, blocking fast sodium channels and preventing the
peripheral transmission of pain. PNBs have been extensively researched in patients with limb
injuries.(29) When performed by experienced practitioners guided by ultrasound and/or
peripheral nerve stimulators, they can be performed in the ICU reducing the risk of intra-hospital
transport without diminishing the quality of the nerve block. Relative and absolute
contraindications to the use of peripheral nerve blocks include an altered mental status,
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coagulopathy, and the potential to confound diagnoses of painful but life-threatening conditions
such as a compartment syndrome and abdominal peritonitis. Recent findings have tempered the
presumption of pain as a sensitive and predictive marker of compartment syndrome and there is
some evidence to support the use of PNB in patients with risk factors for this condition.(29, 64)
Fascial plane blocks
Fascial plane blocks such as a transversus abdominis plane (TAP) block, erector spinae plane
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(ESP) block and serratus anterior plane (SAP) block have been used as opioid sparing adjuncts in
patients with both surgical incisions and traumatic injuries. Advantages of fascial plane blocks
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include effective pain relief in the dermatomes supplied by the nerves being blocked, the ability
to perform them in patients with mild coagulopathies,(65) and low incidence of drug-mediated
hypotension when compared to neuraxial blocks. TAP blocks have definitively demonstrated an
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opioid-sparing effect in patients undergoing abdominal surgical procedures.(66)
The ESP and SAP blocks have been found to be effective opioid-sparing techniques in patients
undergoing breast surgery, ventral hernia surgery and anterior thoracotomy.(67, 68) Recent
clinical reports regarding the use of ESP blocks for rib fracture related pain suggest that they
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may have less adverse effects compared to thoracic epidural block.(69, 70) ESP blocks have the
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ability to provide analgesia to both the anterior and posterior hemithorax, making them
particularly useful in the management of post-thoracotomy pain or trauma-related thoracic pain

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involving the anterior, lateral, and/or posterior chest wall.(71) ESP blocks may also be able
improve respiratory function in patients with rib fractures by improving their respiratory efforts
as evidenced by a sustained increase in incentive spirometry volumes in a small cohort of trauma
patients.(72) Elastomeric infusion pumps (EIP) with a flow regulator such as the ON-Q pain
relief system (I-Flow LLC/Kimberly Clark, Lake Forest, CA, USA) and Ambu® Action™ Fuser
Pain Pump (Ambuusa, Columbia, MD, USA) provide a continuous infusion of a local anesthetic,
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allowing effective, non-narcotic pain relief for up to five days. These pumps can be connected to
catheters inserted directly into the incisional area or to PNB catheters. EIP catheters placed in the
paravertebral space have been used to create a continuous intercostal nerve block and improve
pulmonary function, pain control, and shorten LOS in patients with rib fractures.(73)
Formulating dedicated pathways and protocols utilizing regional analgesia along with
multimodal analgesia regimen in consultation with the acute pain management service can
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provide satisfactory pain control in patients with traumatic injuries. Bundled rib fracture
management protocols are common and have been associated with decreases in morbidity and
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mortality in high-risk trauma patients.(74, 75) As an example, patients presenting with acute rib
and/or sternal fractures should receive multimodal systemic pain management on admission and
the acute pain management service should be consulted for consideration of neuraxial vs ESP
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catheter placement. Unless contraindicated, patients should continue their home pain
medications and oral gabapentin (dose adjusted for age and renal function when indicated), oral
or IV acetaminophen (except in geriatric patients or those with liver dysfunction), and either IV
ketorolac or IV ibuprofen should be added. In addition, patients should be prescribed enteral or

