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“Are perioperative opioids obsolete?” Proceedings of an IASP Acute Pain Special Interest Group Satellite Symposium September 25, 2016 Yokohama, Japan

Carr, Daniel B.; Cohen, Robert I.

doi: 10.1097/PR9.0000000000000604
Meeting Proceedings

This IASP Satellite Symposium surveyed opioid adverse effects upon patients and society, current and future drug and nondrug alternatives, and strategies to optimize postoperative outcomes through quality improvement.

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received April 24, 2017

Received in revised form May 01, 2017

Accepted May 01, 2017

Because of opioids' adverse effects and risks, for over 50 years reduction of postoperative opioid requirement has been a goal of multimodal analgesia for acute postsurgical pain. Indeed, IASP's Acute Pain Special Interest Group (“AP SIG”) had convened a Satellite Symposium at the 2012 Milan World Congress on Pain, organized by its founding Chairs Professors Eddy Neugebauer and Stephan Schug, on the theme of multimodal analgesia, including postoperative opioid sparing. There, one of the present authors (D.B.C.) concluded with a presentation titled “Multimodal Analgesia: Quo Vadis?” (“Where are you going?”). Noting the specific adverse events and risks associated with opioid treatment of acute postsurgical pain—particularly respiratory depression but also nausea, gastrointestinal dysfunction, urinary retention, and so on—we asked “Should the default be zero postop opioid?”

Since then, growing appreciation of short-, intermediate- and long-term adverse opioid effects upon individuals and society (eg, diversion and substance abuse) has intensified progress in identifying and applying nonopioid (including nondrug) analgesics and regional analgesia for moderate to severe pain. Thus, it seemed timely for IASP's AP SIG to explore in greater depth the question of whether postoperative opioid analgesia has now become obsolete.

A Satellite Symposium on this theme was convened in Yokohama on September 25, 2016 just prior to the 16th World Congress on Pain. In the months before the World Congress, recognizing the health burden of pain after surgery, IASP and the European Pain Federation (formerly EFIC, the European Federation of IASP Chapters) had designated 2017 as the “Global Year Against Pain After Surgery.” IASP's AP SIG has long supported its global year campaigns including the 2009–2010 one against acute pain. Indeed, inauguration in 2004 of the Global Year Against Pain concept resulted from the efforts of Professor Harald Breivik (then IASP Liaison to the World Health Organization), the late Professor David Niv (representing EFIC), and one of the present authors (D.B.C.). Using WHO's then-emerging data quantifying the global burdens of various conditions, Drs Breivik and Carr persuaded WHO that the impaired quality of life and shortened life attributed to many conditions that do not bear the word “pain” in their name (eg, anemia, arthritis, diabetes, violence…) in reality result from pain. The initial IASP-WHO-EFIC Global Day Against Pain has grown into an enduring series of educational activities. To support this year's campaign, a number of activities and resources have been implemented worldwide—publication of this Symposium Proceedings among them.

Featuring a world-renowned group of speakers, the Yokohama Satellite Symposium addressed the challenge of providing evidence-based analgesia, when policymakers in many developed nations are focusing on the devastating impact of opioid addiction. In some instances the latter follows perioperative opioid exposure or diversion of opioid medications provided to family members post-discharge after surgery. This Satellite Symposium surveyed the adverse effects of opioids, nondrug alternatives to their use, advances in nonopioid drugs and delivery systems currently available or likely soon to be, and the growing importance of quality improvement and registries to help health systems navigate a “sea change” in practice that could render routine perioperative opioid analgesia obsolete. Although the presentations emphasized adults, 2 eminent pediatric pain researchers/clinicians also presented.

The symposium began with a brief historical overview by the SIG Chair, on the theme “Perioperative opioids—from friend to foe?” [See .1. Are Perioperative Opioids Obsolete? https://youtu.be/05zoaV1xIEA?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28 for video and Powerpoint slides]. Subsequent speakers were clustered into 4 sessions:

1. Opioid adverse effects: synapse to society (Esther Pogatzki–Zahn & Jane Quinlan, co-moderators)

(a) Fred Peyerl: “Big data” mining frames postoperative opioid issues

(b) Pamela Macintyre: Opioid-induced ventilatory impairment—what's the risk and can it be reduced?

(c) Bernard Schachtel: Opioid-induced nausea and vomiting and their prevention

(d) Erica Suzan: Acute opioid tolerance/hyperalgesia—is it significant?

(e) Suellen Walker: Pediatric/developmental considerations

2. Opioid alternatives (I): behavioral and integrative (Robert Cohen & Adriana Desillier, co-moderators)

(a) Beth Darnall: My Surgical Success: A perioperative psychological intervention

(b) Robert Cohen: Hypnosis

(c) Heather Tick: Integrative therapies: the foundation for pain care?

3. Opioid alternatives (II): drugs/devices/delivery (Edward Bilsky, moderator)

(a) Stephan Schug: Update on systemic agents—overview of the latest ANZCA scientific evidence report

(b) Esther Pogatzki–Zahn: Dexmedetomidine for perioperative opioid sparing and analgesia

(c) Jacques Chelly: Local anesthetics including extended release and peripheral catheters

(d) William Schmidt: Soluble epoxide hydrolase inhibitors

(e) Donald Manning: Transcription factor inhibition

4. Making change happen: measurements driving metamorphosis (Gillian Chumley & Babita Ghai, co-moderators)

(a) Ruth Zaslansky: PAIN OUT data as agents of change—a case study

(b) Sean Mackey: Perioperative CHOIR: Daily PROMIS integration and initial results

(c) Allen Finley: Does pediatric postop pain control require opioids?

