management of acute pain in emergency medicine ......3 mrc‐0084 12sep16 course outline overview of...
TRANSCRIPT
Management of Acute Pain in Emergency Medicine: SufentanilSublingual Tablet 30 mcg
EMS World Expo, Learning Center - ALS TractThursday, Oct 6 2016 12:15PM - 12:45PM
Pamela P. Palmer, MD, PhD
2MRC‐0084 12SEP16
Disclosures
AcelRx employee
3MRC‐0084 12SEP16
Course Outline
Overview of acute pain in emergency medicine
Review of advantages/limitations of current analgesic therapies
Provide context for the science behind sublingual sufentanil
Presentation of Sufentanil Sublingual Tablet 30 mcg clinical program
Implications for nursing/paramedic practice
Q&A
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Acute Pain in Emergency Medicine
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Acute Pain: Physiology
The body's response to acute pain can cause adverse physiological effects.1
Untreated pain has the potential to:‒ impede the return of normal pulmonary function‒ modify certain aspects of the stress response to injury‒ alter hemodynamic values and cardiovascular function‒ produce immobility and contribute to thromboembolic complications1.
Clinical research has demonstrated that patients with poorly treated pain were more likely to end up with chronic pain conditions, post‐traumatic stress, depression, and other physical and psychological problems.2
Proper pain management can help with wound healing and get people home from the hospital sooner.2
1. Lewis et al. Effect of analgesic treatment on the physiological consequences of acute pain. Am J Hosp Pharm. 1994 Jun 15;51(12):1539‐54.2. J. Goodwin. How to Manage Pain. EMSWorld; September 2013
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Acute Pain: Management
“Unrelieved pain is a major, yet avoidable, public health problem. Despite 20 years of work by educators, clinicians and professional organizations and the publication of clinical practice guidelines, there have been, at best, modest improvements in pain management practices”
‐ University of Wisconsin–Madison’s Pain Management Improvement Group in a study published in 2000 in Pain Management Nursing, discussing the implications of new pain‐management standards.
1. P. Berry and J. Dahl, The New JCAHO Pain Standards: Implications for Pain Management Nurses. Pain Management Nursing, Vol 1, No 1 (March), 2000: pp 3‐12
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Acute Pain: Emergency Medicine
Pain is the primary reason people call 9‐1‐1 and the most common reason they present to the ED.1, 2
As hospitals and healthcare systems put greater emphasis on pain management, pressure is also increased on paramedics and EMTs to better assess, treat and relieve pain—whether it’s through the use of opioids and other pain relievers, or other techniques to ease the anxiety and distress that can make pain seem even worse2
Emergency Medicine guidelines support use of opioids for moderate‐to‐severe acute pain3, 4
1. Tanabe P, Buschmann M. A prospective study of ED pain management practices and the patients prospective. J Emerg Nurs. 1999;25:171–7.2. J. Goodwin. How to Manage Pain. EMSWorld; September 20133. Berben et. al. Pain prevalence and pain relief in trauma patients in the Accident & Emergency department. Injury. 2008; 39: 578‐85.4. Byers, PA; Counselman, FL. Appropriate Analgesic Use in the Emergency Department. Emerg Med 2014;46(6): 249‐255.
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Acute Pain:ACEP Policy Statement1
The American Society for Pain Management Nursing (ASPMN) and the Emergency Nurses Association (ENA) in collaboration with the American College of Emergency Physicians (ACEP) and the American Pain Society (APS) support efforts to improve pain management for patients in all healthcare settings.
These organizations recognize the need for prompt, safe, and effective pain management.
Analgesic management should begin as soon as possible when indicated and diagnosis of the pain etiology should not delay administration of analgesics.
Development and adoption of analgesic protocols are encouraged and measurement of patient response to pain relief interventions from these protocols is required by accrediting agencies.