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intravenous opioids titrated to effect or side effects. We recommend early utilization of regional
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analgesia, especially ESP catheters in these patients to proactively prevent decompensation in
respiratory status.
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Management of opioid tolerant patients with traumatic injuries
The Food and Drug Administration (FDA) defines a patient as opioid tolerant if, for at least one
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.(76) Managing acute pain in opioid-tolerant patients is a
challenge to even practiced clinicians. (77) Patients admitted to the ICU with traumatic injuries
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will have varying degrees of exposure to opioids. Some patients may have a past history of
OUD, others may have a history of OUD with current opioid agonist therapy (OAT) using
methadone or buprenorphine, and others still may be active opioid users. Once these patients
have been identified, they must be closely monitored for inadequate pain control and for early
signs and symptoms of opioid withdrawal (e.g., anxiety, restlessness, lacrimation, rhinorrhea,
mydriasis, piloerection, and elevations in heart rate, blood pressure, and respiratory rate).(78)
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Furthermore, patients with OUD who are in remission and no longer have signs and symptoms of
physical dependence, continue to be susceptible to triggers and are at a high risk for relapse.
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Opioid-tolerant patients who are on OAT therapy should continue their pre-existing opioid
regimen, using supplemental analgesics as necessary for treatment of superimposed acute
pain(79). Maintenance OAT with methadone and buprenorphine does not provide sustained
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analgesia and increasing home regimens to manage acute pain should be discouraged. Short-
acting opioid analgesics should be combined with OAT to achieve adequate pain control in the
setting of traumatic injuries. Analgesic cross-tolerance is a concern and patients receiving OAT
may have higher opioid requirements to achieve adequate pain control. (80, 81)
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Acute pain management in patients on buprenorphine/naloxone combination therapy is

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especially challenging to the medical provider. The dilemma for clinicians is whether the therapy
should be suspended or continued while in the ICU. Should it be suspended, how should acute
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pain be managed? What is the risk of relapse? If it does not have to be stopped, what type of
analgesic regimen will be safe yet effective? Unfortunately, there is scant literature to address
these important questions.(80, 82) Severe acute pain is more difficult to control with opioid
analgesics in patients taking buprenorphine/naloxone, and higher doses are required. We highly
recommend the judicious use of analgesics adjuncts (acetaminophen, NSAIDs,
gabapentin/pregabalin, alpha-2 agonist, low-dose ketamine infusion) in such patients. If
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buprenorphine/naloxone is discontinued to better treat acute pain with other opioids, close
hemodynamic and respiratory monitoring should be considered for at least 72 hours, considering
the high risk of withdrawal, particularly if patients are downgraded to a lesser acuity.(83)
Should the clinician encounter the opioid tolerant patient after traumatic injury, analgesic
management should begin with an estimation of the amount of daily usage of opioids. This can
be done by calculating the 24-hour oral morphine equivalent (OME) doses, which can help
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compare strengths of different opioid regimens and also help calculate equi-analgesic doses for
oral, transdermal, and intravenous (IV) preparations (Table 4). Multimodal analgesic therapy
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involving non-opioid medications (e.g. ketamine, dexmedetomidine, acetaminophen etc.) and
regional analgesia should be judiciously layered to the opioid regimen to reduce the dose of
supplemental opioids.
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Screening, Brief Intervention, and Referral to Treatment (SBIRT), a comprehensive, integrated,
public health approach to the delivery of early intervention and treatment services for persons
with substance abuse disorders as well as those who are at risk of developing these disorders has
been used among trauma patients at reducing alcohol use.(84) A similar model has been
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demonstrated to be successful in patients with opioid use disorder presenting to the emergency
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department (85) and can be expanded to include trauma patients with moderate/severe opioid use
disorder that are admitted to the ICU. Such patients can be identified based on their history,
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positive urine test for opioids and if able to communicate, using a questionnaire. Once identified,
these patients should be managed using multimodal analgesia therapy during their hospital stay
and should be counselled, with the goal of achieving a patient-centered agreement for engaging
in addiction treatment for opioid dependence upon discharge.
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Iatrogenic opioid withdrawal syndrome (IWS)
Critically ill patients with traumatic injuries will often require high dose opioid infusions for a
prolonged period to help with acute pain control and/or as part of their analgosedation regimen.
Abrupt removal of these infusions can precipitate a withdrawal syndrome and makes weaning
from mechanical ventilation challenging. The incidence of IWS amongst mechanically ventilated
trauma patients has been reported to be as high as 32%.(86) An opioid sparing regimen which
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includes non-opioid analgesics and regional techniques can potentially reduce the risk of IWS. In
high-risk patients (e.g., those who have received high dose opioids for greater than five days),
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decreasing the dose of opioids by 5-10% per day or decreasing the infusion rate initially by 20-
40% and then additional reductions of 10% every 12 to 24 hour has been suggested as weaning
protocol.(87, 88) Enteral administration of long-acting opioids such as methadone to prevent

