Xavier FalièresAnesthesiologist. Medical director day care hospital. Trainer anesthesiology

Albert Schweitzer Hospital. Dordrecht – The NetherlandsPresident of the Dutch Society Ambulatory Care

Executive committee of the International Association for Ambulatory SurgeryUniversity lecturer, University of medicine I, Yangon, Myanmar.

“Opioid Free / Opioid Reduced” in Anesthesia? For sure!

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§ End 80: Briançon (France), Heli, emergency, ICU: fentanyl and R1406

§ Early 90: trainee and then staff member anesthesiology ULg(Liège, Belgium): except Cardio, neuro (high dose opiates) and onco ENT (neurolept droperidol fentanyl), usually 10 mcg sufenta max.

§ Use of adjuvants: clonidine, MgSO4, anti-hypertensive agents.KetaminePropacetamol, NSAIDs IV for incision

§ An in-between year in Luxembourg: opioids are wonderful

§ From 1996: remifentanil. Patients have remarkably much more postop pain with higher opioids needs.

§ From 2002: the Netherlands. From high dose opioids to back to ORA - OFA.

§ Myanmar: 10 mg morphine = 100 spinal. 10 mcg sufenta = 5 patients IV

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Opium has been known since very ancienthistorical times.

Opium seeds and capsules were found in a Swiss Neolithic village (12,000 years ago)

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In the 2nd century AD, Galen, a doctor, realized the risksof excessive use of opium.Emperor Marcus Aurelius, his patient, was the first described opium addict.

The Opium Addiction of Marcus Aurelius Thomas W. Africa Journal of the History of Ideas Vol. 22, No. 1 (Jan. - Mar., 1961), pp. 97-102

War, Plague, Opium and Stoicism: The Life of Roman Emperor

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Opium, called al-yun by the Arabs, was described as the most powerfulof all analgesics.

In the 9th century inhalation anesthesia with Spongiasomnifera, a mixture of opium, mandragora, cicuta andhyosinwas used by Arab doctors for surgical procedures.

During this period, the Arabies introduced opium in India andthen in China, where it was called o-fu-yung.

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At the beginning of the Renaissance, Paracelsus, a Swiss physician who livedbetween 1493 and 1541, reintroduced

opium for medical use in Western Europe:

"Of the drugs offered by the AlmightyGod to relieve human suffering, there is

no such a universal and effectiveopium"

Laudanum: tincture of opium was used until the beginning of the20th century

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To finance their ever-increasing desire for Chinese tea, silk and porcelain, Britain began smuggling Indian opium to China from the 17th century. This resulted in a huge addiction among the Chinese and led to the Opium Wars of the mid-19th century. Subsequent Chinese immigration to work on the railways and the gold feverbrought opium smoke to America.

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The opium trade was legalized

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1909: opium smoking is prohibited.Anti-Heroin Act of 1924 is a federal law of theUnited States that prohibits the import andpossession of opium for the chemical synthesis of an addictive narcotic known as diamorphine or heroin.

When his addictive potential was recognized,Bayer stopped production in 1913

In 1805 Friedrich Sertürner, a German pharmacist's assistant, worked to isolateactive opium principles: the "principium somniferum", or morfium.

1816 Gay Lussac has proposed replacing the name morfium with morphine, whichbecame the permanent name.

In June 3, 1845, Irish physician Francis Rynd was the first to administersubcutaneous liquid morphine.

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• 1898: diamorphine (heroin)

• 1916: oxycodone (developed in Germany)

• 1924: hydromorphon (developed in Germany)

• 1932: pethidine (1st synthetic – Germany)

• 1960: piritramide (Janssen - Belgium)

• 1963: tramadol (Germany)•

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§ During the American civil war (1861 to 1865): massive use of morphine among wounded soldiers: first massive cases of addiction and social problems in the US.

§ British soldiers during the Crimean War, Prussian soldiersduring the war between France and Germany in 1870 have also used morphine injections with the same addictionconsequences.

§ However, concepts of tolerance, psychological and physicaldependence were only widely discussed in the early 20th century (WW1).

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Dr Baron Paul Adriaan Johannes Janssen (12 September 1926 – 11 November 2003) was a Belgian physician and pharmacologist andfounder of janssen pharmaceutica.

