1. science
2. medicine
3. surgery

Non-Opioid Therapies
What’s Old, What’s New
Deb Wagner PharmD, FASHP
Associate Professor of Pharmacy/Anesthesiology
Pediatric Patient Safety Coordinator
Nociceptive vs Neuropathic Pain
Nociceptive
Pain
Mixed Type
Caused by a
combination of both
primary injury or
secondary effects
Caused by activity in neural
pathways in response to
potentially tissue-damaging
stimuli
Neuropathic
Pain
Initiated or caused by
primary lesion or
dysfunction in the nervous
system
CRPS*
Postoperative
pain
Arthritis
Mechanical
low back pain
Sickle cell
crisis
Postherpetic
neuralgia
Neuropathic
low back pain
Sports/exercise
injuries
*Complex regional pain syndrome
Trigeminal
neuralgia
Central postDistal stroke pain
polyneuropathy
(eg, diabetic, HIV)
The pain pathway and interventions that
can modulate activity at each point.
Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg 1993;77:1049.
Why We Need to Do a Better Job
Pain After Surgery
90
80
77
82
Warfield
Apfelbaum
70
60
49
50
47
40
30
23
19
20
21
13
18
8
10
0
Any Pain
Slight
Moderate
Severe
Warfield et al. Anesthesiology. 1995;83:1090-1094;
Apfelbaum et al. Anesth Analg. 2003;97: 534-540
Extreme
The Consequences of Uncontrolled
Pain
•
Peripheral and central sensitization
•
Long term chronic pain
•
Delayed discharge and recovery
•
Decreased patient satisfaction
•
PPP (Persistent Postsurgical Pain)
Risk Determinants of Persistent Postoperative Pain
WU CL. Lancet. 2011
Harmful Effects of Acute Pain
Sinatra R. MD, PhD “Role of COX-2 Inhibitors in the Evolution of Acute Pain
Management” Journal of Pain and Symptom Management Vol. 24 No. 1S July 2002
Incidence of side effects (%)
GI Disturbances Are Among the Most Common
Side Effects of Postoperative Opioid Analgesia
40
31%
30%
30
18%
18%
20
10
3%
0
GI
CNS
Pruritus
Urinary
Respiratory
Common GI symptoms included nausea, vomiting, ileus, and constipation.
Common CNS symptoms included somnolence, sedation, and dizziness.
Wheeler et al. J Pain. 2002;3:159-180.
“Trade-offs” in Pain Management: Patients Have
Concerns That May Hinder Treatment
More post-surgical patients chose less pain relief
than increased/more severe side effects
Side Effect: Vomiting (V)
Itchiness (I)
70%
70
Patients Reporting Selected
Profile (%)
Constipation (C)
65%
65%
N=50
60
50
40
30
35%
35%
30%
20
10
0
vs
“Moderate” V +
“good” pain relief
vs
No side effects +
“fair” pain relief
“Severe” C +
“excellent” pain relief
vs
“Mild” C +
“good” pain relief
“Severe” I +
“excellent”
pain relief
“Mild” I +
“good” pain relief
Gan et al. Brit J Anaesthesia. 2004;92:681-688.
The Multimodal Plan
•
Enhance or achieve analgesia with additive or
synergistic effect
•
Limit the duration and intensity of pain
•
Reduction in doses to minimize or prevent side
effects
•
Attack different portions of the pain pathway
Pre-emptive Analgesia (Preventive
Anesthesia)
•
Utilizing interventions prior to noxious stimulus
•
The Controversy
– Medications used
– Dosage administered
– Time of administration
•
Perioperative period as defined
Points of Impact for Preemptive or
Preventive Analgesia
Preventive Analgesia: Quo Vadimus?.
Katz, Joel; Clarke, Hance; MSc, MD; Seltzer, Ze; ev BMS,
DMD
Anesthesia & Analgesia. 113(5):1242-1253, November 2011.
DOI: 10.1213/ANE.0b013e31822c9a59
Figure 1 . Schematic representation showing the
administration (+) or nonadministration (-) of drugs across
the preoperative, intraoperative, and postoperative phases
of surgery, yielding 8 different treatment combinations and
28 possible 2-group designs to evaluate the efficacy of
preemptive and preventive analgesia. The classic
preemptive analgesia design requires 2 groups of patients to
receive identical treatment before or after incision or
surgery (treatment combinations 2 vs 3 and 2 vs 4). This
represents only one of many possible hypotheses
concerning the effects of blocking noxious perioperative
inputs on postoperative pain and analgesic consumption.
(Adapted with permission from Katz.98)
International Anesthesia Research Society. Published by International Anesthesia Research Society.
