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Opioid Sparing
Techniques
in the Critically Ill
March 8th 2017
Andrea Sikora Newsome, PharmD, BCPS, BCCCP
CTICU/SICU Critical Care Pharmacy Clinical Specialist
Augusta University Medical Center
Image Credit: http://www.hookedsober.com/wp-content/uploads/2015/10/fed-up-opioid-epidemic.jpg
Disclosures
• I have nothing to disclose concerning possible financial or
personal relationships with commercial entities or their
competitors mentioned in this presentation
• This presentation will include mention of off-label uses of
medications
Learning Objectives
1. Review the state and causes of the opiate epidemic
2. Apply pharmacokinetic knowledge to optimize opiate
regimens in patient cases
3. Discuss opiate sparing techniques and modalities
Presentation Outline
Epidemiology
CDC
Guideline for
Outpatient
Therapy
Principles of
ICU
Management
Opioid
Sparing
Techniques
Patient Cases
No drug is benign.
Risk vs. Benefit Evaluation
Opioid Dependence
Opioid-Related
Overdoses, Side
Effects
Effective Pain
Management
• $55 billion in health and social costs
associated with opioid abuse
• $20 billion in hospital care for opioid
poisonings
• 2.4 million Americans have severe
opioid-use disorder (OUD)
• On a given day,
– 650,000 opioid prescriptions
dispensed
– 3,900 initiate non-medical use of
prescription opioids
– 78 people die from opioid-related
overdose
CDC. http://www.hhs.gov/sites/default/files/Factsheet-opioids-061516.pdf (accessed January 2016).
Volkow et al. N Engl J Med 370; 22. 2014.
Opioid Epidemic
Increased illicitly
produced fentanyl
Increased use and
overdose from heroin
Increased epidemic of
addiction, overdose,
and death
Increased opioid
prescriptions
Frieden TR and Houry D. N Engl J Med. 2016 Apr 21;374(16):1501-4.
CDC Guidelines
Image Credit: http://www.hookedsober.com/breaking-news/fed-up-opioid-epidemic/
Non-opioid therapy is preferred for chronic
pain outside of end-of-life care
When opioids are used, the lowest
possible effective dose should be used
Clinicians should exercise caution when
prescribing opioids
Dowell D et al. CDC Guideline for Prescribing Opioids for Chronic Pain-United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49.
Efficacy of Opioids for Chronic Pain
• Most RCT of opioids have lasted ≤ 6 weeks
– No study has evaluated pain, function, or quality of life of opioid therapy with other
treatments for > 1 year
• Trials that last > 6 weeks have consistently poor results
– Suggest that long-term opioids may even potentiate pain
• 3-year prospective observational trial of 69,000 postmenopausal women with recurrent pain conditions. Patients on
opioid therapy were:
– Less likely to have improvement in pain (OR 0.42; 95% CI 0.36 – 0.49)
– More likely to have worsened functional outcomes (OR 1.2; 95% CI 1.04 – 0.51)
Frieden and Houry. N Engl J Med. 2016 Apr 21;374(16):1501-4.
Opiate Induced Hyperalgesia
Paradoxical response wherein nociception is sensitized by exposure to opioids
“When dependence on opioids finally becomes an illness of itself, opposite
effects like restlessness, sleep disturbance, hyperesthesia, neuralgia, and
irritability become manifest.” – Rossbach, 1880
Central Glutaminergic System
Spinal Dysnorphins
Descending Facilitation
Genetic Mechanisms
Decreased Reuptake/Enhanced Nociceptive Response
2013 PAD Guidelines
• ICU patients routinely experience pain, both at rest and with routine care
• Objective pain scales are recommended for monitoring
– Vital signs should not be used alone for assessment of pain
• Pre-emptive analgesia is recommended prior to painful procedures
• Intravenous opioids are first-line drugs to treat pain in critically ill patients
• Analgosedation: Analgesia-based or analgesia-first sedation is recommended
Barr J et al. Crit Care Med. 2013 Jan;41(1):263-306.
Causes of Pain, Agitation, and Delirium
Reade et al. N Engl J Med 2014;370:444-54.