Protocols should be physician/nurse developed and nurse initiated.1. Joint Statement by the American College of Emergency Physicians, American Pain Society, American Society for Pain Management Nursing, and the Emergency Nurses Association. “Optimizing the Treatment of Pain in Patients with Acute Presentations”. Approved by ACEP Board of Directors June 2009
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Introduction to Sublingual Sufentanil
Unmet Analgesic Needs in Battlefield & Emergency Medicine
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Sufentanil Sublingual Tablet 30 mcg Development
U.S. Department of Defense aware of small sublingual sufentanil tablet in development in post‐operative pain
‒ Requested durable, single‐dose, easy to use applicator for field scenarios
Sublingual delivery of sufentanil considered optimal for field‐based analgesia
‒ More rapid onset of analgesia than morphine1
‒ Sublingual tissue perfusion maintained during shock2
‒ Eliminate needle‐stick injury and reduce risk of IV infection
Standard IM morphine is not readily bioavailable during hypovolemic shock (severe vasoconstriction to muscles limits uptake of drug)2
‒ Soldiers can vasodilate following warm IV saline infusion‒ Repeated doses of morphine cross blood‐brain barrier → overdose/death3
1. Melson TI, Boyer DL, Minkowitz HS, et al (2014) Sufentanil sublingual microtablet system versus intravenous patient‐controlled analgesia with morphine for postoperative pain control: a randomized, controlled trial. Pain Pract 14:679–6882. de Moya, M. A. Shock. In Merck manual online, professional version. Retrieved from http://goo.gl/l8Xpa3. US Defense Health Board. Pre Hospital Use of Ketamine in Battlefield Analgesia in Tactical Combat Casualty Care Pain Guidelines. 2012 Mar http://goo.gl/w2rfR0
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Current Concerns with Acute Pain Management in Emergency Medicine Clinical need remains for rapid‐acting, potent analgesic that does not requirean invasive route of delivery
Emergency Medicine IV route
‒ IV lines can be challenging to start in the field or in ambulances1‒ Difficult access: obese, elderly and vasoconstricted (e.g., dehydration or shock) patients2
‒ Patients presenting directly to ED can experience long delays in obtaining IV access and obtaining treatment3
IM route‒ Reduced bioavailability during shock4‒ Painful to administer
Intra‐nasal‒ Route off‐label for most analgesics; unpredictable absorption‒ Immediate access to an atomizer required‒ Burning sensation of nasal mucosa not uncommon
1. Sweeney, T. and Marques, A. Prehospital Vascular Access for the Trauma Patient. In Soreid E. and Grande, C. (Eds) Prehospital Trauma Care (Page 291). CRC Press Feb 02, 20152. Ann Emerg Med. 2005 Nov;46(5):456‐613. Todd KH et. Al.. J Pain. 2007 Jun;8(6):460‐6. Epub 2007 Feb 15. Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study.4. de Moya, M. A. Shock. In Merck manual online, professional version. Retrieved from http://goo.gl/l8Xpa
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Pharmacokinetic Limitations of Current IV Opioid Therapy
IV morphine Delayed CNS penetration resulting in poor analgesic onset and slow offset which can delay discharge
Active metabolite morphine‐6‐glucuronide can cause delayed side effects1
IV hydromorphone Slightly more rapid onset than morphine but known for delayed and prolonged side effects (e.g., sedation, respiratory depression)1
IV fentanyl Known brain penetration results in rapid onset of analgesia but alpha distribution of this lipophilic drug (1.7 minutes) results in quick offset and requires frequent re‐dosing to maintain analgesia2,3
1. Lötsch J. J Pain Symptom Manage 2005; 29(5 Suppl):S90‐S103. 2.Scott JC, Cooke JE, Stanski DR. Anesthesiol 1991; 74:34–42. 3. Shafer, S and Varvel, J. Anesthesiol 1991; 74:53‐63.
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Sufentanil Sublingual Tablet 30 mcg Single-Dose Applicator Designed in collaboration with DoD (light‐weight, extreme‐environment tested, easily handled with gloves)1
Pre‐loaded tablet
Non‐retractable pusherClear plastic to allow tablet visibility
Removable safety lock to avoid premature actuation (not shown)
1. AcelRx data on file (2015‐2016)
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Sublingual SufentanilThe Science
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Why Sublingual Sufentanil?
