Pain and Sedation

1. Pain and Sedation in
Critically Ill Patients
Allison N. Boyd, PharmD, BCCCP
Clinical Pharmacist Specialist – Trauma/Burn
Cell: 401.500.9663 | Office: 401.444.3295
aboyd1@lifespan.org

2. Pain, Agitation, and Delirium
Agitation
Delirium
Pain

3. Pain Management in Critically Ill
Patients

4. Pain Assessment Tools
• Numeric Rating Scale: preferred for adults who can communicate
reliably
• Critical-Care Pain Observation Tool (CPOT): preferred for critically
ill adults unable to self-report pain and in whom behaviors are
observable
Score > 2 indicates
unacceptable level of
pain present
Devlin J, et al. Crit Care Med 2018.

5. Non-Pharmacologic Pain Management
Strategies
• Massage therapy
• Massage for postoperative ICU pain management in cardiac and
abdominal surgery patients showed a reduction in pain intensity scores
(low-quality evidence)
• Music therapy
• Music therapy reduced pain intensity in cardiac surgery patients (low-
quality evidence)
• Cold therapy
• Suggest offering cold therapy for procedural pain management
(conditional recommendation)
• Relaxation techniques
• Suggest offering relaxation techniques for procedural pain management
(conditional recommendation)
Devlin J, et al. Crit Care Med 2018.

6. Acetaminophen
• Mechanism of Action: analgesic effects thought to be due to activation of
descending serotonergic inhibitory pathways in the CNS
• Memis D, et al compared APAP 1 g IV Q6H + IV meperidine vs. placebo + IV
meperidine in 40 postsurgical ICU patients
• BPS and VAS were significantly lower in APAP group at 24 hours (p < 0.05)
• APAP group had lower postoperative meperidine consumption [76.5 (18.2) mg vs. 198
(66.4) mg]
• APAP group had shorter time to extubation [64.3 (40.6) min vs. 204.5 (113) min]
• IV vs. PO?
IV PO
Onset 5-10 min < 1 hr
Duration 4-6 hr 4-6 hr
Absorption N/A Primarily absorbed in small intestine
Devlin J, et al. Crit Care Med 2018.

7. Ketamine
• Mechanism of Action: noncompetitive NMDA receptor antagonist that
blocks glutamate. Subanesthetic doses produce analgesia and modulate
central sensitization, hyperalgesia, and opioid tolerance.
Devlin J, et al. Crit Care Med 2018.
Nicolas G, et al. Anesth Analg 2003 Sep;97(30):843-7.
Objective • To determine whether the addition of small-dose ketamine could reduce
the consumption of morphine and create fewer ADEs in SICU patients
after major abdominal surgery
Methods • RCT including 93 total patients for analysis
• Morphine PCA + placebo (n = 52) vs. morphine PCA + ketamine (n = 41)
• Ketamine dosing: 0.5 mg/kg bolus followed by 2 mcg/kg/min x 24 hrs,
then 1 mcg/kg/min x 24 hrs
Results • Cumulative consumption of morphine was significantly smaller in
ketamine group [80 (37) mg vs. 58 (35) mg; p < 0.05]
Conclusion • Small doses of ketamine were a valuable adjunct to opioids in SICU
patients after major abdominal surgery

8. Ketamine Regulations at RIH
• Ketamine may be administered in the ICU by an RN only when a
provider is present
• Ketamine infusions may be administered in the ICU only when
the patient is on a ventilator
• Ketamine for procedural sedation may be administered in the
ICU by an RN following the procedural sedation policy
• NOTE: when giving IVP (e.g. dressing changes), recommend giving
midazolam IV 2 mg immediately prior to ketamine 0.5 mg/kg IV. May
repeat midazolam + ketamine 15-20 minutes after initial dose once if
needed (max dose 1 mg/kg)

9. Neuropathic Pain Medications
• Gabapentin, carbamazepine, pregabalin
• Mechanism of Action: all work to reduce excitatory neurotransmitters
which participate in nociception
• Some data suggests that gabapentin is superior to other agents
(e.g. carbamazepine)
• May reduce opioid consumption in setting of neuropathic pain
• All agents are renally cleared and require dose adjustments in
renal dysfunction
Devlin J, et al. Crit Care Med 2018.