2
Predictors of Analgesic Consumption
Fig. 3 Predictive factors of postoperative analgesic consumption. ASA =
American Society of Anesthesiologists status; BMI = body mass index
(kg/m2);, black bars = number of studies with significant correlation;,
white bars = number of studies with conflicting results.
Predictors of Postoperative Pain and Analgesic Consumption: A
Qualitative Systematic Review.
Ip, Hui; Abrishami, Amir; Peng, Philip; Wong, Jean; Chung, Frances
Anesthesiology. 111(3):657-677, September 2009.
DOI: 10.1097/ALN.0b013e3181aae87a
© 2009 American Society of Anesthesiologists, Inc. Published by Lippincott Williams & Wilkins, Inc.
16
2
Predictors of Pain Intensity
Fig. 2 Predictive factors of postoperative pain intensity. ASA
= American Society of Anesthesiologists status; BMI = body
mass index (kg/m2); black bars = number of studies with
significant correlation;, white bars = number of studies with
conflicting results.
Predictors of Postoperative Pain and Analgesic Consumption: A
Qualitative Systematic Review.
Ip, Hui; Abrishami, Amir; Peng, Philip; Wong, Jean; Chung, Frances
Anesthesiology. 111(3):657-677, September 2009.
DOI: 10.1097/ALN.0b013e3181aae87a
© 2009 American Society of Anesthesiologists, Inc. Published by Lippincott Williams & Wilkins, Inc.
15
•
52 RPCTs (~5000 patients)
•
Acetaminophen, NSAIDs or COX-2 inhibitors
•
Average morphine consumption – 49 mg/24hrs
•
15-55 % decrease in morphine consumption
•
VAS pain decreased by 1 cm
•
NSAIDs / COX-2 Specific inhibitors
– ↓ Nausea from 28.8% to 22%
– ↓ Sedation 15.4% to 12.7%
– ↑ Renal failure 0% to 1.7%
24-Hour Morphine Consumption
Elia N, Lysakowski C, Tramèr MR. Anesthesiology. 2005;103:1296-1304.
Tried and True:
IV Ketorolac
Ketorolac Compared to Morphine
•
DBRC Ketorolac + Morphine vs Morphine
alone
– 1003 adult patients
– 50% pain reduction at 30 minutes
– Assess reduction in opioid side effects
•
Smallest effect on opioid reduction was 48%
•
NNT = 5 for Ketorolac compared to NNT =
2.6 Ketorlac vs. placebo
Cepeda MS. Anesthesiology 2005
Pain Intensity Reduction
Cepeda MS. Anesthesiology 2005
Side Effects vs. Dose of Morphine
Cepeda MS, Anesthesiology 2005
Potential Issues with Ketorolac – The
Debate
•
•
•
•
Morphine sparing effects vary from 16-33%
GI toxicity is estimated to be 5x’s that of other NSAID’s
– What is the surgeons opinion in key stake holders?
Post-operative bleeding risks
– Particular types of surgeries?
– Rusy, etal; 50 children more difficult hemostasis
– Splinter WM, etal; 64 children undergoing tonsillectomies, 14%
incidence of bleeding
– Are neonates at higher risks?
Effects on Postoperative N/V
– Decreased incidence alone or in combo with APAP
– Romsing J etal, Riegger L etal; decreased incidence of vomiting
postoperatively
– Does timing matter?
New and Improved? IV
Acetaminophen
Mechanism of Action
•
Flower and Vane – discovery of antipyretic activity
•
1990 – discovery of COX 1 and 2
•
Actions:
– COX reducing agent
– Inhibits regeneration of peroxidases
– Inhibits COX 3 in specific tissues
– Self synergistic action between spinal and supraspinal sites
– 5HT participation
– Nitric Oxide pathway effects
– Indirect activation of cannabinoid CB1 receptors
Sebug. et.al. Anesth Anal. 1998
NNT for 50% Pain Relief Following a
Single Dose
Fig. 2. NNT for 50% pain relief in
postoperative pain (single dose). NNT
point estimate is at the junction of the
gray and white bar segments. Gray bar
Evaluating Analgesia: the Challenges.
segment is the lower 95% confidence
McQuay, Henry; Edwards, Jayne; Moore, R
interval; white is the upper.
American Journal of Therapeutics. 9(3):179-187, May/June
Paracetamol data from the work cited
2002.
in this article, source data for the
other drugs from McQuay and Moore.