Intravenous Opioids
Medication
Equivalence
Duration
Bolus
Infusion
Comments
Morphine
10 mg
4 hours
4 – 6 mg IV q4h
(0.05mg/kg)
•
•
•
•
Initial: 1mg/hr
Typical: 1 - 5
mg/hr
No maximum
•
•
•
Fentanyl
0.1 mg (100mcg)
2 hours
50 – 100 mcg IV
q1h
(1-4 mcg/kg)
•
•
Hydromorphone
2mg
4 hours
0.2 – 1 mg IV q4h
•
•
•
Initial: 0.5 –
1mcg/kg/hr (50 –
150mcg/hr)
Typical: 50 –
300mcg/hr
•
Initial: 0.2 –
0.5mg/hr
Typical: 0.2 – 1
mg/hr
No maximum
•
•
•
•
•
•
•
DOC for pain
management
Longer-half
Histamine
Release
Active
metabolites
Accumulates in
adipose tissue
Tachyphylaxis
Not as sedating
Less hypotension
Opioid tolerant
Less hypotension
No active
metabolites
Intermittent
dosing
Oral Opioids
Medication
Equivalence
Duration
Comments
Morphine
7.5 mg
(IV:PO 1:3)
4 hours
•
•
•
•
DOC for pain management
Longer-half as intermittent
Histamine Release
Active metabolites
Oxycodone
5 mg
4-6 hours
•
No active metabolites
Hydromorphone
1 mg
(IV:PO 1:5)
4-6 hours
•
•
•
•
Opioid tolerant
Less hypotension
No active metabolites
Intermittent dosing
Methadone
Variable
24-48 hours (5 days to
achieve steady state)
•
•
Unpredictable dose response
Useful in patients with high
opioid requirements use
Monitor QTc
•
Bowel Regimen
• Estimates up to 83% of critically ill patients have constipation
• Consider empiric bowel regimen in patients receiving opioids and
critically ill patients
Mush
(Docusate)
Push
(Senna,
Miralax)
Bowel
Regimen
van der Spoel J et al. Crit Care Med. 2007 Dec;35(12):2726-31.
Opioid Sparing
Techniques in the ICU
Image Credit: http://www.art.com/products/p15063244409-sa-i6844200/peter-steiner-we-can-give-you-enough-medication-to-alleviate-the-pain-but-not-enough-t-new-yorker-cartoon.htm
American Society of Anesthesiologists Task Force on Acute Pain Management: ANESTHESIOLOGY 2004; 100:1573– 81.
Opioid Sparing Techniques
Acetaminophen
Ketamine
NSAIDs
Gabapentin
Clonidine
Dexmedetomidine
Non-pharmacologic
Techniques
Local
anesthetics
Carroll IR. Reg Anesth Pain Med. 2004 Nov-Dec;29(6):576-91.
Acetaminophen
• MOA: centrally acting analgesic and anti-pyretic
– No anti-inflammatory activity
• Dosing
– Maximum: 4gm/day
– Over the counter maximum: 3gm/day
– Elderly: 2gm/day
• Cochrane review of oral acetaminophen for
postoperative pain found a NNT = 3.5 (2.7 – 4.8) to
reduce pain by 50% of acetaminophen 500mg vs.
placebo
Image Credit: https://www.propublica.org/images/ngen/gypsy_big_image/20150715-tylenol-canada-630x420.jpg
Toms et al. Cochrane Database Syst Rev.(4): CD004602.
Acetaminophen
• Systematic review identified that combinations of acetaminophen and
other NSAIDs increased overall efficacy
• A trial evaluating acetaminophen, NSAIDs, and COX-2 inhibitors found
reductions in morphine but no differences among agents
• No RCTs have evaluated IV vs. PO acetaminophen at equivalent dosing
regimens
Maund et al. British Journal of Anaesthesia 106 (3): 292–7 (2011).
Ong CK et al. Anesth Analg. 2010 Apr 1;110(4):1170-9.
Acetaminophen
Image Credit: http://www.ofirmev.com/
NSAIDS
• Intravenous: Ketorolac
– Should not exceed 120mg/day or > 5 days of therapy
• Oral: Ibuprofen or naproxen
• Notable adverse effects
– Increase risk of GIB
– Kidney injury in combination with nephrotoxic medications
– Platelet dysfunction
• Frequently cited study by Cepeda et al 2005 evaluated 500 postsurgical patients (abdominal, orthopedic, facial, thoracic, etc)
Cepeda et al. Anesthesiology 2005; 103: 1225-32.