10. Lidocaine
• Mechanism of Action: Class Ib antiarrhythmic; blocks both the initiation and
conduction of nerve impulses by decreasing the neuronal membrane’s
permeability to sodium ions
Devlin J, et al. Crit Care Med 2018.
Insler SR, et al. J Cardiothorac Vasc Anesth 1995 Oct;9(5):541-6.
Objective • To evaluate whether a continuous low-dose lidocaine infusion reduces
postoperative pain and anxiety in patients undergoing CABG and to
retrospectively examine time to extubation and ICU and hospital LOS
Methods • Double-blinded, randomized study of 100 patients
• Lidocaine infusion vs. placebo
• Fentanyl/midazolam infusions discontinued post-op, supplemental doses allowed
Results • Mean total doses of fentanyl were not different between groups [620.4 (815.74)
mcg vs. 689.16 (692.99) mcg; p = 0.564]
• No differences in time to extubation, ICU LOS, or hospital LOS
Conclusion • Continuous infusion of low-dose lidocaine did not significantly decrease
supplemental fentanyl, midazolam, or propranolol requirements
• Lidocaine infusion does not result in a reduced time to extubation, ICU LOS, or
hospital LOS

11. Lidocaine – Additional Considerations
• Adverse effects:
• Widely variable volume of distribution (0.7 to 2.7 L/kg) and half-life (30 min
to 2 hours) that are affected by certain disease states (e.g. CHF, liver disease,
shock, severe renal disease)
• Highly protein bound
• Undergoes primarily hepatic metabolism and contains active metabolites
that can accumulate and cause CNS toxicity
• Requires therapeutic drug monitoring
•Bradycardia
•Bronchospasm
•Cardiac arrhythmia
•Confusion
•Drowsiness
•Edema
•Hallucination
•Heart block
•Hypotension
•Seizure
Devlin J, et al. Crit Care Med 2018.

12. Non-Steroidal Anti-Inflammatory Drugs:
Ketorolac
• Mechanism of Action: Reversibly binds to COX-1 and COX-2
enzymes which results in decreased formation of prostaglandin
precursors
• Safety considerations:
• Used for a MAXIMUM of 5 days – longer use is contraindicated
• Black Box Warnings:
• Serious cardiovascular thrombotic events
• Serious GI bleeding
• Hypersensitivity
• Renal risk
• Risk of bleeding
• Concomitant use with other NSAIDs
• Special populations (elderly, low body weight, moderate renal impairment)
Devlin J, et al. Crit Care Med 2018.

13. Non-Steroidal Anti-Inflammatory Drugs:
Ketorolac
Which dose is best?
Motov S, et al. Ann Emerg Med 2017 Aug;70(2):177-84.
Reuben SS, et al. Anesth Analg 1998 Jul;87(1)98-102.
Reuben SS, et al.
(N = 70)
Motov S, et al.
(N = 240)
Intervention Ketorolac 5, 7.5, 10, 12.5, 15, or 30 mg vs.
placebo given to spinal stabilization surgery
patients with morphine PCA
Ketorolac IV 10, 15, or 30 mg
given to ED patients
Pain scores • Significantly higher in control group and
5 mg group
• No differences in other groups
Similar between groups
Rescue Analgesia • TDD of morphine was higher in patients
received no ketorolac or 5 mg ketorolac
• Similar morphine consumption in all
groups receiving > 10 mg
Similar between groups
Adverse effects Patients more sedated in control group; no
differences in other groups
Similar between groups

14. Non-Opioid Analgesics
Generic (Trade) Dose Onset Duration Clinical Pearls
Acetaminophen
PO: 650-975 mg Q6-8 hr
PR: 650 mg Q4-6 hr
IV: 1000 mg Q6-8 hr
PO/PR: < 1 hr
IV: 5-10 min
PO/PR: 4-6 hr
IV: 4-6 hr
Max of 4 g/day unless elderly or hepatic impairment
(then use max 3 g/day)
Gabapentin
(Neurontin®)
PO: 100-300 mg Q8-24 hr 2-4 hr 5-7 hr
Max dose 1200 mg TID
Requires renal dose adjustments
Can be sedating/cause dizziness
Decreased bioavailability with increasing doses
Ibuprofen PO: 200-800 mg Q6-8 hr 30-60 min 6-8 hr
Max dose 3200 mg/day
Can cause interstitial nephritis, GI bleeding
Ketamine
(Ketalar®)
IV: 0.5 mg/kg
CI: 1-2 mcg/kg/min
Within 30 min Up to 60 min
May repeat dose 10-15 min after initial dose
Give bolus doses with benzodiazepine to minimize
emergence phenomenon
IV infusions for intubated patients only at RIH
Ketorolac
(Toradol®)
IV: 15 mg Q6 hr 30 min 4-6 hr
MAX duration 5 days (longer use contraindicated)
Increased risk of GI bleeds
Contraindicated in advanced renal impairment,
concomitant use of other NSAIDs