Sufentanil first synthesized by Janssen in 19741
First approved in US for IV delivery in 19841
Approved for induction of anesthesia
Later approved for epidural delivery as an analgesic in combination with bupivacaine1
Molecular Properties
Lipophilic: 1500 times more fat‐soluble than morphine
20% non‐ionized at physiological pH (fentanyl only 8%)
Fat‐soluble, non‐ionized molecules = more rapid brain penetration than lipid‐insoluble, charged molecules2
1. Stanley TH, Egan TD, Van Aken H. A tribute to Dr Paul AJ Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth. Analgesia. 2008;106(2):451–4622. De Leon‐Casasola et al. Anesth Analg 1996; 83:867‐75.
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Sufentanil Penetrates CNS Due to Lipophilicity (t½ke0)
Commonly used IV opioids have a delayed equilibration time between plasma and CNS Morphine t½ke0 = 2.8 hours1
Hydromorphone t½ke0 = 46 min2
Sufentanil rapidly penetrates the CNS due to its very lipophilic nature Sufentanil t½ke0 = 6 min3
1. Lotsch et al., Anesthesiol 95:1329‐38, 20012. Shafer et al., Geriatric Anesthesiology. 2nd ed. New York, NY: Springer; Chapter 15:209–28, 20073. Scott et al., Anesthesiol 74:34‐42, 1991
P‐Glycoprotein
Hydromorphone
Morphine
2.8 hrs
46 min
t½ke0
Blood BrainBarrier(BBB)Plasma
Central NervousSystem(CNS)
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Plasma Versus Brain Morphine Concentrations Delayed brain uptake leads to disconnect between IV dosing and effect1
*Assumes equipotency of morphine and M6G; other potency ratios achieved similar results1. IV PCA dosing frequency based on IAP309 Phase 3 study; plasma and brain concentrations modelled from published plasma and CNS equilibration values by D.Fisher – consultant to AcelRx
Plasma concentrations with IV morphine dosing
0 2 4 6 8 10 12
0
20
40
60
80
100
Time (hours)
Cp\Ce (ng/mL)
Morphine/M6G in brain
PlasmaEffect Site
Morpine + M6G*
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Sufentanil has Rapid Plasma/CNS Equilibration (t½ke0) Uptake of sublingual sufentanil leads to potential for real‐time tracking between dosing and effect1
Sublingual sufentanil plasma and brainconcentrations track together
PlasmaEffect site
0 2 4 6 8 10 12
0
20
40
60
80
100
Time (hours)
Cp\Ce (pg/mL)
Sufentanil 15mcg
1. Sublingual sufentanil dosing frequency based on IAP309 Phase 3 study; plasma and brain concentrations modelled from published plasma and CNS equilibration values by D.Fisher – consultant to AcelRx
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Sufentanil: High Therapeutic Index and No Active Metabolites
1.Mather, Clin Exp Pharmacol Physiol 1995; 22:833.2. Kumar, Eur J Pharmacol 2008; 597:39 (ED50) and Purdue Pharma MSDS, 2009 (LD50)
3. Clark et al., J Emerg Med 1995 ;13:797–8024. Smith et al., Clin J Pain 2011;27:824–385. Smith et al., Clin Exp Pharmacol Physiol 2000;27:524–86. Wright et al., Life Sci 2001;69:409–207. Smith, H. Mayo Clin Proc 2009;84(7):613‐614
Normeperidine
M6GM3G H6G
H3G
Other OpioidActive Metabolites3‐7
OpioidTherapeutic index
[lethal dose (LD50)/effective dose (ED50) in animal studies]
Meperidine 51
Morphine 711
Hydromorphone 2322
Fentanyl 2771
Sufentanil 26,7161
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Sufentanil: Pharmacokinetics
Sublingual delivery of sufentanil blunts Cmax and extends plasma half‐time compared to IV administration1
ARX‐04 30 mcg IV Sublingual
Bioavailability, %, mean 100 53
Cmax pg/mL, mean 1074 63
CST½ h, median 0.1 2.3
CST½ = context‐sensitive half‐time (time from Cmax to 50% of Cmax)
1. SAP101, data on file, AcelRx
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Sublingual Sufentanil30 mcg Tablet
Clinical Program Update
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ARX-04:Clinical Studies
Study number Phase #
Clintrials.govNCT #
Patient population
Current status of study
SAP202 Phase 2 Dose‐findingPivotal
NCT01710345 Postoperative bunionectomy
Published 20141
SAP301 Phase 3Pivotal
NCT02356588 Ambulatory surgery ‐Postoperativeabdominal
Completed 2015;Manuscript Accepted2
SAP302 Phase 3 NCT02447848 Trauma/injury in the ED
Enrollmentcomplete; manuscript in process
SAP303 Phase 3 NCT02662556 Postoperative; elderly and organ impaired
Enrollmentcomplete; manuscript in process1 Singla NK, et al. A dose‐finding study of sufentanil sublingual microtablets for the management of postoperative bunionectomy pain. J.
