Accepted Manuscript

OPIOID-BASED ANESTHESIA FOR ADULT CARDIAC SURGERY:

HISTORY AND NARRATIVE REVIEW OF THE LITERATURE

Dr. Lloyd Edward Kwanten Locum Consultant ,

Dr. Benjamin O’Brien Clinical Director of Perioperative Medicine ,
Dr. Sibtain Anwar Consultant in Cardiothoracic Anaesthesia

PII: S1053-0770(18)30386-0
DOI: 10.1053/j.jvca.2018.05.053
Reference: YJCAN 4747

To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Received date: 8 February 2018

Please cite this article as: Dr. Lloyd Edward Kwanten Locum Consultant ,
Dr. Benjamin O’Brien Clinical Director of Perioperative Medicine , Dr. Sibtain Anwar Consultant in Cardiothoracic A
OPIOID-BASED ANESTHESIA FOR ADULT CARDIAC SURGERY: HISTORY AND NARRATIVE
REVIEW OF THE LITERATURE, Journal of Cardiothoracic and Vascular Anesthesia (2018), doi:
10.1053/j.jvca.2018.05.053

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 ACCEPTED MANUSCRIPT

OPIOID-BASED ANESTHESIA FOR ADULT CARDIAC SURGERY:

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HISTORY AND NARRATIVE REVIEW OF THE LITERATURE

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Dr. Lloyd Edward Kwanten
Locum Consultant,
Department of Perioperative Medicine
Barts Heart Centre, Barts Health NHS Trust
London EC1A 7BE
lloyd.kwanten@bartshealth.nhs.uk US
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Dr. Benjamin O’Brien
Clinical Director of Perioperative Medicine
Barts Heart Centre, Barts Health NHS Trust
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London, EC17BE
Ben.OBrien@bartshealth.nhs.uk
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Dr. Sibtain Anwar

Consultant in Cardiothoracic Anaesthesia,
Barts Heart Centre, Barts Health NHS Trust
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London, EC17BE
sibtain.anwar@bartshealth.nhs.uk

Keywords: Analgesics, Opioid; Hyperalgesia; Acute Pain; Thoracic Surgery; Cardiac

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Surgical Procedures; Anesthetics

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Introduction:

It was only in the middle of the twentieth century that open-heart surgery became possible.

Since then, the outcomes of cardiac surgery have improved considerably, with evolution of

surgical techniques, cardiopulmonary bypass technology and significant improvements in

the delivery of anesthesia and intensive care. Anesthetic practice has transitioned from sole

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dependence on high dose opioids to a multimodal approach of intravenous, inhalational and

regional anesthetic techniques, alongside reducing doses of opioids. There remains

considerable variability in the use of opioid agent as well as dose, amongst international

cardiac centers, and not one opioid is seen as an ideal agent.

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We present first a short history of the use of opioids in cardiac anesthesia, followed by a

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detailed comparison of the different opioids used. Firstly, we look at the difference in

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analgesic efficacy among agents, as well as the routes of administration. Following this, we

describe the advancements in opioid pharmacology which facilitated expedited recovery of

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patients in the postoperative critical care environments, to be known as fast track cardiac

anesthesia (FTCA). With the decline in postoperative mortality over the years, the outcome
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focus has shifted to being more patient-centered, such as quality of recovery and prevention

of chronic pain. Thus, we examine the evidence for the effects that different opioids play in
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postoperative hyperalgesia and the development of chronic pain. There are animal and in

vitro models to support the role that opioid receptors and exogenous opioids play in
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cardioprotection of the heart perioperatively, and we examine the newer evidence available.

Topical issues such as the role of perioperative opioid use in the global opioid crisis are
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discussed, and we conclude with a discussion on opioid-sparing techniques and new opioid

in development that may play a role in cardiac anesthesia.

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We selected some important or topical outcome variables – including postoperative

analgesia, FTCA, chronic pain, and cardiac protection – and looked at the evidence that

opioids play and comparisons among opioids. A PubMed literature search between 1980 to

week 12 of 2017 with search terms included combinations “heart surgery”, “cardiac

surgery”, “thoracic surgery” AND “opioids”, “opiate”, “morphine”, “fentanyl”, “remifentanil”,

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“alfentanil”, “sufentanil”, “oxycodone”, “methadone”, “hydromorphone”, “narcotic analgesic

agent” AND “pain”, “acute pain”, “chronic pain”, “hyperalgesia”, “post-thoracotomy pain

syndrome”, “chronic post-sternotomy pain”, “cardioprotection”, “heart protection”,

“extubation”, and “fast track”. The search was limited to reviews and original research

articles of adults, and English language, and the titles and abstracts were read to obtain

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relevant studies. Pertinent historical papers and case reports were also included. Articles

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were excluded if there was no direct comparison of opioids, were related only to lung-

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related surgery (including video-assisted thoracoscopic surgery) or with postoperative

sedation.