15. Opioid Analgesics
Generic (Trade) Dose Onset Duration
Hemodynamic
Effect
Clinical Pearls
Fentanyl
IV: 25-100 mcg Q1-2 hr
CI: 25-200 mcg/hr
30 sec 30-60 min
Relatively neutral,
some bradycardia
Preferred agent for CI
No active metabolites
Can cause chest wall rigidity with
prolonged duration
Hydromorphone
(Dilaudid®)
PO: 2-4 mg Q4-6 hr
IV: 0.5-2 mg Q3-6 hr
CI: 0.5-1 mg/hr
PO: 15-30 min
IV: 5 min
PO: 3-5 hrs
IV: 3-5 hrs
Neutral
Better PRN than fentanyl; longer
acting
Morphine
PO: 15-30 mg Q4 hr
(Q8-12 hr for SR)
IV: 2-5 mg Q3-5 hr
CI: 5-15 mg/hr
PO: 30 min
IV: 5-10 min
PO: 3-4 hr
IV: 3-4 hr
Circulatory
depression
Active metabolite (renally excreted)
Histamine release can cause
itching/hypotension
Oxycodone
(Oxycontin®)
PO: 5-15 mg Q4-6 hr 15-30 min 4-6 hr Neutral
Preferred use as PRN when on
scheduled APAP
Oxycodone/APAP
(Percocet®)
PO: 1-2 tab (5/325 mg) Q4-6 hr 15-30 min 4-6 hr Neutral
Preferred at discharge so patient
receives APAP
Hydrocodone/APAP
(Lortab®)
PO: 1-2 tab (5/325 mg) Q4-6 hr 60 min 4-6 hr Neutral
Preferred at discharge so patient
receives APAP

16. Opioid Conversion and Potency
Opioid IV Oral
Codeine 120 mg 200 mg
Fentanyl 0.1 mg (100 mcg) N/A
Hydrocodone N/A 30 mg
Hydromorphone 1.5 mg 7.5 mg
Methadone Contact Pharmacy
Morphine 10 mg 30 mg
Oxycodone N/A 20 mg
 Tolerance to one opioid does not mean tolerance to all opioids
 When converting from one to another, decrease dose ~25-50%
 Always have PRN agent available when titrating to account for difference in doses

17. Outpatient Prescribing Rules and
Regulations
• Patients may be prescribed 30 MME for acute pain upon discharge
• Equivalent to oxycodone 5 mg po #20 tablets
• If a patient needs additional opioid medication once initial prescription has
run out, the patient does not need to be seen again – an electronic
prescription may be sent if the provider thinks it is appropriate
• If a patient is going to a SNF or acute rehab, the patient would be able to
continue to taper off current dosing as appropriate and not necessarily be
required to jump down to 30 MME

18. Key Takeaways
• Multimodal pain management is key to optimizing
care
• Evaluate patient-specific risk factors prior to initiating
any medication for pain
• Opioids still have a place in therapy, but we must
ensure we are being good stewards of these
medications

19. Managing Sedation and Agitation
in Critically Ill Patients

20. Richmond Agitation and Sedation Scale
Score Term Description
+4 Combative Overtly combative, violent, immediate danger to self
+3 Very agitated Pulls or removes tube(s) or catheter(s); aggressive
+2 Agitated Frequent non-purposeful movement, fights ventilator
+1 Restless Anxious but movements not aggressive or vigorous
0 Alert and Calm
-1 Drowsy Not fully alert, but has sustained awakening (eye-
opening/eye contact) to voice (≥ 10 seconds)
-2 Light sedation Briefly awakens with eye contact to voice (< 10 seconds)
-3 Moderate sedation Movement or eye opening to voice (but no eye contact)
-4 Deep sedation No response to voice, but movement or eye opening to
physical stimulation
-5 Unarousable No response to voice or physical stimulation
Devlin J, et al. Crit Care Med 2018.