§ Janssen introduced the Dextromoramide in 1956 (Palfium, out of trade 2015) and in 1957 the Phenoperidine (known in France as R1406 and in use until the late 1980s)

§ Studies on new phenylpiperidine products led to§ 1960: Fentanyl, the first of these new opioids (piritramide also in

1960)

§ Between 1974 and 1976, the following fentanyl analogues weredeveloped: § 1974: carfentanil (suitable for very large animals, such as elephants, hippos, lions)

§ 1974 sufentanil§ 1976 alfentanil

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1992: It’s widely said Dr. Paul Janssens invented remifentanil, but refused to

market remifentanil and sold it to Beecham, afraid of unknown long-term

effects of opioids...

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The pressure coming from the pharmaceutical industry

to use more and more opioids will grow till the beginning of the 21st

century

Misuse of opioids perioperatively

=

Chronic pain

=

Opioid addiction risk

Hypnosis

Analgesia Relaxation

AmnesiaHemodynamic

stabilityImmobilisation

Balanced anesthesiaInhalation, opioids, NMB

TIVA (TCI): propofol, opioids, NMB

§ Analgesia: αναλγησία absence of pain

§ Anesthesia: αναισθησία absence of sensations

In the practice of medicine, anesthesia is a state of temporary induced loss of sensation or awareness.

A patient under the effects of anesthetic drugs is referred to as being

anesthetized.

§The questions we may ask ourselves:

ØIf the patient is deep asleep, do we need opioid analgesia?

ØDo we feel pain during anesthesia?

ØDo we need opioids to achieve hemodynamic stability?

A. Cividjian, F. Petitjeans, N. Liu, M. Ghignone, ... L. Quintin Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception. Best Practice & Research ClinicalAnesthesiology. Volume 31, Issue 4, December 2017, Pages 445-467

NOCICEPTION ≠ PAIN

§ 3 tools:§ Pupillometry§ ANI§ NOL

Ongoing studies with encouraging preliminary results.

OFA = ORA = OBA

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§ 1992: Dr Paul Janssens invented remifentanil but refused to market remifentanil and sold it to Beecham afraid of unknown long-lasting effects of opioids…

§ Opioids Induced Hyperalgesia: ØPatients receiving opioids, also at low dose, become more

sensitive to painØPatients receiving opioids during surgery will need higher doses

morphine postoperatively

Hyperalgesia induced by low-dose opioid treatment before orthopaedic surgery: An observational case–control studyHina, Nabil; Fletcher, Dominique; Poindessous-Jazat, Frédérique; Martinez, Valéria European Journal of Anaesthesiology (EJA): April 2015 -Volume 32 - Issue 4 - p 255–261Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis D. Fletcher and V. Martinez British Journal of Anaesthesia112(6): 991–1004 (2014)

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Glare P, Aubrey K, Myles PS. Transition from acute to chronic pain aftersurgery. Lancet 2019; 393: 1537–46.Neuman MD, Bateman BT, Wunsch H. Inappropriate opioid prescription after surgery. Lancet 2019; 393: 1547–57.Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia. Lancet 2019; 393: 1558–68.

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Ambulatory status was found to have a strong interaction with opioid associated 30-day readmission(P<0.001).In ambulatory populations, where this association is particularly strong, long-acting doses abovethe equivalent of approximately 0.4 mg i.v. hydromorphone and short-acting doses on the order of 100mg fentanyl were significantly associated with readmission.

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Philip Montgomery: Faces of an Epidemic. 2019 Photo Contest, Contemporary Issues, Stories, 3rd Prize

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G. T. T. Helmerhorst, T. Teunis, S. J. Janssen, D. Ring. An epidemic of the use, misuse and overdose of opioids and deaths due to overdose, in the United States and Canada is Europe next? Bone Joint J 2017;99-B:856–64

In The Netherlands

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Immunosuppression by opioids? Doubts since 1979

What we know:

Ø Morphine decreases natural and acquired immunity, both directly and indirectly via the activation of central receptors.

Ø Opioid-induced changes in the immune system may affect the outcome of surgery, including bacterial and viral infections and cancer.

