1. The Opioid Epidemic and Perioperative Implications
17th Annual Practical Updates in Anesthesiology
February 2 – February 7, 2014
Peter Stiles, MD
Paul Hilliard, MS, MD

2. 35 year old female
CC: abdominal pain and bloating x1 year PMH: Rheumatoid arthritis (managed without opioids) Allergies: Reports “severe intolerance” of morphine and codeine PSH: Unspecified spinal fusion, TAH, bladder suspension

3. 35 year old female Found a pancreatic cyst – NOT an emergency
Gen surg performs an uncomplicated whipple; no pre-op discussion of pain management apart from thoracic epidural placement in pre-op by OR team
ACUTE PAIN SERVICE (APS) consult for severe post-op pain
No apparent explanation for 11/10 pain
The patient had a working epidural with a level, good IV with IV split opioids; physiologically, it would appear her pain should be well controlled; adjuncts were started, etc.

4. 35 year old female Generated 17 notes in 6 days
Resulted in multiple episodes of hypotension, significant sedation
Unanticipated SICU admission for uncontrollable pain - Multiple infusions
Highly tolerant hydromorphone PCA
Patient stating 10/10 pain throughout hospitalization
Extreme dissatisfaction per the patient, regrets surgery

5. 35 year old female PSH: Spinal fusion, TAH, bladder suspension
No issues after those procedures

6. What’s different?

7. 360mg daily PO morphine equivalents
What’s different?
Over the preceding months, her abdominal pain had been treated with increasing opioids, up to 80mg Oxycontin TID
360mg daily PO morphine equivalents

8. Outline
Review the state of opioid prescriptions and abuse in the United States
Investigate how this will impact anesthesia practice and what can be done
Introduce the Michigan High-Dose Opioid Taper Initiative – suggestions for pre-op management
Review opioid induced hyperalgesia
What to do the morning of surgery

9. Pain is relevant to every practice
> 100 million people
#1 presenting complaint to health professionals
Est. $560 - $635 Billion
Roughly the cost of cancer, heart disease, and DM…..combined!
Committee on Advancing Pain Research, Care, and Education, Institute of Medicine. "Summary." Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press, 2011.

10. Endorsed by 2 separate pain societies in 1996 --Seemed like a great idea…
Image Credits: Themanualtherapist, psychologyofpain.blogspot.com, pilothealthadvocates.com

14. Opioid Prescriptions Reach Epidemic Proportions
In 3 months of he received at least 11 prescriptions for painkillers from eight doctors – 370 tablets
May 12th, 2011 he died from a accidental overdose of oxycodone

15. Opioid Prescriptions Reach Epidemic Proportions
Poisoning is the leading cause of injury-related death in the United States.
In 2011, more people died of drug over­dose (mostly accidental) than died of vehicle (car, truck, ATV, etc) accidents!
Of all poisoning deaths, about 75% of all poisoning deaths are from legal pharmaceutical grade opioids.
National Vital Statistics System. Table 2. Deaths, death rates, and age-adjusted death rates for 113 selected causes, Injury by firearms, Drug-induced Injury at work, and Enterocolitis due to Clostridium difficile: United States, final 2010 and preliminary Available at 

17. Pay close attention the scales used on the charts, they had to revise the scales for the three on the left because there was such a significant discrepancy
International Narcotics Control Board uses a calculation of “defined daily doses for statistical purposes (S-DDD) consumed per million inhabitants per day”
It extrapolates that while national or regional consumption of opioids cannot be identified as the “the right amount or adequate” they established generalities that consumption of analgesics via the S-DDD metric of was inadequate, thereby meaning that the region or country probably was not appropriately addressing the pain needs of their population. <100 was considered very inadequate.