(d) Edward Michna: Postsurgical outpatient opioid analgesia as a community risk

(e) Debra Gordon: From quality improvement to system change

For ease of reference, the abstracts are presented in the same sequence as listed above. Other topics could well have been covered; additional subtopics and speakers had initially been included but fell victim to unexpected travel delays or illness. Every presenter provided an abstract afterwards when the AP SIG was offered the opportunity to publish the Symposium Proceedings in PAIN Reports. Videos of the presentations as well as corresponding Powerpoint files are available for viewing at https://www.iasp-pain.org/SIG/AcutePain.

And what of the question around which the 2016 Satellite Symposium was assembled? From the AP SIG Chair's point of view, the totality of the presentations led to the conclusion that the question itself is misleading, as it suggests a simple, binary answer. Instead, it should be asked according to the individual patient, type of operation, resources of the particular health care setting, and community situation as regards the risk of opioid diversion and abuse. From that perspective a tentative conclusion may be reached: for some operations and patients, “not yet,” and for increasing proportions of those remaining, “yes.”

To better envisage the dynamics of this change in practice, in opening the 2016 AP SIG Satellite Symposium, D.B.C. presented 2 conceptual figures shown during the 2012 AP SIG Satellite Symposium. We felt that referring to these 2 figures could help clarify discussions as to the relative place of different analgesic strategies in acute pain control, and how postsurgical pain control could increasingly minimize or eliminate routine reliance upon opioids. Figure A depicts the hypothetical distribution of pain intensity scores reported by patients soon after the same surgical operation. It emphasizes that the techniques of surgery (eg, minimally invasive) and anesthesia (eg, regional anesthesia), as well as patient factors (eg, preoperative hyperalgesia) can shift this curve to the left or right. Figure B conveys the concept of intrinsic analgesic efficacy: for a given level of early postoperative pain intensity, what percentage of patients report good pain control in response to treatment with different classes of medications.

Superimposing Figure B upon Figure A permits visualization of how treatments with various degrees of intrinsic analgesic efficacy, including nondrug strategies such as psychological interventions or acupuncture, may provide good pain control for patients with various starting levels of pain intensity. These graphs are idealized and oversimplified—pain mechanism may be more important than initial pain intensity in dictating the response to NSAIDs, for example, and coadministered drugs or other concurrent strategies may display synergy. That said, framing discussion in terms of these figures might allow us to visualize strategies leading to a time when postoperative pain intensity will never exceed “mild” and perioperative opioids will no longer be included in the routine, default analgesic regimen for postsurgical pain.

Daniel B. Carr

Editor, Acute Pain 2016 Satellite Symposium Proceedings

Chair, IASP Acute Pain Special Interest Group, 2012–2016

Tufts University School of Medicine, Boston, MA, USA

Robert I. Cohen

Co-editor, Acute Pain 2016 Satellite Symposium Proceedings

Editor, IASP Acute Pain Special Interest Group Newsletter, 2012–2017

(formerly) Harvard Medical School, Boston, MA, USA

Disclosure: The editor and co-editor report no conflict of interest. When present, commercial affiliations of presenters are indicated in each abstract.

Acknowledgments: We thank Dr Justine Carr for capably managing multiple organizational aspects of the 2016 AP SIG Satellite Symposium, and Yvonne Butters, IASP's Director of Meetings, for ensuring that the logistics of the Symposium were in place beforehand and functioned flawlessly on site in Yokohama.

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Session 1

1. Opioid adverse effects: synapse to society (Esther Pogatzki–Zahn & Jane Quinlan, co-moderators)

(a) Fred Peyerl: “Big data” mining frames postoperative opioid issues

(b) Pamela Macintyre: Opioid-induced ventilatory impairment—what's the risk and can it be reduced?

(c) Bernard Schachtel: Opioid-induced nausea and vomiting and their prevention

(d) Erica Suzan: Acute opioid tolerance/hyperalgesia—is it significant?

(e) Suellen Walker: Pediatric/developmental considerations

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“ Big data” mining frames postsurgical opioid issues: retrospective analysis of a large US electronic health record database

Fred W. Peyerl, Victor S. Khangulov, Georgios V. Varsos, Anna K. Talaga, Hannah Fan, Fabian T.W. D'Souza

Boston Strategic Partners, Inc, Boston, MA, USA

Contact Information: fred.peyerl@bostonsp.com

Introduction: The presence of opioid-related adverse events (ORADEs) can have a substantial economic impact to hospital care. We retrospectively examined treatment and outcome trends of opioid use in acute postsurgical pain management using a large sample of US patients.

Methods: A de-identified US electronic health record database (Cerner HealthFacts) with >56 million patients from 614 hospitals was used, with analysis including patients ≥18 year old who underwent an ICD-9 coding-identified surgical procedure during 2009–2015. Pain severity levels were assessed with the 0–10 Numeric Pain Score method on the first day post-op.

Results: The study included 1,581,795 postsurgical patients (58% female, 42% male), with abdominal/pelvic the most common surgical procedure (41% of patients). Approximately 1/3 of patients experienced severe pain post-op, irrespective of gender, age, and surgery type. Over 90% of patients received opioids for pain management, and approximately 30% received opioid-only treatments. Multimodal treatment (combination of opioids/non-opioids) was not found to be associated with a reduced opioid use in the postsurgical population when compared to opioid-only treatment, irrespective of surgical procedure. 11.3% of patients receiving opioids experienced at least one ORADE, while increased opioid use was associated with increasing ORADE rates across all surgical procedures. A higher opioid use was also associated with increased hospital length-of-stay (LOS).

Discussion: This study highlights the necessity for pain management, with approximately one in 3 patients being in severe pain post-op. The majority of patients use opioids in their postsurgical pain management regimen, the increased use of which is associated with increasing rates of adverse events and LOS.

Big data mining frames postsurgical opioid issues https://youtu.be/LjUeDVDvJSw?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Opioid-induced ventilatory impairment: what's the risk and can it be reduced?