Ø The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients.

Choosing anesthetic drugs without an effect on immuneresponses may be an important consideration in anesthesia.

Wybran J. Suggestive evidence for receptors for morphine and methionine-enkephalin on normal human blood T lymphocytes. J Immunol. 1979;123:1068-70Paola Sacerdote, Silvia Franchi and Alberto E. Panerai. Non-Analgesic Effects of Opioids: Mechanisms and Potential Clinical Relevance of Opioid-InducedImmunodepression. Current Pharmaceutical Design. 2012; 18: 6034Kim J Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence Transl Med (2018) 16:8

It is also emerging that not all opioids induce the same immunosuppressive effects and evaluating each opioid profile is important for ap- propriate analgesic selection. The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients. Indeed, it is evident that the possibility of reaching adequate and equivalent paincontrol by choosing either immunosuppressive drugs or drugs without an effect on itninune responses may be an impor- tam consideration in opioid therapy.

Dozens of articles: contradictory conclusions but all retrospective

WAITING?OR

ACTION NOW?

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Injury, Int. J. Care Injured 49 (2018) 1266–1271

Opioids impair recovery from injury; if they also predispose to injury, the ongoing opioid epidemic could presage an increase in nonunion prevalence.

How toavoid opioids?

Hypnosis and immobilization: Classical TIVA / TCI, inhalational

agents with or without muscle relaxants

§ Direct sympathetic block central – peripheral:§ Clonidine, Dexmedetomidine, B blockers

§ Indirect block of sympathetic effects:§ Nicardipine, lidocaine, Mg sulfate, inhalation vapor

§ Low dose ketamine, lidocaine

§ Multimodal analgetics (non opioids) loading up per-operative to be active when waking up:§ Dexamethason, NSAID’s, paracetamol

§ Truncal blocks, plexus blocks, distal nerves and local infiltration block

§ Analgesic spinal / single shot epidural analgesia.

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§ Clonidine and dexmedetomidine are the 2 α2-adrenergic agonists used in anethesia

§ Clonidine is widely used in GA, epidural, spinal and peripheral blocks since the 90’s

§ Dexmedetomidine: § approved in 1999 by the US Food and Drug Administration (FDA) as

a short-term sedative and analgesic (<24 hours) for critically ill or injured people on mechanical ventilation in the intensive care unit (ICU).

§ In 2008 the FDA expanded its indication to include non-intubated people requiring sedation for surgical or non-surgical procedures

§ Now widely used off label in G.A.§ More and more publications over the use of dexmedetomidine in

epidural, spinal and peripheral blocks (off label)

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Reduce stress response. Very useful e.g. in laparoscopic surgery. Esmolol contributes to a significant decrease in postoperative pain and PONV and facilitates earlier discharge.

§ 33% reduction vs placebo in opioid consumption postoperative when the lidocaine infusion was maintained for 1 hour

§ 83% reduction vs placebo in opioid consumption postoperative when the lidocaine infusion was maintained for 24 hours.

§ Earlier return of bowel function, allowing for earlier rehabilitation and shorter duration of hospital stay.

§ Duration of hospital stay was reduced by an average of 1.1 days in the lidocaine-treated patients.

§ Intravenous lidocaine did not result in toxicity or clinically adverse events.

§ Oncolytic effect: more and more proofs

McCarthy G. Impact of Intravenous Lidocaine Infusion on Postoperative Analgesia and Recovery from Surgery A Systematic Review of Randomized Controlled Trials. Drugs. 2010;70:1149-63Kim J Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence Transl Med (2018) 16:8

Effect of lidocaine on per-op hypnotics

§ Mechanism of action:

§ blockade of NMDA and HCN1 receptors,§ cholinergic, aminergic, and opioid systems appear to play both a positive

and negative modulatory role in both sedation and analgesia.

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There were no negative effects of ketamine on POD / POCD

(es)Ketamine reduces opioidinduced hyperalgesia

§ First publications in the 90’s. Lower considerably the postoperative morphine consumption.

§ Study from 2010: Thoracotomy patients received Fentanyl as required and 30-50 mg/kg MgSO4 followed by continuous infusion of 500 mg/h or placebo. Fentanylconsumption during the operation was significantly lower in the Mg treated groupversus placebo.