18. This is killing us….
Admissions for treatment of opioid addiction per 100,000 people
Rate (per 100,000) of unintentional drug overdose deaths
Official statistics are only available through 2007, projected numbers are even higher today

19. Rate (per 100,000) of unintentional drug overdose deaths
The figure above shows the rate of unintentional drug overdose deaths in the United States during 1970–2007. In 2007, approximately 27,000 unintentional drug overdose deaths occurred in the United States, one death every 19 minutes. Prescription drug abuse is the fastest growing drug problem in the United States. The increase in unintentional drug overdose death rates in recent years has been driven by increased use of a class of prescription drugs called opioid analgesics.
National Vital Statistics System. Available at 

20.  Human Development Index (HDI) is a composite statistic of life expectancy, education, and income indices to rank countries into tiers of human development; created by economist Mahbub ul Haq, followed by economist Amartya Sen in 1990, and published by the United Nations Development Programme

26. US makes up 4.7% of the World population, yet we prescribe 80% of all opioids prescribed worldwide

27. Deaths attributable to Heroin, Cocaine and Opioids
This trend continues…
The figure above shows the number of unintentional drug overdose deaths involving opioid analgesics, cocaine, and heroin in the United States during 1999–2007. Since 2003, more overdose deaths have involved opioid analgesics than heroin and cocaine combined.
National Vital Statistics System. Multiple cause of death dataset. Available at 

28. The White House Responds
In response to recent CDC findings the government issued a plan which calls for a multiagency, multispecialty approach with the goal of decreasing opioid use in the United States over the next few years
“Research and medicine have provided a vast array of medications to cure disease, ease suffering
and pain, improve the quality of life, and save lives. This is no more evident than in the field of pain
management. However, as with many new scientific discoveries and new uses for existing compounds,
the potential for diversion, abuse, morbidity, and mortality are significant. Prescription drug misuse and
abuse is a major public health and public safety crisis. As a Nation, we must take urgent action to ensure
the appropriate balance between the benefits these medications offer in improving lives and the risks
they pose. No one agency, system, or profession is solely responsible for this undertaking. We must
address this issue as partners in public health and public safety. Therefore, ONDCP will convene a Federal
Council on Prescription Drug Abuse, comprised of Federal agencies, to coordinate implementation of
this prescription drug abuse prevention plan and will engage private parties as necessary to reach the goals established by the plan.”
The White House. Epidemic: Responding to America’s Prescription Drug Abuse Crisis. Accessed October 21, 2012.

30. Why is this a problem for periop patients?
SAFETY
SATISFACTION
How is this relevant to us, as anesthesiologists and pain medicine specialists? We certainly use opioids regularily. 3 domains that impact out patients and our healthcare system…that we can directly affect. This ‘untold story’ likely will not make the lay-press, but it is something of which we must be aware.
COST

31. Patient Safety
Remember the introductory case?...it’s not uncommon
Between 350,000 to 750,000 in-hospital cardiopulmonary arrests occur annually in the United States.
Roughly 80% of the victims don’t survive to discharge
About half of patients with in hospital arrests had been receiving opioids.
Overdyk FJ, et al. Improving outcomes in med-surg patients with opioid-induced respiratory depression. American Nurse Today Nov;6(11)

32. Patient Safety
Difficult to study with RCTs

33. Patient Safety
Difficult to study with RCTs

34. Copyright © 2012 American Medical Association. All rights reserved.
From: Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths
JAMA. 2011;305(13): doi: /jama
Figure Legend:
Date of download: 3/26/2013
Copyright © 2012 American Medical Association. All rights reserved.