Pamela Macintyre

Royal Adelaide Hospital, Adelaide, Australia

Contact Information: pamela.macintyre@adelaide.edu.au

Introduction: A major concern about the use of postoperative opioids is the risk of opioid-induced ventilatory impairment (OIVI) and death. However, the true risk of OIVI in the postoperative period is difficult to determine from the literature or large databases, in large part because OIVI is defined in different ways, usually using surrogate and possibly inaccurate measures. This means that the true incidence of OIVI is remains largely unknown—although whatever it is it must be lower.

Methods/Results: While the most accurate measure of OIVI is PCO2, most studies continue to report the incidence of respiratory rate (RR) <10 or 8 breaths/min, or to a lesser extent, oxygen saturation levels (SPO2), as indicators of adequacy of ventilation.

Discussion: Brian Ready's group clearly showed, in their 1988 paper, that patients with high PCO2 levels could maintain a reasonably normal RR but all were sedated. Many case reports of OIVI-related death also appear to show an over-reliance on RR as an indicator of OIVI. However, sedation scores, using definitions indicating a progress decrease in LOC, are still not part of routine patient monitoring in some centers. Or if they are, increasing sedation does not trigger an appropriate response and early intervention.

Reduction of risk will require at least:

1. Improved monitoring (sedation scores at a minimum and CO2 where possible) of ALL patients and not just those considered to be high-risk—with appropriate interventions as needed

2. Avoidance of concurrent sedative administration where possible, including high-dose gabapentinoids

3. Age-based opioid dosing in opioid-naïve patients

Opioid-induced ventilatory impairment: what's the risk, and can it be reduced? https://youtu.be/obrslgdNL5c?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Opioid-induced nausea and vomiting

Bernard Schachtel

Yale School of Public Health, New Haven, Connecticut, and Charleston Laboratories, Jupiter, FL, USA

Contact Information: bschachtel@charlestonlabs.com

Introduction: Publications from clinical trials indicate that approximately 40% of patients treated with opioids report nausea and/or vomiting.

Methods: Instead of relying on patients' voluntary reports, our studies on opioid-induced nausea and vomiting (OINV) implemented structured assessments of nausea and vomiting, scheduled before and at regular intervals after standard opioid treatment under randomized, double-blind, placebo-controlled conditions.

Results: Utilizing active surveillance methods, 56% of 455 post-operative patients randomized to hydrocodone 7.5 mg/acetaminophen 325 mg (HC) were identified with OINV (any moderate or severe nausea, any vomiting or any use of an anti-emetic), significantly more than placebo-treated patients. Greater incidence of OINV was observed in HC-treated patients (compared to placebo-treated patients) who were possibly or likely at risk for OINV or whose medical histories indicated they were not at risk. Most patients who developed OINV after HC initially experienced these symptoms on the first post-op day; others developed OINV only after 1 to 2 days of HC treatment or after discharge. Compared to placebo-treated patients, significantly more patients without pre-treatment nausea reported nausea/vomiting after HC treatment, and significantly more patients with mild post-operative nausea developed clinically significant (moderate/severe) nausea after HC treatment.

Discussion: Based on active ascertainment methods, these findings indicate that OINV can occur in any patient, including patients whose medical histories are only suggestive of risk for OINV as well as not-at-risk patients; OINV worsens the severity of nausea in patients with pre-existing post-op nausea; OINV can develop in patients who are discharged without nausea or vomiting; and OINV is a distinct clinical outcome.

2-3: Opioid-induced nausea and vomiting. No presentation associated with this abstract.

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Acute opioid tolerance/hyperalgesia: is it significant?

Erica Suzana,b, Elon Eisenberga,c

aInstitute of Pain Medicine, Rambam Health Care Campus, Haifa, Israel

bFaculty of Social Welfare and Health Sciences, University of Haifa, Israel

cThe Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa, Israel

Contact Information: erica.dol@gmail.com

Introduction: Opioid induced alterations in sensitivity to pain can be the result of several phenomena. These include tolerance, withdrawal or opioid induced hyperalgesia (OIH). These conditions result in increased postoperative pain intensity and thus may seem very much alike, leading to their improper diagnosis and treatment. The aim of this brief review was to present an overview of these phenomena in the context of post-operative pain.

Methods: Literature was reviewed for studies examining the effect of presurgical opioid administration on postoperative pain measures. Studies were divided into 3 subgroups according to the timing of presurgical opioid administration: chronic pre-operative opioid use, pre-emptive opioid administration and opioid administration during surgery. OIH was measured postoperatively by collecting data on pain intensity and on opioid requirements.

Results: In all 3 subgroups, preoperative opioid administration yielded less favorable results in terms of increased postoperative pain intensity and opioid consumption, compared to no opioid treatment. Moreover, opioid-treated patients had longer hospitalization and slower recovery rates.

Discussion: Opioid administration before the end of a surgical procedure can lead to clinical hyperalgesia, but study designs to date seem to represent opioid withdrawal rather than true OIH. This observation is strengthened by the fact that in some of the studies an increased rather than decreased opioid dose was required for adequate postoperative pain control. Nonetheless, regardless of the terminology or specific mechanism, opioid administration both before and during surgery has a negative impact on acute postoperative pain.

2-4. Acute opioid tolerance/hyperalgesia: is it significant? https://youtu.be/5sZBTqmDeFg?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Perioperative opioids: pediatric and developmental considerations

Suellen M. Walker, MBBS, MMed, MSc, PhD, FANZCA, FFPMANZCA

Reader and Honorary Consultant in Paediatric Anaesthesia and Pain Medicine, UCL GOS Institute of Child Health, London, United Kingdom

Contact Information: suellen.walker@ucl.ac.uk

Introduction: Opioids are frequently utilized for perioperative pain management at all ages from preterm neonates to adolescents. Age-related differences in dose requirements may influence both treatment efficacy and risk of adverse events.

Methods: A literature search identified recent clinical and laboratory data (PubMed key words: opioid; postoperative; children; neonate; development). Additional articles were identified from previous hand searches and reviews.