Ketamine
• Non-competitive N-methyl-D-aspartate (NMDA) receptor
antagonist
Sensory Input
Thalamus
Limbic
System
• Role
– Opioid tolerant patients refractory to other treatments
Rapid
Onset
Sufficient
Duration
Minimal
Adverse
Effects
Rapid
Recovery
Perception
Ketamine
Dexmedetomidine
• Alpha 2-adrenoreceptor agonist utilized for sedation
• No respiratory depression
• Sedative effects are limited to RASS 0 to -1
• Significant risk for hypotension and bradycardia
• Design: RCT comparing dexmedetomidine to midazolam or
propofol in critically ill mechanically ventilated patients
Jakob et al. JAMA. 2012;307(11):1151-1160.
• Systematic review identified seven studies (n = 492)
• Observed a reduction in ’rescue’ opioid consumption in the first 24 hours after surgery with no
clinically important differences in postoperative pain
• At three hours after surgery, we found low-quality evidence that intravenous morphine
equivalent consumption was reduced with dexmedetomidine:
– Mean difference of -5.20 mg (95% CI -5.79 to -4.61) for Bakhamees 2007 (n = 80), 51%
reduction
– Mean difference of -3.65mg (95%CI -6.04 to -1.26) for Tufanogullari 2008 (n = 77), 39%
reduction
• Low quality of evidence due to methodological limitations and substantial heterogeneity
among the seven included studies. Publication bias could not be ruled out
• Patient-important outcomes such as gastrointestinal function, mobilization, and adverse effects
could not be satisfactorily determined
Lundorf et al. Cochrane Database of Systematic Reviews 2016, Issue 2. Art. No.: CD010358.
Gabapentin & Pregabalin
• Structurally related to GABA; anti-hyperalgesia activity from action in
dorsal root ganglia and spinal cord
• Well documented activity in neuropathic pain of various origins
• Frequently cited as part of a multi-modal strategy for pre- and postoperative pain relief
• Renal dose adjustments required
• Dizziness, somnolence are frequent side effects
• PAD Guidelines: 100mg TID in combination with opioids and may
increase (maximum dose: 3,600mg daily)
Arumugam et al. Journal of Pain Research 2016:9 631–640.
Multi-Modal Post-operative Pain Management
Crew. JAMA. Vol 288, No. 5. 2002.
Non-pharmacologic Techniques
Behavioral
Cognitive
Environment
Interventional
Physical
Movement
Website: www.nhqualitycampaign.org/files/Guide_to_Evidence-based_NonPharmacologic_Interventions_for_Pain.pdf. Accessed January 2016.
Enhanced Recovery After Surgery (ERAS)
Patient Cases
Patient Case #1
A 53 year old male s/p exploratory laporatomy with extensive surgical abdomen history due to
gastric cancer currently mechanically ventilated in the SICU. He is extremely agitated and keeps
desaturating. The team would like to extubate once he is more stable.
Home Pain Regimen: fentanyl 200mcg patch, oxycodone 30mg q4h PRN pain, gabapentin 900
TID, docusate 100 BID, and senna 187 BID
Current Pain and Sedation Regimen: dexmedetomidine infusion + fentanyl 25mcg q1h prn pain
What is your treatment plan?
a.
Initiate fentanyl drip and titrate to RASS 0 to -2
b.
Continue with non-opioid modalities including gabapentin, dexmedetomidine, and scheduled
acetaminophen
c.
Restart home medication regimen with additional hydromorphone 1mg q2h prn breakthrough pain
d.
Initiate ketamine infusion and titrate to RASS 0 to -2
Patient Case #1
A 53 year old male s/p exploratory laporatomy with extensive surgical abdomen history due to
gastric cancer currently mechanically ventilated in the SICU. He is extremely agitated and keeps
desaturating. The team would like to extubate once he is more stable.
Home Pain Regimen: fentanyl 200mcg patch, oxycodone 30mg q4h PRN pain, gabapentin 600
TID, docusate 100 BID, and senna 187 BID
Current Pain and Sedation Regimen: dexmedetomidine infusion + fentanyl 25mcg q1h prn pain
What is your treatment plan?
a.
Initiate fentanyl drip and titrate to RASS 0 to -2
b.
Continue with non-opioid modalities including gabapentin, dexmedetomidine, and scheduled
acetaminophen
c.