35. Patient Safety
Higher opioid requirements postoperatively, not surprisingly, are associated with more side effects
55% of patients receiving opioids required nausea, vomiting and/or constipation pharmacologic treatments.
IV opioids had nearly 5x risk of GI side effects compared to oral nonopioid analgesics
Urinary retention
Design  Case-cohort study.
Setting  Veterans Health Administration (VHA), 2004 through 2008.
Participants  All unintentional prescription opioid overdose decedents (n = 750) and a random sample of patients (n = 154 684) among those individuals who used medical services in 2004 or 2005 and received opioid therapy for pain.
Main Outcome Measure  Associations of opioid regimens (dose and schedule) with death by unintentional prescription opioid overdose in subgroups defined by clinical diagnoses, adjusting for age group, sex, race, ethnicity, and comorbid conditions.
Sun D-C, Kim MS, Chow W, Jang E-J. Use of medications and resources for treatment of nausea, vomiting, or constipation in hospitalized patients treated with analgesics. Clin J Pain. 2011;27:508-17

36. Pain Control
Difficult to measure
Not many chronic pain patients will be excited about reducing the daily dose of opioid
BUT….some evidence exists in support of tighter opioid management

37. Pain Control (Satisfaction)
Tolerance
A point exists where we cannot further increase opioid dose
This can make treating acute surgical pain, on top of the patient’s baseline pain and opioid dependence very difficult and unsafe
Opioid Naive
Opioid Tolerant
Analgesic Response
Dose

38. Pain Control
Opioid-Induced Hyperalgesia

39. Pain Control Opioid-Induced Hyperalgesia
“A state of nociceptive sensitization caused by exposure to opioids”
Not yet fully understood, 5 proposed mechanisms
All implicate neuroplastic changes in both the peripheral and central nervous systems
Most widely accepted hypothesis involves the Central Glutaminergic System
NMDA receptors see increased glutamate from transport inhibition; various linkages implicated – result in apoptotic cell death in the dorsal horn
Give example of a patient on 8 hours of remifentanil; we can induce this…but imagine someone on 20 years of oxycontin

40. Fig. 2 Sensitization of peripheral nerve endings.
Opioid-induced Hyperalgesia: A Qualitative Systematic Review
Angst, Martin S.; Clark, J David
Anesthesiology. 104(3): , March 2006.
Fig. 2. Neuroanatomical sites and mechanisms implicated in the development of opioid-induced hyperalgesia during maintenance therapy and withdrawal. (1) Sensitization of peripheral nerve endings. (2) Enhanced descending facilitation of nociceptive signal transmission. (3) Enhanced production and release as well as diminished reuptake of nociceptive neurotransmitters. (4) Sensitization of second-order neurons to nociceptive neurotransmitters.Figure 2does not illustrate all potential mechanisms underlying opioid-induced hyperalgesia, but rather depicts those that have been more commonly studied. DRG = dorsal root ganglion; RVM = rostral ventral medulla.
Sensitization of peripheral nerve endings.
Enhanced descending facilitation of nociceptive signal transmission.
Enhanced production and release as well as diminished reuptake of nociceptive neurotransmitters.
Sensitization of second-order neurons to nociceptive neurotransmitters
Copyright © 2013 Anesthesiology. Published by Lippincott Williams & Wilkins.

41. Cost
A nation-wide 2005 study demonstrated that a single day admission to the ICU requiring mechanical ventilation was $10,794
A prolonged PACU stay can cost $4-$8 per minute
Adverse outcomes can cost the hospital millions
Don’t forget indirect costs…
Dasta JF, et al. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005 Jun;33(6):
Weinborum AA, et al. Efficiency of the operating room suite. American Journal of Surgery. 2003;185:244–250

42. What to do!? National epidemic Dissatisfied patients
Uncontrollable pain (both patient and provider….)
Rising costs our country cannot afford

43. 35 year old female with abd pain
s/p whipple, 11/10 pain despite: - Working epidural - IV PCA - Dexmedetomidine infusion - Appropriate adjuncts
What can we do before she arrives in pre-op?
What can we, and should we, have done – before and after her surgery, to optimize her care? Ideally, decrease opioids, set realistic expectations, planned for appropriate level of monitoring.
--Just like we would not go to the OR if a patient’s BP was 200/120 in pre-op, for fear of difficult to control BP intra- and post-op, so to should we be mindful of pre-op pain and opioid needs

45. Goal: optimize perioperative patient safety and pain control
Identify high risk patients at the initial visit
Connect with and support PCPs/prescribers to set expectations and taper opioids
Improve utilization of opioid adjuncts
Improve post-op pain control, safety, satisfaction and cost

54. We do not record doses or frequencies of opioids in centricity; medical records can be vague; this is a way to look them up, even the morning of surgery

55. Michigan Automated Prescription System

56. 22 states now have instant access!