Results: Opioids are commonly prescribed to hospitalized children. Developmental changes in both pharmacokinetic (eg, reduced clearance in neonates) and pharmacodynamic profiles (eg, alterations in opioid receptor distribution, density and function) contribute to age-dependent differences in dose requirements and risk of side effects. Large audits have shown variability with age, type of surgery, and prior experience, and an increased risk of respiratory depression in infants born preterm and children with comorbid neurodevelopmental, respiratory and cardiac conditions. Multimodal therapy is recommended and co-administration of nonsteroidal anti-inflammatory drugs and/or paracetamol reduces opioid requirements. Codeine is no longer recommended as high metabolizer genotypes are at risk for respiratory complications, particularly following tonsillectomy in children with sleep apnea. In neonatal intensive care, routine morphine infusion for sedation (as opposed to analgesia) may be associated with dose-dependent hypotension and adverse outcome. Children are susceptible to withdrawal following prolonged opioid exposure, and age-appropriate assessment tools and management strategies are available.

Discussion: Opioids can be safely and effectively used as part of multimodal perioperative analgesia in children. Age-appropriate dosing and administration, with regular monitoring and validated pain assessment tools, facilitate titration against individual response to improve efficacy and minimize side-effects.

2-5. Perioperative opioids: pediatric and developmental considerations https://youtu.be/VftcF8liyDw?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Session 2

(2) Opioid alternatives (I): behavioral and integrative (Robert Cohen & Adriana Desillier, co-moderators)

(a) Beth Darnall: My Surgical Success: A perioperative psychological intervention

(b) Robert Cohen: Hypnosis

(c) Heather Tick: Integrative therapies: the foundation for pain care?

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My surgical success: an internet-based perioperative pain psychology intervention

Pamela Flooda, Amanda Wheelerb, Chloe Tauba, Melissa Wibowoa, Ian Mackeya, Corinne Junga, Beth Darnalla

aDepartment of Anesthesiology, Perioperative and Pain Medicine and bDepartment of Surgery, Stanford University, Stanford, CA, USA

Contact Information: bdarnall@stanford.edu

Introduction: Preoperative pain catastrophizing strongly predicts postoperative pain intensity and duration, opioid use, and recovery. Prior work found that a brief, targeted class reduced pain catastrophizing in chronic pain outpatients. We conducted a randomized controlled trial to test the feasibility and preliminary efficacy of an automated, online, intervention designed to reduce psychological distress and pain catastrophizing in patients scheduled for breast cancer surgery.

Methods: Patients were referred by their surgeons and 121 enrolled online prior to being randomized to one of 2 presurgical treatment arms: (1) online text health education (HE); (2) My Surgical Success (MSS), a pain psychoeducational program comprised of a 90-minute video, a relaxation audio file, and downloadable worksheets. Data were collected at baseline (pre-randomization) and 1 to 2 days prior to surgery. Post-surgical data collection: pain and opioid use were rated daily for the first month; major time points were monthly to month 3.

Results: Eighty-seven women completed the trial (MSS = 45; HE = 41). The main reason given for not completing the trial was lack of time prior to surgery. Data are currently in analysis.

Discussion: This project aims to demonstrate feasibility and preliminary efficacy for a low-cost, accessible, perioperative pain psychology intervention that targets pain catastrophizing. Targeted therapies are needed to improve surgical outcomes including pain, opioid use, and psychological experience.

3-1. My surgical success: an internet-based perioperative pain psychology intervention https://youtu.be/-_xRM4fxoig?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Behavioral and integrative nonopioid alternatives: hypnosis

Robert I. Cohen, Elvira V. Lang

Harvard Medical School (formerly)

Contact Information: ricohen12@gmail.com

Introduction: This survey summarizes research published by the senior author (EVL) and others showing the opioid-sparing effects of: (1) avoiding negative suggestions, and (2) reading scripted hypnoidal language before medical procedures. Patients learn to comfort themselves and require less or no additional medication.

Methods: A fundamental component of the active interventions included a team training approach whereby nonphysician, non-mental health professionals acquired knowledge and skill to confidently help patients learn to comfort themselves during a medical procedure. In one series of articles, pain, anxiety, satisfaction, opioid dose, duration, and cost outcomes were compared for cohorts of patients before (control) and after team training in hypnoidal language (treatment). The teams reviewed videos of the procedures. In the control arm, there were many incidents where providers warned patients they would feel pain or have an undesirable experience immediately before a potentially painful stimulus. These were tallied as were negatively loaded (but ostensibly sympathetic) comments after the stimulus.

Results: Patients who received “standard care” (control group) had steadily increasing levels of pain and anxiety. The hypnosis (treatment) group reported a significant decrease in opioid dose, procedure duration, cost, and an increase in satisfaction. Healthcare providers' avoidance of negative suggestions and reading a short hypnoidal language script one to 3 minutes in length before starting the procedure, produced an effect that persisted to procedure completion, irrespective of duration. Pre-stimulus warnings with negatively loaded wording occurred frequently in the control but not the hypnosis (treatment) group, and was associated with greater pain intensity (3.9 vs 2.7, P = 0.0261) and anxiety scores (4.4 vs 3.6, P = 0.0007). Sympathizing statements after stimuli were not associated with increased pain (2.7 vs 2.5, P = 0.3351), but did increase anxiety scores (3.7 vs 2.9, P = 0.0339).

Discussion: Techniques based on hypnosis can be applied by nonphysician, non-mental health professionals to help patients learn to comfort themselves during painful medical procedures. A brief opioid sparing intervention appears to provide a long-lasting “immunization” against pain and anxiety that otherwise both increase steadily during procedures. Providers not yet trained in how to choose and deliver words of comfort, despite having good intentions offered negatively loaded words of warning before a stimulus, or sympathy afterwards, increasing patient distress and answering affirmatively the question, “can words hurt?”