© 2002 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
4
48
IV Acetaminophen (Ofirmev)
•
Concentration 100mg/ml (1gm vial)
•
For Single Use administration only
•
Contains excipients
– Mannitol 3850mg
– Cysteine HCl 25mg
– Sodium Phosphate 10.4mg
•
Osmolality 290mOsm/kg
•
pH 5.5
•
Infuse over 15 minutes
•
Adults 1gm q6 hours, Pediatrics 15mg/kg q6 hours (>50kg)
Stability of Intravenous Acetaminophen (10
mg/mL) at Room Temperature in Varying
Storage Containers
Samplea
a1
Actual Initial Drug
Concentrationb
(mg/mL)
% Initial Concentration Remaining
48 hours
72 hours
24 hours
1
9.94 ± 0.05
99.11 ± 0.52
100.54 ± 0.69
100.08 ± 0.38
100.02 ± 0.53
2
9.96 ± 0.02
99.66 ± 1.11
99.61 ± 0.68
99.83 ± 0.89
99.80 ± 0.35
3
9.96 ± 0.03
100.13 ± 0.37
99.83 ± 0.64
99.92 ± 058
99.68 ± 0.55
4
9.98 ± 0.03
99.67 ± 0.36
100.07 ± 1.26
99.37 ± 0.24
99.53 ± 0.41
5
9.93 ± 0.04
99.76 ± 0.33
100.03 ± 0.59
100.54 ± 0.58
100.31 ± 1.22
84 hours
= 100 mg (10 mL in 10 mL syringe), a2 = 250 mg (25 mL in 30 mL syringe), a3 = 500 mg (50 mL in 60 mL syringe), a4 =
250 mg (25 mL in original bottle), a5 = 900 mg (90 mL in original bottle) were prepared.
bMean ± S.D. of duplicate determinants for three samples (n = 3).
Cmax of IV:PO Acetaminophen
N=106
IV
P
O
Van der Westhuizen J. Anaesth Int Care. 2011
Percent of Patients with Therapeutic
Concentrations
I
V
P
O
Van der Westhuizen J. Anaesth Int Care.
2011
Acetaminophen Plasma Concentrations
Pain Practice 2012 Apr 24 doi:
10.1111/j.1533-2500.00556.x.
Acetaminophen Comparison of CSF
Concentrations
Pain Practice 2012 Apr 24
doi:10.1111/j.1533-2500.00556.x.
Summary of Opioid Sparing Effects
Reduction in opioid consumption
Literature review of placebo controlled trials (≥6 hrs)
Sinatra et al 2005 (hip/knee arthroplasty)
33% **
Viscusi et al 2008 (hip arthroplasty)
53% *
Gimbel et al 2008 (hip arthroplasty)
63% **
Koppert et al 2006 (hip arthroplasty)
54% *
4% NS
Miller et al 2009 (abdominal laparoscopy)
Minkowitz et al 2008 (vaginal hysterectomy)
64% *
10% NS
Candiotti et al 2008 (abdominal)
Arici et al 2009 (abdominal)
59% *
Atef et al 2008 (tonsillectomy)
78% **
50% NS
Cattabriga et al 2007 (sternotomy)
Kempainnen et al 2006 (endoscopic sinus)
67% **
0%
* p<0.05
** p<0.01
NS – not significant
1
20%
40%
60%
80%
% reduction in opioid consumption for
IV paracetamol vs. placebo
100%
Safety and Beyond…
HEPATIC SAFETY DATA FOR
ACETAMINOPHEN INJECTION1
Peak ALT/AST value postbaseline: % of patients in all repeated-dose,
placebo-controlled, all-adult studies*
IV Acetaminophen
Placebo
(n=402)
(n=379)
ALT
>3x ULN
>5x ULN
1.1% (n=4)
0.3% (n=1)
1.7% (n=6)
0.6% (n=2)
AST
>3x ULN
>5x ULN
1.0% (n=4)
0.5% (n=2)
1.1% (n=4)
0.8% (n=3)
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
*Data from a pooled analysis of 5 repeated-dose clinical studies involving adult patients.
Acetaminophen should be used with caution in patients with the following conditions: hepatic impairment or
active hepatic disease, alcoholism, chronic malnutrition,
severe hypovolemia, or severe renal impairment2
1. Data on file. Cadence Pharmaceuticals, Inc. 2. OFIRMEVTM (acetaminophen) injection [Prescribing Information]. San Diego, CA: Cadence
Pharmaceuticals, Inc.; 2010.