57. Michigan Automated Prescription System
Detailed history of all the Schedule 2-5 controlled substances that a particular patient has legally obtained
Helpful determining:
Dose of medication
Contact information of prescriber(s)
Number of opioid prescribers
ED visits for opioids
Polypharmacy

59. Where are the patients getting their opioids?
The figure above shows the percentage of patients and prescription drug overdoses, by risk group in the United States. Among patients who are prescribed opioids, an estimated 80% are prescribed low doses (<100 mg morphine equivalent dose per day) by a single practitioner, and these patients account for an estimated 20% of all prescription drug overdoses. Another 10% of patients are prescribed high doses (≥100 mg morphine equivalent dose per day) of opioids by single prescribers and account for an estimated 40% of prescription opioid overdoses. The remaining 10% of patients seek care from multiple doctors, are prescribed high daily doses, and account for another 40% of opioid overdoses.
National Vital Statistics System. Available at 

61. Patient Contact and Education

62. PCP Contact and Education

64. Patients should be open to opioid adjuncts in the perioperative period
It is likely not possible, or safe, to reduce the patient’s postoperative pain score below his or her baseline
Limiting the preoperative opioid regimen is in the patient’s best interest
Patients should be open to opioid adjuncts in the perioperative period
Pain control expectations, patient participation and surgical outcome
The goal of pain control is to restore function
Expectations and pain management should not end at hospital discharge
It is likely not possible, or safe, to reduce the patient’s postoperative pain score below his or her baseline – Even if the surgery aims to improve the patient’s chronic pain, there will be an acute component postoperatively. The patient needs to be aware, prior to surgery, that a degree of discomfort is expected after the surgery.
Limiting the preoperative opioid regimen is in the patient’s best interest ­– This may be difficult to convey to patients that are dependent on opioids; limiting pre-op opioids leaves more room for safe escalation of these medications following the surgical insult.
Patients should be open to opioid adjuncts in the perioperative period – The perioperative team may suggest procedures (epidurals, nerve blocks) or medications (gabapentin, ketamine, Tylenol, etc) with which the patient may not be familiar. It should be reinforced that such measures are in the patient’s best interest and should be considered with an open mind.
Pain control expectations, patient participation and surgical outcome – Poor communication and pain treatment after surgery can impair function, ADL participation/ambulation, physiologic function (circulation, respiration, GI function, etc.), psychological well-being and quality of life. Two-way communication between patients and providers is essential. Further, patients must own an active role in their recovery, working through expected pain, to optimize outcome.
The goal of pain control is to restore function – A principle of chronic pain management is functional restoration. This should also be a perioperative goal for patients on high-dose opioids. Providers will work with patients to establish a safe level of pain relief, allowing patients to meaningfully participate in recovery activities (incentive spirometery, physical therapy).
Expectations and pain management should not end at hospital discharge – Recovery from surgery takes weeks to months; patients will likely experience increased pain during this period. Depending on the goal and outcome of the surgery, the patient’s baseline pain may be altered. Surgery is not an “easy fix,” it takes dedication and hard work on the part of both patients and primary providers.