3-2. Behavioral and integrative non-opioid alternatives: hypnosis https://youtu.be/w7cOXockagw?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Integrative therapies: the foundation for pain care

Heather Tick

University of Washington, Seattle, WA, USA

Contact Information: htick@uw.edu

Introduction: During current efforts to reduce opioid consumption and avoid long-term dependence on opioids, there is renewed interest in integrative pain medicine (IPM) and the nonpharmacologic treatments used with this approach.

Methods: Literature on some of the most commonly used nonpharmacologic therapies was reviewed as well as the methodological differences between conventional care and IPM.

Results: IPM uses a patient-centered approach to health creation. It begins preoperatively with proper nutrition using an anti-inflammatory diet with ample plant-based foods and attention to common micronutrient deficiencies. Common deficiencies in the US are vitamins D and B12, magnesium, and omega-3 fatty acids. The use of turmeric for its anti-inflammatory and analgesic properties in the perioperative period is being studied as a safe and effective alternative or addition to NSAIDs and opioids. Additional IPM strategies of relevance not only to postsurgical pain include acupuncture and acupressure, chiropractic, yoga and massage. The US Department of Defense and Veterans Health Administration have reported on the use of these practices for acute and chronic pain control in military medicine and attest to their “the evidence basis for their effectiveness, their robust patient acceptance, and broad safety margin.”

Discussion: IPM has an excellent safety record but has not enjoyed the robust level of funding given to pharmacological agents. However, many IPM therapies are generations if not centuries old. Given the known iatrogenic harm that arises from the commonly used pharmacologic treatments for pain after surgery, and the safety and effectiveness of IPM, there are good arguments to use these nonpharmacologic therapies early and when needed, persistently for pain after surgery.

3-3. Integrative therapies: the foundation for pain care https://youtu.be/I5FR3jnZnVY?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Session 3

(3) Opioid alternatives (II): drugs/devices/delivery (Edward Bilsky, moderator)

(a) Stephan Schug: Update on systemic agents—overview of the latest ANZCA scientific evidence report

(b) Esther Pogatzki–Zahn: Dexmedetomidine for perioperative opioid sparing and analgesia

(c) Jacques Chelly: Local anesthetics including extended release and peripheral catheters

(d) William Schmidt: Soluble epoxide hydrolase inhibitors

(e) Donald Manning: Transcription factor inhibition

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Update on systemic agents—overview of the latest ANZCA scientific evidence report

Stephan A. Schug

University of Western Australia, Perth, Australia

Contact Information: stephan.schug@uwa.edu.au

Introduction: At the end of 2015 the fourth edition of the document “Acute Pain Management: Scientific Evidence” was published by the Australian and New Zealand College of Anaesthetists and its Faculty of Pain Medicine.

Methods: The document aims, as did preceding editions, to present a review of the best available evidence on acute pain management and align this with current clinical and expert practice. Key messages in the document are presented as concise statements with the highest level of evidence listed. These include clinical practice points based on clinical experience or expert opinion.

Results: Multimodal analgesia is defined as the combination of multiple analgesics with different mechanisms or sites of action. This stategy should lead to improved analgesia while being opioid-sparing and hence reducing adverse effects of opioids. The following key messages were highlighted: Systemic agents that have been shown to achieve these goals are paracetamol, NSAIDs, gabapentinoids, ketamine, systemic local anesthetics, alpha-2-agonists and (to a very limited extent) dexamethasone. The evidence level for all these key messages is level 1 (meta-analysis or systematic review of randomized controlled trials).

Discussion: These results confirm the concept of multimodal or balanced analgesia as an approach to reduce the reliance on opioid analgesics for the management of acute pain. This method will lead to a reduction of opioid side effects and improve postoperative recovery. However, future research needs to address the question of which combinations of how many systemic analgesics provide the optimal analgesic efficacy, as this question remains currently unanswered.

4-1. Update on systemic agents–overview of the latest ANZCA Scientific Evidence report https://youtu.be/X5ZlfLeFFm0?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Dexmedetomidine for perioperative opioid sparing and analgesia

Esther Pogatzki-Zahn

Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany

Contact Information: pogatzki@anit.uni-muenster.de

Introduction: Besides their other adverse effects, intraoperative opioids may enhance postoperative pain by proalgesic mechanisms. One aim therefore is to reduce or eliminate the use of strong opioids intra- and postoperatively by adding substances with opioid-sparing effects. One group of drugs possibly able to potentiate the analgesic effects of opioids and produce analgesic effects are alpha-2 adrenoreceptor agonists. Dexmedetomidine (DEX) is the pharmacologically active dextro-enantiomer of medetomidine, the methylated derivative of etomidine. DEX is the most selected a-2 adrenoreceptor agonist clinically available and is 8 times more specific for α-2 adrenoceptors with α-2: α-1 selectivity ratio of 1620:1, compared with 200:1 for clonidine, especially for the 2a subtype.

Methods: The results of 3 recently published meta-analyses (Schnabel et al, Pain 2013;154(7):1140–9; Baudszun et al, Anesthesiology 2012;116:1312–22; Schnabel et al, Paediatr Anaesth 2013;23(2):170–9) investigating the effect of DEX administered intraoperatively on analgesic consumption and pain postoperatively were reviewed and discussed. Furthermore, results from one procedure-specific meta-analysis (Lundorf et al, Cochrane Database of Syst Rev 2016, Issue 2. Art. No.: CD010358.) and one meta-analysis investigating the facilitatory effects of perineural DEX on neuraxial and peripheral nerve block (Abdallah, Brull, Br J Anaesth 2013;110(6):915–25) were reviewed as well.