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and/or treat IWS has been found to be safe and efficacious in critically ill pediatric patients.(89)
At least one study in adults has demonstrated methadone’s efficacy in facilitating weaning from
opioid infusions.(90)
Consequences of inadequate pain treatment

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Pain is an adaptive physiological phenomenon critical for the avoidance of further bodily
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damage. However, many patients develop a maladaptive response, resulting in the development
of chronic pain in the absence of the original painful stimulus. This transition is heavily reliant
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on neuronal plasticity in response to the persistent acute pain, is likely initiated by the
sensitization of peripheral nociceptors and results in the development of primary
hyperalgesia.(91) Significant reductions in activities of daily living, work performance, social
engagement and increased subjective feelings of pain have been described by patients after
intensive care treatment.(92) This has led to the recognition of chronic intensive care-related pain
syndrome (CIRP) as a potential source of long-term disability. CIRP has been defined as
19

persistent pain at least six months after ICU admission, lasting for at least 3-6 months and not
present prior to ICU admission.(93) CIRP appears to be strongly related to length of ICU stay
and length of mechanical ventilation, both markers of disease severity in critical illness.
Uncontrolled pain, pain of high intensity, and pain of longer duration can lead to acute pain
transitioning to chronic pain(94), thus making appropriate management of pain in the ICU
essential. In addition, somatization of previous painful experiences may result in debilitating
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psychiatric conditions. Association of inadequate pain control with post-traumatic stress disorder
(PTSD) has been reported in injured soldiers as well as patients with traumatic injuries. (95, 96)
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In a nationwide study looking at post-traumatic stress amongst patients hospitalized with
physical injury, pain at three months’ post injury was associated with significantly increased risk
of symptoms consistent with PTSD.(97) At this time, it is unclear whether better pain control or
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choice of analgesia will reduce the incidence of PTSD, although adequate pain control has been
found to be an effective secondary prevention strategy for PTSD in certain patient
populations.(98) Similarly, the use of ketamine in burn patients during the perioperative period
was associated with a reduction in PTSD symptoms.(99)

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Conclusion
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Opioid-related harm has now reached epidemic levels and has led to substantial increases in
morbidity and mortality. As increasing numbers of patients with opioid use disorder are admitted
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to ICUs with traumatic injuries, intensivists will be required to devise increasingly complex pain
management regimens. The onus will be on the critical care community to adopt a pragmatic
approach when providing analgesia to these patients. Balancing adequate pain management with
risks of hemodynamic, respiratory, and pharmacological misadventure in critically ill trauma
patients is a task that requires a significant devotion to detail. In addition, mitigating the effects
of inadequate analgesia and withdrawal must be addressed with each patient. At this time, opioid
20