66. Why do I need to know all that?!
In the chronic pain population: Make plan before surgery

67. Why do I need to know all that?!
Pre-Op Clinic Considerations
Taper opioids down to the lowest tolerated dose
Communicate with opioid prescriber and plan for perioperative considerations
Allay fears of needles, tylenol
SET EXPECTATIONS

68. BEEP, BEEP, BEEEEEEP!!

69. ADD ON – OR 17, ORIF s/p MVA; pt in resus bay C; pt takes Xanax and Methadone; NPO since 0600.

70. Morning of Surgery Set Expectations Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

71. Morning of Surgery Set Expectations Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

72. Morning of Surgery Regional or Epidural if possible Set Expectations
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

73. Morning of Surgery Consider available adjunct medications
Set Expectations
Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

74. Multimodal Analgesia Treat pain at multiple sites on pain pathway
Improved pain control
Opioid-sparing
Decreased side effects

75. Multimodal Analgesia Opioids Cyclooxygenase inhibitors
alpha-2 agonists
Membrane stabilzers
Ketamine
Nitrous Oxide
Magnesium
Local anesthetics (epidural & infiltration)

76. Morning of Surgery Continue long acting opioids Set Expectations
Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

77. Morning of Surgery
Set Expectations
Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

78. Morning of Surgery Arrange for appropriate post-op destination
Set Expectations
Regional or Epidural if possible
Consider available adjunct medications
Continue long acting opioids
Calculate the baseline need and ensure that is met and, within safe reason, exceeded
Arrange for appropriate post-op destination

79. Special Case Meds

80. Periop Management of Methadone
DISCERN INDICATION
If for chronic pain, continue perioperatively and supplement with opioids and other analgesics
If for addiction, dose will be very high, saturating opioid receptors and causing patient to act similar to suboxone user

81. A Growing Consideration

82. Periop Management of Buprenorphine
Buprenorphine (Suboxone) – partial opioid agonist, blocks opioid receptors, used for addiction and chronic pain
Elective vs. Emergent

83. Periop Management of Buprenorphine

84. Periop Management of Buprenorphine
Elective surgery –
If not in pain and procedure is amenable (i.e. ambulatory), may continue with surgery with adjunct medications
If in pain before procedure or procedure is invasive, refer to prescriber for taper then treat with standard doses of opioids, regional anesthesia, multimodal techniques

85. Periop Management of Buprenorphine

86. Periop Management of Buprenorphine
Emergent surgery
If patient is pain-free, continue buprenorphine and use adjunct medications, cautious with opioids
If patient is in pain,
start PCA (likely high dose)
consider ICU admission
maximize adjuncts (tylenol, NSAIDs, gabapentin, ketamine or dexmedetomidine infusions),
regional anesthesia
Be wary of rapid decrease in opioid tolerance when buprenorphine clears (24-72hrs)

87. Preparation pays off: a final case example
56yo male presenting for spinal traction, then fusion
Crohn’s disease, LE amputations, bowel resections, at least 6 prior spine surgeries, chronic pain, intrathecal pain pump
Extensive Past surgical hx
Huge medication list
Allergic to Neurontin, Lyrica, Ambien, Remicade
No significant Family or Social Hx

88. Preparation pays off: a final case example
Intrathecal Dilaudid, 7.991mg daily
PO Dilaudid, 8mg every 8 hours
Methadone, 40mg every 8 hours
16546 mg of PO morphine equivalents!!!

90. APS consultation SET EXPECTATIONS
Discussed goals, ICU admission, adjuncts
Tapered off short acting opioids
Minimized Methadone
Continued intrathecal opioids
Started on tylenol, SSRI

92. Post-op management
Planned ICU admission
Dexmedetomidine gtt
Lidocaine patches near surgical sites
Diazepam for spasms
Dilaudid PCA followed by a slow wean
Continued baseline methadone, intrathecal meds
Allergic to gabapentin and pregabalin, so unable to use membrane stabilizers
For most of the patient’s recovery, his pain was at or below his baseline!

93. Satisfaction: 5/5! Met our 3 goals:
Improved safety (no hypotension, oversedation, or re-intubation)
Lowered costs (bypassed PACU, abbreviated ICU stay)
Optimized Satisfaction
Satisfaction: 5/5!