Effects of IV Acetaminophen on
PONV
•
Prospective, placebo controlled RDB
•
86 children between 2-14 yr old
•
Saline vs Paracetamol 15mg/kg IV
•
Outcome was PONV within 24 hours postop
– Nausea: 33% placebo, 14.6% APAP
– Vomiting: 24.4% placebo, 7.3% APAP
•
Opiate use higher in the placebo grp
COK OY. et.al. Euro J Anaesth. 2011
Beyond Opioid Sparing Effects
•
Wininger S. Clin Ther 2010
– Abdominal Laparoscopy 200pts
• Patient Satisfaction 70% Placebo/ 87% APAP
•
Sinatra RS. Anesth. 2005
– Total Hip and Knee 101pts
• Patient Satisfaction 23% Placebo/ 41% APAP
•
Gimbol. AAPM Mtg. 2008
– Total Hip 61pts
• Patient Satisfaction 39% Placebo/ 86% APAP
New Players on the Block
•
Capsaicin
•
Gabapentin
•
Lidocaine infusions
•
Liposomal Drug Delivery Systems
Capsaicin: Mechanism of Action
• Capsaicin selectively activates
Brain
TRPV
-1
C
neuron
Aδ
neuron
TRPV-1
• TRPV-1 located on nociceptors
(predominantly C-fibers)
• TRPV-1 activation
– Initially induces action potentials
Followed by disruption of pain
receptor
• Regeneration of pain receptors
occurs over weeks to months
• Noxious pain is blocked, but not
adaptive pain and position sense
White P: Anesth Analg 2008; 107:6-9
Capsaicin for Acute Pain
•
Stimulates unmyelinated C fiber afferent
neurons
•
Peripherally acting
•
Dose dependent affects
•
Injectable form
– ALGRX 4975
– 1000mcg instilled dose
•
Neurotoxicity caution
Structure Activity Relation
Why Gabapentin or Gabapentenoids?
•
Reduce physiologic sensitization and attenuate
hyperexcitability
•
Timing doesn’t matter
•
Seems to affect both NMDA and non-NMDA
receptors
•
Anxiolytic properties
– Meniguax et al. significant pre-induction reduction
of anxiety
•
Pregablin has an improved bioavailability and
faster onset
Perioperative Gabapentin 1200 mg
Adverse Events
OR
P value
Nausea
0.72 (0.51-1.01)
0.06
Vomiting
0.58 (0.39-0.86)
0.007
Pruritus
0.27 (0.1-0.74)
0.01
Sedation
3.86 (2.5-5.94)
0.00001
Respiratory Dep
1.07 (0.21-5.49)
0.93
Ho et al. Pain 2006;126:91-101
Median Effective Gabapentin Dose
VanElstraet AC. Anesth Anal. 2008
Mean % Change in Pain Tolerance
P + G ([black small square], n = 12), M + P
([white diamond suit], n = 12), M + G
([black up pointing small triangle], n = 12).
Gabapentin enhances the analgesic effect of morphine in
healthy volunteers.
Eckhardt K; Ammon S; Hofmann U; Riebe A; Gugeler N;
Mikus G
Anesthesia & Analgesia. 91(1):185-91, 2000 Jul.
International Anesthesia Research Society.
2
Serum Concentrations after Oral
Administration
(M + P: [white circle], n = 12) or M +
gabapentin (M + GBP: *, n = 12). B,
Serum concentration-time curves of
GBP after the oral administration of
GBP + P ([white square], n = 12) or
GBP + M ([black small square], n = 12).
Gabapentin enhances the analgesic effect of morphine in
healthy volunteers.
Eckhardt K; Ammon S; Hofmann U; Riebe A; Gugeler N;
Mikus G
Anesthesia & Analgesia. 91(1):185-91, 2000 Jul.
International Anesthesia Research Society.
3
Prevention of Chronic Postsurgical
Pain
•
Meta-analysis of studies of CPSP > or = 2
months post surgery
•
11 trials: 8 with Gabapentin, 3 with Pregablin
– 50% success with Gabapentin, 100% success with
Pregablin
•
Moderate to large reductions
•
Increased patient function
Clarke H. Anesth Analg. 2012
Dosing Recommendations?
•
Adult spinal fusions
– 62 patients
– Goal of 24hr total morphine dose <44mg
– Oral dose 2.5 hrs prior to induction
– ED50=21.7mg/kg
•
Pediatric spinal fusions
– 59 patients age 9-18 yo
– 15mg/kg x 5days
– Significantly less morphine use in PACU and day 1 and 2
Rusy LM. Anesth Anal. 2010
VanElstraete AC. Anesth. Anal. 2008
What about Pregablin?