21. Target Level of Sedation
• Light sedation preferred to deep sedation in critically ill,
mechanically ventilated adults
• The 2013 PAD guidelines defined ‘light sedation’ as RASS scale
score > -2 and eye opening of at least 10 seconds
• 2018 PADIS update: this level of sedation is probably deeper than required
for management of mechanically ventilated adults in an ICU
• Exceptions:
• ARDS/invasive ventilation mode
• Chemically paralyzed patients (goal RASS -5)
• Elevated ICP
Devlin J, et al. Crit Care Med 2018.

22. Wake Up and Breathe
• Spontaneous Awakening/Spontaneous Breathing Trial
• Should occur every morning if no exclusion criteria met
• Spontaneous Awakening Trial Protocol (SAT)
• Sedative is held if RASS score is -5 to -2 while analgesic is
continued
• If RASS -5 to -2 despite stopping sedative, opioid infusion rate
is decreased by 50% (if applicable)
• Sedation should continue to be held if patient remains in RASS
goal
• If patient becomes agitated (RASS score above goal), sedation
is restarted at 50% previous rate

23. Choice of Sedative Agent
• Propofol and dexmedetomidine are preferred over benzodiazepines due to
improved outcomes such as ICU LOS, duration of mechanical ventilation, and
decreased rates of delirium
• Risks and benefits of intermittent benzodiazepines is unclear, general practice
at this time is to avoid if possible due to risks known to be associated with
continuous infusions
• When utilizing a neuromuscular blocking agent: dexmedetomidine not
appropriate as a sedative agent
• Bispectral index (BIS) monitoring is utilized at some institutions
• At RIH, it is imperative to initiate sedative agents prior to neuromuscular blocking agent to
ensure adequate sedation (RASS -5) prior to paralyzing the patient
• RASS cannot be utilized to assess sedation once patient is paralyzed
Devlin J, et al. Crit Care Med 2018.

24. Propofol
• Mechanism of action: GABA agonist
• Possesses sedative, anxiolytic, and anticonvulsant properties
• Sedative of choice in patients with traumatic brain injury due to
ICP-lowering benefits and anti-inflammatory and anti-oxidant
properties
• Limiting factor is often hypotension and/or bradycardia
• Not renally cleared, very quick acting
• Provides 1.1 kcal/mL

25. Propofol Related Infusion Syndrome (PRIS)
• Commonly presents as otherwise unexplained metabolic
acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury,
hypertriglyceridemia/lipemia, elevated liver enzymes, and
cardiac dysfunction
• Caused by impairment of mitochondrial beta-oxidation of fatty
acids, disruption of the electron transport chain, and blockage of
beta-adrenoreceptors and cardiac calcium channels
• Can occur as a result of higher doses or prolonged infusions
• High-dose propofol (65-83 mcg/kg/min) for > 48 hours
• Monitoring: check triglycerides and lipase every 3-4 days
Fong JJ, et al. Crit Care Med 2008;36(8):2281-7.

26. Dexmedetomidine
• Mechanism of action: selective alpha-2 agonist (ratio of alpha-
2:alpha-1 receptor binding is 1620:1)
• Has been shown to decrease rates of delirium when compared to
benzodiazepines and has opioid sparing and anxiolytic properties
• Lighter level of sedation when compared to propofol and
midazolam; does not cause respiratory depression
• Limiting factor is often bradycardia and/or hypotension
Devlin J, et al. Crit Care Med 2018.

27. Clonidine?
• Mechanism of action: stimulates alpha-2 adrenoreceptors in the
brain stem resulting in reduced sympathetic outflow from the
CNS (ratio of alpha-2:alpha-1 receptor binding ratio is 220:1)
• Enteral/PO clonidine has a bioavailability of 75-88%
• Gagnon DJ, et al. evaluated transitioning dexmedetomidine to
clonidine in 20 ICU patients
• 75% of patients were successfully transitioned within 48 hours
• Clonidine doses ranged from 0.2-0.5 mg Q6H
• No differences in efficacy data (CPOT, NRS, SAS, CAM-ICU) during
dexmedetomidine and clonidine maintenance phases
• No differences in safety outcomes
Gagnon DJ, et al. Pharmacotherapy 2015 Mar;35(3):251-9.