Trauma. Acute. Care. Surg. 2014;77(3 Suppl 2):S198–S2032. Manuscript formally accepted by Pain Practice Journal September 2016
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SAP301Outpatient Abdominal Surgery
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SAP301:Study Design
Postoperative ambulatory surgery patients following abdominal surgery• Open hernia repair• Abdominoplasty• Any laparoscopic abdominal surgery
Randomized 2:1, active:placebo• Total of 163 randomized and 161 dosed (ITT population)
Pain score had to be ≥ 4 prior to administration of first dose
Minimum time between doses: 60 minutes
Study completed at 24 hours after first dose• Dosing could extend out to 48 hours if needed
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SAP301:Key Endpoints
Primary efficacy variable: Time‐weighted SPID‐12• Essentially an area under the curve measurement of the drop in pain intensity from baseline over the first 12 hours of the study
• Pain intensity (PI) measured on a 0–10 NRS(0 = no pain, 10 = worst pain imaginable)
Safety: • Adverse events• Vital signs and oxygen saturation• Concomitant medications
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SAP301:Demographics
Category Category
Sex, female, % 68 Surgery, %Age, years, mean 41 Abdominoplasty 50
Race/ethnicity, % Laparoscopic 30
Caucasian 40 Open hernia 20Hispanic 38 ASA status, %
African American 19 1 64Asian 3 2 32
BMI <30, % 70 3 4
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SAP301:Primary Endpoint: SPID-12Pain intensity (PI) measured on a scale of 0–10
Assessment ARX‐04 Placebo P‐value
Baseline PI 5.6 5.5 NS
SPID‐12 25.8 13.1 <0.001
NS, not significant
25.8
13.1
0.0
5.0
10.0
15.0
20.0
25.0
30.0
ARX‐04 Placebo
SPID
SST 30 mcg
(p<0.001)
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SAP301: PID Over First Hour by Surgery Type
‐1‐0.5
00.51
1.52
0 15 30 45 60
* p<0.01** p<0.001
***
****
Time (Minutes)
Abdominoplasty
Hernia repairPain In
tensity
Differen
ce
Laparoscopic Abd
Placebo (All)
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SAP301:Drug Utilization & Rescue
Time periodNumber of tablets, median (range)
Inter‐dosing interval, mean
0–12 Hours 4 (1–9) 185 minutes
0–24 Hours 7 (1–15) 221 minutes
ARX‐04 Placebo P‐valuePatients using rescue, % 27.1 64.8 P<0.001
Number of 30mcg tablets dosed
Rescue Medication ‐ 1mg IV Morphine
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SAP301:Adverse Events (>3% in Either Group)
No statistical difference between cohorts
Adverse Event, %Sufentanil Sublingual
Tablet 30 mcg PlaceboNo Adverse Event 42.1 37.0Nausea 32.7 29.6Headache 19.6 18.5Vomiting 7.5 1.9Dizziness 5.6 3.7Hypotension 4.7 3.7Flatulence 3.7 7.4Somnolence 2.8 3.7Procedural nausea 2.8 5.6Pruritus 1.9 3.7
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SAP302Emergency Department
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SAP302: Study Design
Study Details
Inclusion: 18 years and older moderate‐to‐severe acute pain due to trauma or injury Exclusion: Opioid‐tolerant (>15mg oral MSO4 equivalent daily) Dependent on supplemental oxygen Pregnant
Inclusion/Exclusion
Multicenter, Single‐Arm, Open‐Label Study
Two Cohorts:
Single‐dose (after 1 hour, other opioids administered if needed)
Multiple‐dose up to 5 hours (rescue opioids allowed if study drug not effective)
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SAP302:Outcome Measures
Primary Endpoint
Sum of the pain intensity difference to baseline over the first hour of treatment (SPID1)
Key Secondary Efficacy Endpoints
PID assessments
Patient and Healthcare Global Assessment
Use of rescue medication
Drop‐outs due to inadequate analgesia
Safety Endpoints
Adverse Events
Vital Signs
Six‐item Cognitive Screener
Concomitant Medications