•
6 x’s more potent
•
Doses < 100mg have generally been ineffective
•
Surgeries with a high likelihood of nerve damage
– Postthoracotomy
– Postherniorrhaphy
– Postamputation
– Postmastectomy
– Spinal Fusion
•
Risk of sedation increased with dose
Perioperative Oral Pregabalin Reduces Chronic
Pain After Total Knee Arthroplasty: A
Prospective, Randomized, Controlled Trial
•
Pregabalin 300 mg preop, 150-50 BID postop for
14 days.
•
At both 3 and 6 months postoperatively, the
incidence of neuropathic pain was less frequent in
the pregabalin group (0%) compared with the
placebo group (8.7% and 5.2% at 3 and 6 months).
Buvanendran K et al. Anesth Analg 2010;110:199 –207)
Perioperative Oral Pregabalin Reduces Chronic Pain
After Total Knee Arthroplasty: A Prospective,
Randomized, Controlled Trial
CONCLUSION: Perioperative pregabalin administration
reduces the incidence of chronic neuropathic pain after
TKA with less opioid consumption and better range of
motion during the first 30 days of rehabilitation.
However, in the doses tested, it is associated with a
higher risk of early postoperative sedation and
confusion.
Buvanendran K et al. Anesth Analg 2010;110:199 –207)
Recommendations on Gabapentinoids
• Alpha-2 delta subunit blockers, not approved for acute pain
• Reduces opioid requirements
• May limit development of hyperalgesia
• Useful for opioid dependent patients, and patients at risk for
developing neuropathic pain.
• Oral dose Gabapentin (600 to 1200 mg) or pregabalin (150mg) given
the morning of surgery
• Doses may be continued postoperatively for patients with severe pain
and tolerating oral medications
•No conclusions with regard to adverse effect reduction
Lidocaine Infusions
•
Meta-analysis 250 patients
– Moderate but statistically significant reduction in
pain scores
– Decreased N/V and LOS
•
Lauwick et al.
– 40 patients, lidocaine vs saline for 24 hrs post op
– Primary outcome was functional walking
– Smaller reduction in walking capacity and less PCA
use
•
Appears to have moderate and short lasting effects
Lidocaine for
Postoperative Ileus and Pain
•
Lidocaine infusion
– 24 h infusion 60 mg/hr
– Lidocaine has anti-inflammatory effects
– Evidence for prevention of secondary sensitization
– BM and hospital discharge greater than a day earlier in treatment
group
•
Other studies limit to only pre- and intra-operative
infusions
•
A new role for lidocaine in the multimodal
armamentaria of postoperative management?
Harvey K, et al. The American Journal of Surgery 2009;198;231-26
Liposomal Bupivacaine
•
Slow release form of bupivacaine encapsulated
in a liposomal delivery system
•
Expressed as mg of free base
– 266mg = 300mg HCl
•
Achieves same peak conc. as bupivacaine but
with both an immediate and delayed peak
•
Preservative free suspension 13.3mg/ml
•
No studies in children < 18 yo.
Multivesicular Liposome
Chambers
filled with
drug
Viscusi ER, et al: Reg Anesth 2005;30: 292-294.
Liposomal Bupivacaine
Pharmacokinetics
Biphasic Peak of Liposomal
Bupivacaine
Milligram Dose Equivalents for Liposomal
Bupivacaine Expressed as the Free Base and
Bupivacaine HCl
Dose of liposome bupivacaine
expressed as the free base (mg)
Equivalent dose of bupivacaine
HCl (mg)
66
75
93
105
106
120
133
150
155
175
160
180
199
225
266
300
306
345
310
350
399
450
532
600
Time to First Postsurgical Use of Supplemental
Opioid Pain Medication Through 72 hours
Liposome
bupivacaine (n
= 780)
Bupivacaine
HCl (n = 409)
Placebo (n =
190)
619
343
180
First quartile
1.8
0.7
1.2
Median (95% CI)
9.3 (7.6, 11.0)†
6.4 (4.2, 8.5)
3.6 (2.8, 4.0)
Third quartile
31.8
25.3
5.4
Number of patients
who used
supplemental
medication
Quartiles* (hours)
Bergese S. J. Pain Res. 2012
24 hour Pain Reduction
Bergese SD. J.Pain Res. 2012
72 hours Pain Reduction
Bergese DS. J.Pain Res. 2012
Safety Concerns
Outpatient Surgery
Archives Aug. 2012
Conclusions:
•
New era of acute pain management is here or
coming soon to an amphitheater near you
•
Be a champion for multimodal therapy
•
Engage leadership to not just look at pharmacy
cost but cost reduction in other areas of care
•
WE CAN IMPROVE patient satisfaction with
pain management
Out Run Pain!
Questions?