analgesics remain the frontline drugs to treat acute post-surgical and post-trauma pain. Based on
promising clinical findings, the incorporation of non-opioid analgesic adjuncts and appropriate
use of regional analgesia can both reduce opioid consumption and improve the quality of
analgesia. Effective and timely treatment of acute pain will likely decrease the incidence of CIRP
and reduce PTSD in patients sustaining major traumatic injuries. Reductions in opioid use will
have favorable downstream effects on chronic opioid use disorders. As the primary physicians
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caring for patients with traumatic injuries, traumatologists will be tasked with minimizing these
long-term risks by devising thoughtful analgesic regimens that minimize opioids and maximize
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alternative strategies for analgesia. Furthermore, there is a paucity of high-quality data evaluating
alternative non-opioid analgesic treatments in trauma patients. Well-designed prospective
clinical trials evaluating their efficacy are urgently needed. In summary, we recommend the
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judicious use of non-opioid analgesics, regional anesthesia, and other opioid-sparing modalities
to improve management of pain in critically ill trauma patients.

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21

Acknowledgements
We would like to acknowledge Dr. Steven E. Ross MD, FACS, FCCM for reviewing and
assisting with the writing of the manuscript.
Author contributions
KK, MLD, JCK, ZJC: literature search, writing and editing the manuscript; AB, SRA: editing the
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manuscript
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Conflicts of interest: None
Sources of funding: None

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22

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TE
99. McGhee LL, Maani CV, Garza TH, Gaylord KM, Black IH. The correlation between
ketamine and posttraumatic stress disorder in burned service members. J Trauma. 2008;64(2
Suppl):S195-8; Discussion S7-8.

EP
C
C
A
34

Figure legends
Figure 1: Consequences of inadequate pain control
D
TE
EP
C
C
A
35

Figure 1
D
TE
EP
C
C
A
36

Table 1. Precipitants of pain in the ICU
Type Examples
Constant background pain Postoperative: surgical incision, surgical

(usually requires infusion of opioids) drains, chest tubes
Pre-existing: exacerbation of chronic pain,
arthritic pain
D
Neurological conditions: phantom limb pain,
spinal cord injuries, demyelinating
neuropathy-related pain, multiple sclerosis
Trauma: amputations, fractures, soft tissue
TE
injuries, burns, pressure ulcers
Intermittent/peri-procedural pain Invasive procedures: central/arterial line

(usually requires boluses of opioids) placement, endotracheal tubes, nasogastric
tubes, chest tubes, urinary catheters
Routine care: position change,
EP
physiotherapy, tracheal suctioning,
mobilization, wound/burn dressing changes
C
C
A
37

Table 2. ICU related factors affecting the pharmacologic properties of drugs
i. Pathological Condition ii. Adverse Consequences
iii. Ileus iv. Unpredictable absorption of orally administered drugs.

v. Deranged acid–base balance
vi. Increase in free drug fractions (e.g. hypoalbuminemia, liver
D
failure, fluid overload) affects the ionized and bound fractions
of drugs.
TE
vii. Altered splanchnic bloodviii.
flow Reduces liver-dependent metabolism (i.e. in patients with
shock, on vasopressors and inotropes, or both).
ix. Drug induced worsening ofx. Hepatic and renal dysfunction reduces the metabolism and
organ dysfunction excretion of drugs and their active metabolites.
xi. Drug interactions xii. Effects on both metabolism and effectiveness of concurrently
EP
administered drugs.
C
C
A
38

Table 3. Commonly used opioids in the ICU
Opioid Onset Half- Context Active Important
of life sensitive metabolites considerations
action half-life
Fentanyl 1-2 min 2-4 h 200 min (6 hr None Accumulation in liver
infusion); impairment
D
300
min (12 hr
infusion)
TE
Morphine 5-10 3-4 h N/A Yes, M6G & M6G more potent,
min M3G accumulates in renal
impairment. M3G-
delirium
Hydromorphone 5-15 2-3 h N/A None Caution in liver

EP
min impairment
Remifentanil 1-3 min 3-10 3-4 min None Non-renal/hepatic
min metabolism
M6G, Morphine-6-Glucoronide; M3G, Morphine-3-Glucoronide