Martin R. Tramer, MD; Jurg Schneider, MD; Rene-Andreas Marti, MD; Kaplan Rifat, MD Role of Magnesium Sulfate in Postoperative Analgesia Anesthesiology 2 1996, Vol.84, 340-347.Kogler The analgesic effect of magnesium sulfate in patients undergoing thoracotomyJ Acta Clin Croat. 2009;48:19-26.

The mechanism of the analgesic effect of Mg is not clear but interference with calcium channels and N-methyl-D-aspartate (NMDA) receptor seem to play an important role.

§ Dexamethasone: positive effects in anesthesia know since 1959: Vey active on postop PONV and postoperative pain. 0,15 mg/kg (0,1 to 0,2 mg/kg).

§ No problem in DM patient if only single dose.

§ No problem in oncological surgery

§ Non opioid analgesics: begin before incision.Ø Paracetamol: loading 40 mg/kg, max 2 g

Ø NSAID’s: loading diclofenac 2 mg/kg max150 mg or ketorolac 40 mg

Ø When available: metamizol up to 2 g loading

§ Local infiltrations, analgesic blocks: use lower concentration, high volume. Before incision if possible. Calculate toxic dose.

Massera G. Indications for steroid anesthesia. Acta Anaesthesiol. 1959;10:541-9.Tiippana E. Effect of paracetamol and coxib with or without dexamethasone after laparoscopic cholecystectomy.Acta Anaesthesiol Scand. 2008;52:673-80

§ Use wound infiltration.

§ Give blocks: § Breast surgery: PECS I + SAB / PVB / ESPB § Thorax: SAB / PVB / ESPB / Epidural§ GI surgery: TAP / ESPB / Epidural

§ Use adjuvants, liposomal bupivacaine.

§ Use catheters for continuous infusion LA in postoperative painful surgery.

§ Postoperative pain < 4, not 0 using opioids

§ Opioid prescribing at hospital discharge for a toolong period: determinant of persistent postoperative opioid use

§ Prescribing opioids at hospital discharge topreviously opioid-naive patients is a risk factor forchronic opioid use 1 year after discharge.

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Calcaterra SL, Yamashita TE, Min SJ, Keniston A, Frank JW, Binswanger IA. Opioid prescribing at hospital discharge contributes to chronicopioid use. J Gen Intern Med. 2016;31: 478–485.Wu, Christopher L. And al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Opioid Minimization in Opioid-Naïve Patients. Anesth Analg 2019;129:567–77

For outpatient open hernia repair and

cholecystectomy, a standardized pain care bundle

decreased opioid prescribing significantly and

frequently eliminated opioid use, while adequately

treating postoperative pain and improving patient

satisfaction.

Luke B Hartford and al, Standardization of Outpatient Procedure (STOP) Narcotics: A Prospective Non-Inferiority Study toReduce Opioid Use in Outpatient General Surgical Procedures. J Am Coll Surg 2019;228:81-88.

Very few:

§ Severe hart diseases, Low LVEF, ASA 4, bad condition patients, trauma, acute bleeding, etc…

§ Allergy to one of the drugs.

"Successive transition from one paradigm to another via revolution is theusual developmental pattern of mature science."

Thomas Kuhn, The Structure of Scientific Revolutions, 1962.

§ More studies focused on quality of outcome are needed.

§ Try to limit opioid use in anesthesia Ø from liberal policy to restrictiveØ from restrictive to OFA when possible

Stress induced postoperative pain has a negative influence on outcome: use opioids if needed but titrate them.

Postoperative opioid free is also the new debate in the literature

We need to inverse our way of thinking:

From opioid based anesthesia with non opioids medication as rescue

To

Non opioid based anesthesia with opioids only when needed

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Opioids

Block stress responseEsmolol

InfusionsLidocaine Ketamine

Wound Local infiltration

Analgesic peripheral neuro-axial blocks

Non-opioid analgesicsParacetamol NSAIDS Dexamethasone

Opioid-free / reduced anesthesia and other opioid-free / reduced pain relief strategies are

essential in the control of the opioid crisis. Postoperative complications can be reduced or

prevented.

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