Restart home medication regimen with additional hydromorphone 1mg q2h prn breakthrough pain
d.
Initiate ketamine infusion and titrate to RASS 0 to -2
Patient Case #2
A 43 year old female undergoes aortic valve replacement due to chronic aortic valve
insufficiency. She has no other past medical history. There is a family history of substance
abuse.
What post-operative pain regimen would you initiate?
A.
B.
C.
D.
Oxycodone-APAP 5-325mg 1 tablet q4h prn for pain score 1-3, oxycodone-APAP 5-325
two tablets q4h prn for pain score 4-6, and hydromorphone 0.2mg IV q4h for pain
score 7-10
Acetaminophen 975mg q6h x 48 hours, oxycodone 5mg 1 tablet q4h prn for pain
score 1-3, oxycodone 10mg q4h prn for pain score 1-3, hydromorphone 0.2mg IV q4h
for pain score 7-10
Acetaminophen 975mg q6h hours x 48 hours, ketorolac 15mg IV q6h x 48 hours,
oxycodone 5mg q4h for pain, hydromorphone 0.2mg IV q4h for breakthrough pain
Hydromorphone 0.2 mg IV q4h prn for pain score 1-3, hydromorphone 0.4 mg IV q4h
prn for pain score 4-6, and hydromorphone 0.6mg IV q4h for pain score 7-10
Patient Case #2
A 43 year old female undergoes aortic valve replacement due to chronic aortic valve
insufficiency. She has no other past medical history. There is a family history of substance
abuse.
What post-operative pain regimen would you initiate?
A.
B.
C.
D.
Oxycodone-APAP 5-325mg 1 tablet q4h prn for pain score 1-3, oxycodone-APAP 5-325
two tablets q4h prn for pain score 4-6, and hydromorphone 0.2mg IV q4h for pain
score 7-10
Acetaminophen 975mg q6h x 48 hours, oxycodone 5mg 1 tablet q4h prn for pain
score 1-3, oxycodone 10mg q4h prn for pain score 1-3, hydromorphone 0.2mg IV q4h
for pain score 7-10
Acetaminophen 975mg q6h hours x 48 hours, ketorolac 15mg IV q6h x 48 hours,
oxycodone 5mg q4h for pain, hydromorphone 0.2mg IV q4h for breakthrough pain
Hydromorphone 0.2 mg IV q4h prn for pain score 1-3, hydromorphone 0.4 mg IV q4h
prn for pain score 4-6, and hydromorphone 0.6mg IV q4h for pain score 7-10
Patient Case #3
A 55 year old male is admitted for VATS secondary to lung cancer. He remains
intubated post-operatively. At home he takes MS Contin 60 BID with
oxycodone 10mg q4h PRN, which he reports taking several times a day.
What are reasonable options for pain control?
A.
B.
C.
D.
Hold home medications for possible respiratory depression; OxycodoneAPAP 5-325mg 1 tablet q4h prn for pain score 1-3, oxycodone-APAP 5-325
two tablets q4h prn for pain score 4-6, and hydromorphone 0.2mg IV q4h
for pain score 7-10
Initiate fentanyl drip at 0.5mcg/kg/hr and titrate to RASS 0 to -2
Convert home regimen to equi-analgesic oxycodone q4h with
hydromorphone 0.4 mg q4h prn breakthrough pain
Initiate acetaminophen 975mg PO q6h, ketorolac 30mg q6h x 24 hours,
and hold other opioids in preparation for extubation
Patient Case #3
A 55 year old male is admitted for VATS secondary to lung cancer. He remains
intubated post-operatively. At home he takes MS Contin 60 BID with
oxycodone 10mg q4h PRN, which he reports taking several times a day.
What are reasonable options for pain control?
A.
B.
C.
D.
Hold home medications for possible respiratory depression; OxycodoneAPAP 5-325mg 1 tablet q4h prn for pain score 1-3, oxycodone-APAP 5-325
two tablets q4h prn for pain score 4-6, and hydromorphone 0.2mg IV q4h
for pain score 7-10
Initiate fentanyl drip at 0.5mcg/kg/hr and titrate to RASS 0 to -2
Convert home regimen to equi-analgesic oxycodone q4h with
hydromorphone 0.4 mg q4h prn breakthrough pain
Initiate acetaminophen 975mg PO q6h, ketorolac 30mg q6h x 24 hours,
and hold other opioids in preparation for extubation
Patient Case #4
A 45 year old male (110kg) s/p valvular repair with a history of heroin
and polysubstance abuse. Overnight, he is agitated and requires fourpoint restraints while intubated. His fentanyl drip is at 5mcg/kg/hr and
is midazolam drip is running at 6mg/hr.