95. Thank you for your attention!!
Search “Michigan Opioid Taper” for the resources I’ve introduced
See me for a card with the website
Thanks to:
Anesthesiology QA committee
Dr. Paul Hilliard
My wife, Stephanie (she’s probably by the pool)
Department of Orthopedic Surgery
UM Preoperative Clinics
UM School of Computer Science
Health Science Library
UM Hospital Legal Team
MiChart Development Team
ECCA (Executive Committee on Clinical Affairs)

96. References
Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg Aug;97(2):
Bialosky, JE, Bishop, MD, Cleland JA. Individual Expectation: An Overlooked, but Pertinent, Factor in the Treatment of Individuals Experiencing Musculoskeletal Pain. Phys Ther. 2010 Sept; 90(9):1345–1355.
Keltner JR, Furst A, Fan C, Redfern R, Inglis B, Fields HL. Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study. J Neurosci Apr 19;26(16):
Stomberg MW, Oman UB. Patients undergoing total hip arthroplasty: a perioperative pain experience. .J Clin Nurs Apr;15(4):451-8.
Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA, Blow FC. Association Between Opioid Prescribing Patterns and Opioid Overdose-Related Deaths. JAMA. 2011;305(13):
Dasta JF, et al. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005 Jun;33(6):
Overdyk FJ, et al. Improving outcomes in med-surg patients with opioid-induced respiratory depression. American Nurse Today Nov;6(11)
Weinborum AA, et al. Efficiency of the operating room suite. American Journal of Surgery. 2003;185:244–250
Committee on Advancing Pain Research, Care, and Education, Institute of Medicine. "Summary." Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press, 2011.
Sun D-C, Kim MS, Chow W, Jang E-J. Use of medications and resources for treatment of nausea, vomiting, or constipation in hospitalized patients treated with analgesics. Clin J Pain. 2011;27:508-17
The White House. Epidemic: Responding to America’s Prescription Drug Abuse Crisis. Accessed October 21, 2012.
Maund E, McDaid C, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth Mar;106(3):292-7.
Brummet C. Management of Sublingual Buprenorphine (Suboxone and Subutex) in the Acute PerioperativeSetting.
Berkowitz, B.A., Finck, A.D., Hynes, M.D. & Ngai, S.H. (1979). "Tolerance to nitrous oxide analgesia in rats and mice". Anesthesiology 51 (4): 309–12
Sawamura, S., Kingery, W.S., Davies, M.F., Agashe, G.S., Clark, J.D., Koblika, B.K., Hashimoto, T. & Maze, M. (2000). "Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors". J. Neurosci. 20 (24): 9242–51.
Angst, MS & Clark, DJ: Opioid-induced hyperalgesia: A qualitative systematic review. Anesthesiology 2006; 104:570–87
Lee M, Silverman S, Hansen H, Patel V, Manchikanti L. A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician 2011;14:
Song JW, Lee YW, Yoon KB, Park SJ, Shim YH. Anesth Analg. 2011 Aug;113(2): doi: /ANE.0b013e31821d72bc. Epub 2011 May 19.
Pesonen A, et al. Pregabalin has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth Jun;106(6): doi: /bja/aer083. Epub 2011 Apr 6
Tiippana EM, Hamunen K, Kontinen VK, Kalso E. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg Jun;104(6):
Weinger MB. Dangers of postoperative opioids. APSF Newsletter  ;21:61-7

97. Deaths attributable to Heroin, Cocaine and Opioids
This trend continues…
The figure above shows the number of unintentional drug overdose deaths involving opioid analgesics, cocaine, and heroin in the United States during 1999–2007. Since 2003, more overdose deaths have involved opioid analgesics than heroin and cocaine combined.
National Vital Statistics System. Multiple cause of death dataset. Available at