C
C
A
39

Table 4. Calculating oral morphine equivalent (OME)* doses
OPIOID CONVERSION FACTOR

(mg/day except as noted)
D
Codeine 0.15
Fentanyl transdermal (mcg/hr) 2.4
TE
Hydrocodone 1
Hydromorphone 4
Methadone
1-20 mg/day 4
EP
21-40 mg/day 8
41-60 mg/day 10
 61-80 mg/day 12
Morphine 1
C
Oxycodone 1.5
Oxymorphone 3
C
* Oral to IV Morphine conversion is 3:1 (oral:IV); Source: cdc.gov

A
40
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Pain Management in Trauma Patients Affected by The Opioid Epidemic: A

Article in Journal of Trauma and Acute Care Surgery · April 2019

John Klick Melissa Linskey

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Anthony Bonavia Zyad Carr

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Pain Management in Trauma Patients Affected by The Opioid Epidemic: A

Medical Center, Hershey, PA, USA.

John C. Klick: jklick@pennstatehealth.psu.edu

Melissa Linskey Dougherty: mlinskey@pennstatehealth.psu.edu

Anthony Bonavia: abonavia@pennstatehealth.psu.edu

Steven R. Allen: sallen4@pennstatehealth.psu.edu

Zyad J. Carr: zcarr@pennstatehealth.psu.edu

Kunal Karamchandani, MD, FCCP

Department of Anesthesiology & Perioperative Medicine, H187

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500 University Dr., Hershey, PA, USA 17033

Financial Disclosure: None

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likelihood of hospital admissions as a result of traumatic injuries. Furthermore, patients admitted

Study type: Narrative review

Level of evidence: Moderate to High

Keywords: Pain management, Opioid epidemic, Multimodal analgesia, Critical illness

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

public health consequences of inappropriate emphasis on opioid-centric pain management is

and, of those patients, an estimated 4% to 6% transition to heroin abuse.(4) As the incidence of

Pre-injury opioid use

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observed in patients with pre-injury use of controlled substances including opiates.(10)

can lead to significant neurological and psychiatric consequences. Physiologically, inadequate

intrinsically linked to deleterious psychiatric and neurological outcomes culminating in severe,

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

emphasized. Despite evidence highlighting the detrimental effects of uncontrolled pain,

post-ICU opioid dependence may all play a role.(20)

time to determine the adequacy of therapeutic interventions to treat pain. To maintain

possible and physiological indicators of pain are nonspecific. Pain-related physiological

derangement can be masked by sepsis, inotrope/vasopressor therapy, arrhythmias, and

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

be used to broadly determine the presence or absence of pain.(25)

the development of paradoxical hypersensitivity, or opioid-induced hyperalgesia (OIH), a

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

potential to prevent OIH.(27, 28) We discuss these interventions in detail below.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

administration in patients with traumatic injuries.

hypnotics, a regimen based on continuous fentanyl infusion should be considered for

equivalent unit calculations. Intravenous intermittent dosed hydromorphone is a useful adjunct to

patient-controlled analgesia using hydromorphone or morphine can be a viable alternative in

patients that are awake and alert.

include acetaminophen, ketorolac, ibuprofen, gabapentinoids, ketamine, alpha -2 agonists

(clonidine and dexmedetomidine) and lidocaine.

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prostaglandins and thromboxane and consequently reducing inflammation-mediated pain, in

addition to their anti-pyretic properties. Traditional non-selective NSAIDs (ibuprofen, ketolorac)

decreased incidence of pneumonia, and increased ventilator-and ICU-free days.(39) Furthermore,

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traumatic rib fractures unless contraindicated.

The anticonvulsants gabapentin and pregabalin are structural analogs of gamma-amino-butyric

prevent the transformation of acute pain to chronic pain. Disadvantages to gabapentinoids

an extensive list of adverse effects including somnolence, dizziness, visual disturbances,

Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has demonstrated efficacy as both