What would be the first modification to consider?
A.
B.
C.
D.
Switch from midazolam to propofol infusion
Switch from fentanyl to hydromorphone infusion
Add dexmedetomidine infusion to the current regimen
Add ketamine infusion to the current regimen
Patient Case #4
A 45 year old male (110kg) s/p valvular repair with a history of heroin
and polysubstance abuse. Overnight, he is agitated and requires fourpoint restraints while intubated. His fentanyl drip is at 5mcg/kg/hr and
is midazolam drip is running at 6mg/hr.
What would be the first modification to consider?
A.
B.
C.
D.
Switch from midazolam to propofol infusion
Switch from fentanyl to hydromorphone infusion
Add dexmedetomidine infusion to the current regimen
Add ketamine infusion to the current regimen
Patient Case #4 – continued
The patient’s agitation is better controlled on hydromorphone infusion
at 2mg/hr; however, the midazolam is still running at 6mg/hr. The team
is hoping to extubate soon, but there is concern about respiratory
depression.
What is a reasonable next step?
A.
B.
C.
D.
Switch from midazolam to propofol infusion
Switch from midazolam to ketamine infusion
Discontinue midazolam infusion
Discontinue hydromorphone infusion
Patient Case #4 – continued
The patient’s agitation is better controlled on hydromorphone infusion
at 2mg/hr; however, the midazolam is still running at 6mg/hr. The team
is hoping to extubate soon, but there is concern about respiratory
depression.
What is a reasonable next step?
A.
B.
C.
D.
Switch from midazolam to propofol infusion
Switch from midazolam to ketamine infusion
Discontinue midazolam infusion
Discontinue hydromorphone infusion
Patient Case 5
A 67 year old female s/p 2v CABG. She is post-op day 4 and doing well.
Her current pain regimen includes: acetaminophen 975mg q6h prn pain
score 1-3, oxycodone 5mg q6h prn pain score 4-6, oxycodone 10mg q6h
prn pain score 7-10, and hydromorphone 0.2mg for breakthrough pain.
What is the next step for reducing opioids if her pain is well controlled?
A.
B.
C.
D.
Discontinue IV opioids
Change to tramadol 50mg for pain score 4-6
Encourage physical activity with PT/OT
All of the above
Patient Case 5
A 67 year old female s/p 2v CABG. She is post-op day 4 and doing well.
Her current pain regimen includes: acetaminophen 975mg q6h prn pain
score 1-3, oxycodone 5mg q6h prn pain score 4-6, oxycodone 10mg q6h
prn pain score 7-10, and hydromorphone 0.2mg for breakthrough pain.
What is the next step for reducing opioids if her pain is well controlled?
A.
B.
C.
D.
Discontinue IV opioids
Change to tramadol 50mg for pain score 4-6
Encourage physical activity with PT/OT
All of the above
Pearls
• Restart home pain regimens whenever able to avoid getting behind
• Multiple modes of “round the clock” opioid schedules exist (continuous infusions and
scheduled oral)
• Discuss both dose and frequency of PRNs (is it not relieving the pain or wearing off too
early or both?)
• Ask what OTC medications the patient uses at home
• Take advantage of normal renal and hepatic function with regard to non-opioid
modalities
• Consider non-pain causes of agitation (withdrawal, delirium, sepsis, etc.)
Frieden and Houry. N Engl J Med. 2016 Apr 21;374(16):1501-4.
Conclusions
• No medication is benign
• Pain management is a multi-factorial clinical challenge
• The opioid epidemic poses significant risk to patients
• Increased understanding of both opioid and opioid
sparing techniques may help reduce this epidemic
Questions?
Opioid Sparing
Techniques
in the Critically Ill
March 8th 2017
Andrea Sikora Newsome, PharmD, BCPS, BCCCP
CTICU/SICU Critical Care Pharmacy Clinical Specialist
Augusta University Medical Center