Results: All meta-analyses consistently show that DEX significantly decreases postoperative pain intensity and nausea, and had an opioid-sparing effect compared with placebo after i.v. administration in adults. Subgroup analysis indicates a smaller opioid sparing effect for a bolus alone, or infusion alone, compared with bolus followed by infusion. DEX seems to be more effective than clonidine in opioid sparing but direct comparisons are missing. Similar results for DEX were found in children; postoperative pain and the need for postoperative opioids were reduced if DEX was applied intraoperatively in comparison with placebo. Furthermore, emergence agitation and PONV were reduced by perioperative DEX in children. Finally, DEX seems to have a potentiating effect upon local anesthetics injected intrathecally or peripherally as part of a peripheral nerve block.

Discussion: DEX is able to reduce opioid consumption and pain after surgery if administered intraoperatively. The effect seems to be increased with higher doses and durations of infusion. However, dose-finding studies are few and more need to be done. In children emergence agitation is reduced in addition to the analgesic and opioid-sparing effect. The most important adverse event is intraoperative bradycardia and possibly concomitant hypotension; additional safety data are needed before DEX can be recommended for perioperative use in adults and children. Together, the intraoperative effect of DEX in adults and children is meaningful; what remains to be defined is the most appropriate (effective) dose with least harm for adults and children for acute postoperative pain, and whether long-term follow up provides clues to possible prevention of chronic pain after surgery with DEX.

4-2. Dexmedetomidine for perioperative opioid sparing and analgesia https://youtu.be/5yxSRdGy-o8?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Local anesthetics including extended release/duration and peripheral nerve block catheters: a narrative review

Jacques E. Chelly

Division of Acute Interventional Perioperative Pain, Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA, USA

Contact Information: ChelJE@anes.upmc.edu

Introduction: Regional anesthesia including peripheral nerve blocks has proven to be an effective alternative to the sole use of opioids for management of acute pain in adults and children.

Methods: A narrative review of the literature was conducted.

Results/Discussion: Although the administration of opioids is effective when administrated neuroaxially alone and/or in combination with local anesthetics, local anesthetics alone can provide equal or superior analgesia. For such indications they can be administered as a single bolus and/or a continuous infusion or a combination of both. Although single blocks are performed more frequently than continuous nerve blocks, their use is sometimes limited by surgical requirements, eg, preservation of motor function, and emergence of pain because of their relative short half-life. The use of continuous peripheral nerve blocks allows prolonged duration of the block and better preservation of motor function, especially when a low concentration of local anesthetic is infused slowly. More recently, liposomal preparations of local anesthetics (mainly bupivacaine) have been developed so as to prolong the effects of “single-shot” blocks. Their therapeutic place remains to be established. The most commonly used local anesthetics used for regional anesthesia are lidocaine, mepivacaine, bupivacaine and ropivacaine. Use of mepivacaine alone and/or in combination with lidocaine has been advocated for blocks of deliberately short duration. The use of ropivacaine allows a block of longer duration. In addition, at low doses, ropivacaine has been established to preserve motor function resulting in a predominantly sensory block. In the past few years, we have seen an evolution from nerve blocks to field blocks. This difference of technique has been facilitated in part by the growing use of ultrasound-guided needle placement. Although these field blocks are increasingly used, they require larger volumes and the use of local anesthetic at higher concentrations, raising concern about dose-related toxicity. Further, we have witnessed the increasing use of mixtures of local anesthetics together with varied drugs including steroids, buprenorphine, dexmedetomidine, and epinephrine. Regardless of agent administered for neural blockade, the time pressures of busy surgical practices and shift to outpatient surgery from inpatient settings have driven a return to predominant use of single blocks rather than longer-duration, catheter-based infusions. Finally, the use of local anesthetics as analgesic cannot overlook their cautious, monitored systemic (intravenous) infusion in the early postoperative period as part of a multimodal approach.

4-3. Local anesthetics, including extended release/duration and peripheral nerve block catheters https://youtu.be/z3A_d5zbfzc?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Soluble epoxide hydrolase inhibitors as novel non-opioid analgesics

William K. Schmidt

EicOsis LLC, Davis, CA, USA

Contact Information: schmidtwk@sbcglobal.net

Introduction: Epoxyeicosatrienoic acids (EETs) are endogenous anti-inflammatory and analgesic lipids that are rapidly degraded by soluble epoxide hydrolase (sEH). We hypothesized that a synthetic inhibitor could extend the half-life of EETs from minutes to hours with the goal of producing a novel non-opioid medication for treatment of acute or chronic pain.

Methods: EC5026 (Ki = 50 pM vs recombinant human sEH) was selected for human development. A related compound, EC1728, was selected for veterinary development. Both are kinetically reversible, tight binding inhibitors of sEH with a slow off-rate predictive of once daily dosing.

Results: sEH inhibitors block both inflammatory and neuropathic pain in rodents without affecting sensorimotor parameters. They are functionally inactive in the absence of pain and do not show reward activity in rodent conditioned place preference tests. EC5026 has a greater efficacy profile in neuropathic pain models than pregabalin and, unlike pregabalin, produces no adverse motor or cognitive deficits in rodents. EC1728 reduces natural age-induced osteoarthritis pain in dogs (oral 1–5 mg/kg per day). EC1728 (0.1 mg/kg i.v. per day) successfully treated laminitis-related pain, inflammation, and morbid hypertension in a thoroughbred race horse that was scheduled for humane euthanasia. The horse had a full recovery after failing to respond to several days of treatment with NSAIDs, steroids, or gabapentin.

Discussion: With the support of an NIH Blueprint Neurotherapeutics grant awarded in 2016, EC5026 is being prepared for human clinical studies with an expected Investigational New Drug filing with the US Food and Drug Administration in 2017. EC1728 is being prepared similarly for veterinary use in companion animals.