Study sitesHennepin County Medical Center, Minneapolis, MN (James Miner, MD)Memorial Hermann‐Memorial City Medical Center, Houston, TX (Harold Minkowitz, MD)Baylor College of Medicine, Ben Taub General Hospital, Houston, TX (Zubaid Rafique, MD)
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SAP302:Demographics (n=76)
Category Category
Sex, male, % 61 BMI, %
Age, years, mean 42 < 30kg/m2 61
Race, % > 30kg/m2 39
Caucasian 45 ASA Classification, %
African American 34 1 61
Native American 7 2 33
Ethnicity, % 3 7
Hispanic/Latino 16 Baseline Pain 8.1/10
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SAP302:Demographics (n=76)
Injury Type Number Percent Total
Fractures 25 32.9%
Sprains/strains 23 30.3%
Contusion/hematoma (soft tissue) 13 17.1%
Laceration 8 10.5%
Joint dislocation 4 5.3%
Burns 2 2.6%
Infections 1 1.3%
Trauma classifications
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SAP302:Combined Cohorts Efficacy (n=76)
0
1
2
3
0 15 30 45 60
PID = 1.31
Pain Intensity
Differen
ce to
Baseline
1.Bijur, Polly E., et al.. Validation of a Verbally Administered Numerical Rating Scale of Acute Pain four Use in the Emergency Department. Academy Emergency Medicine. 2003;10: 390‐392.
Time (minutes)
Over 35% drop in pain intensity by 60 minutes
A clinically significant drop in pain intensity when administering 0‐10 point numerical rating scale (NRS) to measure pain is 1.31
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SAP302:Multiple-Dose Cohort Efficacy (n=36)
0
1
2
3
0 15 30 45 60 120
Pain Intensity
Differen
ce to
Baseline
Time (minutes)
Redosing allowed hourly if needed 75% of patients did not require redosing
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SAP302:Use of Rescue Analgesia
Study Period
Patients Requiring Use of Rescue Opioid
Single‐DoseCohort (n = 40)
Multiple‐DoseCohort (n = 36)
Use in First Hour 7.5% 0%
Use after First Hour NA 8.3%
Low rate of rescue opioid usage
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SAP302:Adverse Events (> 2% of patients)
Adverse Event, n (%)ARX‐04 (30 mcg)
n=76
No Adverse Event 79%
Nausea 9%
Somnolence 5%1
Vomiting 4%
Oxygen Desaturation 3%2
1. All 4 patients with somnolence were rated as mild2. Two patients experienced transient room air oxygen desaturations below 95% (88% and 94% which immediately improved with nasal cannula oxygen)
Majority of patients experienced no side effects
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SAP302:Six-Item Screener (SIS) Cognitive Test
DoD requested cognitive test before and 1 hour after dosing of sublingual sufentanil 30 mcg Impaired cognitive skills a concern with other field‐based analgesics used in the military (e.g., ketamine) 73 patients either had the same score or increased their score while only 2 patients had a decrease of 1 point compared to baseline.
Sublingual sufentanil not associated with cognitive impairment
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Study Conclusions
Single dose of sufentanil sublingual 30 mcg tablet results in approximately a 3‐point drop in pain intensity within 60 minutes, with clinically meaningful analgesia in < 20 minutes
Sublingual sufentanil was well‐tolerated with most commonly reported AEs of nausea and somnolence
Clinical studies showed no cognitive impairment
Additional research is indicated to assess safety and efficacy in actual field‐based environments
Questions?
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Discussion:Emergency Medicine Pain Management What percentage of patients present with moderate‐to‐severe acute pain?
How long does it take a typical patient to receive their first dose of analgesia for moderate‐to‐severe pain?
Are there nurse‐initiated protocols in place for nurses to place IV lines, assess and treat pain prior to physician assessment?
What percentage of patients present with difficult venous access?
What may be some benefits/limitations of using a sublingual therapy for patients in the EMS/emergency medicine setting?
Thank you