28. Benzodiazepines
• Associated with increased rates of delirium, longer duration of
mechanical ventilation, and increased ICU length of stay
• Place in therapy: the hemodynamically unstable patient
• Continuous infusion at RIH: midazolam (Versed®)
• Pharmacokinetics become unpredictable at 48-72 hours due to high
lipophilicity
• Contains an active metabolite that is renally excreted – will accumulate
in renal failure
• Use the lowest effective dose for the shortest duration possible
Devlin J, et al. Crit Care Med 2018.

29. Commonly Used Sedative Agents
Generic (Trade) Dose Onset Duration
Hemodynamic
Effect
Clinical Pearls
Propofol
(Diprivan®)†
CI: 5-80 mcg/kg/min 30 sec 3-10 min
Bradycardia
Hypotension
Provides 1.1 kcal/mL
Doses > 80 mcg/kg/min associated
with PRIS
Dexmedetomidine
(Precedex®)†
CI: 0.3-1.5 mcg/kg/hr 5-10 min 60-120 min
Bradycardia
Hypotension
Rebound HTN
Lighter level of sedation
Opioid-sparing
Expensive (10x cost of propofol)
No respiratory depression
Lorazepam
(Ativan®)
PO: 2-4 mg Q4-6 hrs
IV: 2-4 mg Q2-6 hrs
PO: 30-60 min
IV: 5-20 min
6-8 hrs
Some
hypotension
No active metabolite
Midazolam
(Versed®)
IV: 2-5 mg Q1-2 hrs
CI: 2-10 mg/hr
3-5 min 1.5-3 hrs
Some
hypotension
Active metabolite
Highly lipophilic – PK/PD become
unpredictable after 48-72 hours
†Preferred sedatives

30. Antipsychotics
• Not recommended for the prevention of delirium
• Not recommended for routine treatment of delirium
• Patients who experience significant distress secondary to symptoms of
delirium such as anxiety, fearfulness, hallucinations, delusions, or who
are agitated and may be physically harmful to themselves or others may
benefit
Devlin J, et al. Crit Care Med 2018.
Medication
EPS/Tardive
dyskinesia
QTc
prolongation
Sedation Hypotension
Anticholinergic
side effects
Haloperidol +++ + ++ 0 0
Olanzapine 0 0 + + ++
Quetiapine 0 0 ++ ++ ++
Ziprasidone 0 ++ 0 0 0

31. Commonly Used Antipsychotics
Generic (Trade) Usual Dose Onset Half-Life Clinical Pearls
Haloperidol
(Haldol®)
IM/IV/PO:
2.5-5 mg Q6 hr
PO: 2-5 hrs
IM/IV: 20 min
PO: 14-37 hrs
IM/IV: 20 hrs
Can cause QTc prolongation and extrapyramidal
symptoms
Do NOT administer to patients with a diagnosis
of Parkinson’s Disease
Quetiapine
(Seroquel®)
PO: 25-200 mg
Q8-12 hr
1.5 hrs
6 hrs (parent)
12 hrs
(metabolite)
Can cause QTc prolongation
Max dose studied for delirium is 400 mg/day;
doses up to 800 mg/day are used for other
indications
Becomes more antihistaminergic at higher doses
Olanzapine
(Zyprexa®)
PO/IM/IV:
5-10 mg Q24 hr
IM/IV: 30 min
PO: 6 hrs
PO/IM/IV: 30
hrs
Can cause QTc prolongation
Half-life 1.5 longer in elderly patients
Max dose studied for delirium is 10 mg/day,
doses up to 20 mg/day are used for other
indications
Ziprasidone
(Geodon®)
PO: 20-40 mg
Q12 hr
IM: 10-20 mg
Q12 hr
PO: 6-8 hrs
IM: < 1 hr
PO: 7 hrs
IM: 2-5 hrs
Can cause QTc prolongation
PO formulation requires taking with a high
calorie meal (>500 cal) for adequate absorption
Maximum IM dose = 40 mg/day

32. Key Takeaways
• Using the lightest level of sedation possible while still keeping
the patient comfortable has been associated with the best
outcomes
• Benzodiazepines should be avoided if possible but may be
necessary in the hemodynamically unstable patient
• Antipsychotics may be used for the agitated patient who is
experiencing delirium

33. Pain and Sedation in
Critically Ill Patients
Allison N. Boyd, PharmD, BCCCP
Clinical Pharmacist Specialist – Trauma/Burn
Cell: 401.500.9663 | Office: 401.444.3295
aboyd1@lifespan.org