4-4. Soluble epoxide hydrolase inhibitors as novel non-opioid analgesics https://youtu.be/X79-BMeIuiI?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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AYX1, an EGR1 decoy oligonucleotide, provides long-term reduction of postoperative pain and prevention of chronic pain after TKA

Donald C. Manning

Adynxx Inc, San Francisco, CA, USA

Contact Information: donaldcmanning@gmail.com

Introduction: Postsurgical opioid-based pain management leaves many patients inadequately relieved. A significant number develop chronic pain leading to prolonged opioid use. A novel treatment approach is to preemptively inhibit the transcription factor EGR1 that triggers the long-term gene regulations supporting neuronal sensitization. AYX1 is an oligonucleotide decoy specifically binding and inhibiting EGR1 activity. It is delivered via a bolus intrathecal injection immediately prior to surgery and prevents the maintenance of mechanical hypersensitivity in animal models.

Methods: In 2 Phase 2 randomized, double-blind, placebo controlled clinical studies in unilateral TKA patients with a standard of care anesthetic/analgesic regimen, AYX1 or placebo was administered intrathecally once preoperatively and followed for 42 days. Primary efficacy endpoints were mean pain rating (11-pt NRS) while walking 5 m (0–48 hours) and 15 m (7–28 days). Secondary endpoints included pain at rest.

Results: Two hundred twenty-two subjects were enrolled, 216 dosed and received AYX1 at either 110 mg/3 mL, 330 mg/3 mL, 660 mg/6 mL or 1100 mg/10 mL doses or volume-matched placebo. AYX1 660 mg/6 mL significantly reduced pain with walking and at rest from days 7 to 28 compared to placebo (P = 0.026, 0.033 respectively), markedly reduced the incidence of pain ≥4 with walking (0% vs 21%) and pain >0 at rest (26% vs 74%) compared to placebo at day 42. Safety was comparable between AYX1 and placebo with no AYX1-related serious adverse events.

Discussion: Preoperative administration of AYX1 660 mg/6 mL significantly reduced pain with walking and at rest from 7 to 28 days, which persisted throughout the study providing evidence of chronic pain prevention and the potential for reduction of long-term opioid use.

4-5. AYX1 provides long-term reduction of postoperative pain and prevention of chronic pain after TKA https://youtu.be/NXD-xwaGR90?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Session 4

(4) Making change happen: measurements driving metamorphosis (Gillian Chumley & Babita Ghai, co-moderators)

(a) Ruth Zaslansky: PAIN OUT data as agents of change—a case study

(b) Sean Mackey: Perioperative CHOIR: Daily PROMIS integration and initial results

(c) Allen Finley: Does pediatric postop pain control require opioids?

(d) Edward Michna: Postsurgical outpatient opioid analgesia as a community risk

(e) Debra Gordon: From quality improvement to system change

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Perioperative pain management practices associated with “GOOD” patient reported outcomes in patients undergoing surgery for total knee replacement

Ruth Zaslanskya, C. Richard Chapmanb, Marcus Komanna, Winfried Meissnera

aDepartment of Anesthesiology & Intensive Care, Friedrich-Schiller University Hospital, Jena, Germany and bPain Research Center, Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA

Contact Information: ruth.zaslansky@gmail.com

Introduction: This study sought to identify perioperative management practices in wards where Patient Reported Outcomes (PROs) were “GOOD.” Consented criteria and thresholds to judge quality of care are lacking. We proposed that “GOOD” wards would have the highest proportion of patients with worst pain since surgery ≤4 AND pain relief ≥0.7 AND time spent in severe pain on postoperative day one (POD1) ≤10% AND patients would not wish to receive additional pain treatment. The study involved 2 phases: (1) identify “GOOD” wards; (2) examine treatment practices, including opioids, on those wards.

Methods: Findings were analyzed from wards participating in PAIN OUT, a perioperative pain registry (www.pain-out.eu), contributing data from ≥40 patients, undergoing total knee replacement as a single procedure. Patients filled in a questionnaire assessing PROs on POD1; surveyors abstracted perioperative practices from patient records. Logistic regression with “quality” as criterion and 10 process indicators, as predictors, was employed to detect perioperative processes in “GOOD” wards.

Results: Fourteen centers, 1159 patients, qualified for the analysis. PROs in 2 wards, 203 patients, were best. Management practices in “GOOD” wards included: sedation as pre-medication, anesthesia with femoral or spinal blocks, regional analgesia in recovery, perioperative non-opioids, and pain measurement on the ward. Effect sizes for these predictors were medium to large, indicating meaningful clinical impact on being “GOOD,” however, confidence intervals were large. Perioperative opioids were not associated with “GOOD” outcomes.

Discussion: PAIN OUT offers “real world” findings to guide providers. Opioids did not contribute to “GOOD” outcomes. Future work in other surgical models could further elucidate which treatment processes lead to “GOOD” PROs.

5-1. Perioperative pain management practices and “GOOD” patient-reported outcomes in TKR surgery https://youtu.be/qPDbsmn0OJY?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Perioperative Collaborative Health Outcomes Information Registry (CHOIR) as a learning health system: motivation, development and initial results

Sean Mackey

Division of Pain Medicine, Stanford University

Contact Information: smackey@stanford.edu

Introduction: There is a need for capture of high quality, high volume and high value data to inform clinical care in the perioperative environment and for real-world research discovery. The US National Academies of Medicine (NAM) have called for the development of Learning Healthcare Systems (LHS) to address this need. We have previously developed a Collaborative Health Outcomes Information Registry (CHOIR) as an open-source LHS for the outpatient clinical environment. We now show the extension of CHOIR into the perioperative and the initial results.

Methods: The American Academy of Pain Medicine hosted a perioperative pain summit at Stanford University with the goal of defining a minimal outcomes dataset in the perioperative period. This included assessment during the immediate pre-surgical baseline and repeated longitudinal assessments at weeks 1, 4, 8, 12, 26, and 52. Assessments include a battery of PROMIS CAT measures of physical, psychological and social functioning as well as demographics and information on opioids. We built these assessments into a tailored version of CHOIR. CHOIR was then integrated into the Stanford Anesthesia Preoperative Evaluation Clinic and their daily workflow.

Results: Perioperative CHOIR has been successfully running and integrated into the clinical workflow for approximately 1 year. Clinical adoption of the system by patients, staff and clinicians has been high. As a preliminary modeling effort using a general additive model, over 5,000 patients were assessed during a 5 month sample window. We demonstrated that hospital length of stay (LOS) can be predicted using several of the baseline PROMIS and demographic measures.

Discussion: We have demonstrated feasibility and adoption of Preoperative CHOIR to capture high volume, high quality data in the perioperative period. Future goals will be to (1) release the code for other academic collaborators, (2) integrate educational and psychobehavioral tools to impact future pain opioid use, and (3) further develop predictive models for software decision support.

5-2. Perioperative Collaborative Health Outcomes Information Registry (CHOIR) learning health system https://youtu.be/L2YvETx7-TI?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Does pediatric postop pain control require opioids?

G. Allen Finley

Dalhousie University, Halifax, Canada

Contact Information: Allen.Finley@Dal.Ca

Introduction: Recommendations for treatment of moderate to severe acute pain in children were reviewed. Economic and political barriers to utilization of opioid to treat pain in children were discussed.

Methods: The essential role played by opioids was highlighted by matching opinion and discussion points with current evidence-based guidelines.

Results: Opioid sparing techniques available in resource-rich nations include the use of psychological techniques, epidural infusions, spinal and plexus blocks, the use of sophisticated drug delivery devices such as peripheral perineural catheter infusions and duration-extending drug formulations. Although not available to resource-poor nations, alternative low-tech, low-cost solutions were described. For example, rather than an expensive continuous infusion pump, the same effect can be accomplished by intermittent opioid injection into a subcutaneous butterfly needle. When sophisticated regional anesthetic techniques are not available, simple wound infiltration with local anesthetic can provide some of the same benefits. While some pediatric procedures may be managed without opioid analgesia, many do. Listed examples included spinal fusion, ventricular-peritoneal-shunts, surgical stabilization of multi-trauma, major abdominal or thoracic procedures and cleft palate repair. The use of paracetamol and non-steroidal anti-inflammatory drugs were discussed as part of multimodal care with and without opioid as a first step in treating mild to moderate pain. Additionally, most new procedures and medications for which safety testing occurs in adults, are not approved for use in children for many years if at all.

Discussion: This review provided a positive response to the question posed in the title of this presentation. The important historical quote by Sir Thomas Sydenham, is particularly illustrative: “Among the remedies which it has pleased almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium.” Despite the US Centers for Disease Control's promulgation of the thesis that prescription opioids are the “major” drug problem, we would say that the larger “drug problem” is making opioids readily available to those with moderate to severe acute pain worldwide, including children.

5-3. Does pediatric postoperative pain control require opioids? https://youtu.be/t8SLC8UdBtg?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Perioperative opioid analgesia as a community risk

Edward Michna

Director, Pain Trial Center, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA

Contact Information: emichna@bwh.harvard.edu

Introduction: Perioperative opioids can have adverse events at the individual level both in the short-term and the long term. Of the latter, the most serious are substance abuse and fatal overdose.

Methods: A literature search combined with the results of clinical studies from the author's institution identified epidemiological data of gaps in evidence, and empirical strategies to try to minimize these adverse effects.

Results: The growth of new nonmedical opioid use was partially attributed to prescription analgesics. The lack of specific knowledge as to how perioperative exposure of patients to opioids contributes to the above problems inhibits the ability to effectively address this aspect of the problem.

Discussion: Clinicians must practice using incomplete information at the individual and population-wide level. This reality has led our center to assess opioid misuse risk in patients receiving postoperative pain control. But we still do not know:

(1) the proportion of patients given perioperative opioids who develop substance use disorder

(2) whether the choice of specific opioid molecules or formulations influences this progression

(3) how best to identify at-risk patients preoperatively

(4) what effect universal use of standardized risk assessment tools and monitoring protocols (eg, urine drug testing) has upon preventing substance use disorder

(5) the secondary and/or unintended consequences of a torrent of numerous new laws and prescribing restrictions directed towards minimizing postoperative opioid availability

5-4. Perioperative opioid analgesia as a community risk https://youtu.be/9fHCrD8OGqI?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

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Acute opioid pain care in the crosshairs, from QI to systems change: the Harborview Medical Center experience

Debra B. Gordon

Anesthesiology & Pain Medicine, Harborview Medical Center, University of Washington, Seattle, WA, USA

Contact Information: debrag3@u.washington.edu

Introduction: Opioids serve as the cornerstone for severe acute postoperative pain management with proven efficacy for this indication. Nevertheless, a balanced, rational multimodal analgesic approach is most effective in controlling pain, while at the same time minimizing opioid doses and their resultant side effects that interfere with rehabilitation.

Methods: The U.S. opioid epidemic demands a transformation of care using a systems approach focused on an interprofessional acute pain team, pathways of care and management of care transitions. This presentation describes the expanded role of the Acute Pain Service and psychological treatment, including brief and effective behavioral interventions to reduce catastrophizing that can be applied across transitions of care to enhance recovery and reduce length of stay. Comprehensive team-based care is provided across preoperative, postoperative and transitional care with structured opioid taper when necessary until back to primary care. Pain specialists are also integrated within primary care clinics to support patients in the medical home.

Results: This model has been successful in fostering cultural transformation with improved screening and early intervention of high risk patients, increased use of multimodal analgesia, recognition and engagement in addiction recovery programs for identified individuals and partnering with community-based care programs.

Discussion: Challenges include valid, reliable and timely measurement of harm and cost avoidance. Sustained improvements require a change in mindset and the relentless work of operational redesign. Ongoing work is needed to monitor progress, address institutional barriers to change, and integrate multiple teams' work.

5-5. Acute opioid pain care in the crosshairs, from QI to systems change https://youtu.be/k6OO8w6TWPw?list=PLsCqqM167wVEGqZ4BgzmFixtsfzAaNH28.

© 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.