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We present here a discussion of the publications included, structured into the following
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sub-sections: route of opioid administration, dose of opioids and FTCA, opioid induced

hyperalgesia and chronic neuropathic pain, cardioprotection, and a discussion on the opioid
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crisis and novel opioids in development. We refer to the group of drugs in this manuscript

as ‘opioids’ rather than ‘opiates’ (a subset of opioids) or ‘narcotics’ (imprecisely defined and
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typically has negative connotations). A summary of the opioids and recommendations for

use in renal and hepatic impairment is shown in Table 1.1,2 For a recent review of the
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pharmacology of opioids, we refer the reader to Pathan and Williams.3

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The Early Era

In the 1960s, Edward Lowenstein and colleagues described the use of a high-dose morphine

technique (up to 3mg/kg) as the primary anesthetic for cardiac surgery.4 The ‘cardiac

anesthetic’ as it came to be known, consisted of oxygen, a muscle relaxant, and high-dose

morphine. It gained widespread popularity because it provided favorable hemodynamics in

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patients with limited circulatory reserves that may be unable to tolerate conventional

anesthetic agents. This technique had limitations, including an inability to cause reliable

unconsciousness and amnesia, the histamine release led to hypotension in some patients,

and the requirement of prolonged postoperative mechanical ventilation.5 In equipotent

doses, meperidine (pethidine) decreased myocardial contractility and caused peripheral

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vasodilation, the combination of which led to a marked decreased in cardiac output, thus

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unsuitable for use in those with impaired cardiovascular function. Historically, other

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opioids including papaveretum, diamorphine, pentazocine and buprenorphine have also

been studied in post-cardiac surgical patients, but there is no recent evidence in efficacy

over opioid agents that have succeeded them.6

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Paul Janssen, a Belgian chemist, was instrumental in the development of fentanyl in 1960.

The chemical structure, based on the piperidine ring, reduced histamine release compared
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with morphine, allowing for increased potency while retaining cardiovascular stability.

Theodore Stanley and colleagues gave their cardiac surgery patients high-dose fentanyl as
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the sole anesthetic and ventilation with oxygen, noting that complete anesthesia was

achieved at doses of 25µg/kg.7 Compared with morphine, it was better able to blunt the
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hemodynamic responses from intubation and surgical stimulation, and with faster times to

liberation from mechanical ventilation.

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Sufentanil was introduced into the market in 1979. It had several characteristics that made

it suitable for cardiac anesthesia, it was more potent than earlier opioids and was able to

maintain hemodynamic stability, and a shorter context sensitive half-time was apparent

clinically as faster times to waking and extubation.8,9 Because of these favorable

characteristics, sufentanil is still used today in some countries as bolus dosing or infusion

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regimes in cardiac surgery.

Another piperidine derivative, alfentanil, introduced in 1983, has a shorter half-life than

fentanyl and the added advantage of being used as the sole anesthetic as a target-controlled

infusion, and increasingly in combination with propofol to provide a ‘balanced anesthesia’.10

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The concept of balanced anesthesia was not new, but increased during this decade with the

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development of inhalational and intravenous anesthetics agents that provided greater

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cardiac stability and evidence of cardioprotection.

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The age and comorbidities of cardiac surgical patients and complexity of procedures

increased rapidly towards the end of the twentieth century, with increasing demand for
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stretched intensive care resources. Several factors led to the demise of the ‘high-dose opioid

anesthesia’ era, including the development of intravenous anesthetic agents with rapid
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offset. There was also mounting evidence of protection afforded by inhalational agents

against myocardial ischemia and reperfusion injury (‘cardioprotection’) rather than a

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coronary steal phenomenon that was previously susspected. Focus turned instead to

enhancing recovery, which was aided by the next major development in the opioid class, the
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ultra-short-acting remifentanil. From initial efficacy and safety trials, remifentanil, at doses

of 1.0 µg/kg/min, gained widespread popularity because of its ability to provide

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strong analgesia against intraoperative stimuli whilst maintaining vascular stability with
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predictable pharmacokinetics. It is suitable for infusions and allows for faster extubation

times after cardiac surgery compared with earlier opioids.11

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Route of Opioid Administration

Moderate to severe acute pain is often described following cardiac surgery, as a result of

skin incision, tissue damage, sternal retraction, and insertion of drains. Amelioration of this

nociceptive input is important, not only to decrease pain, suffering and anxiety, but also to

blunt sympathetic neurohormonal responses and prevent increases in oxygen consumption.

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The intravenous route of administration of opioids is ideal in the immediate perioperative

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period: allows for titration to hemodynamic responses, can be used in infusions and can be

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continued postoperatively using patient-controlled analgesia (PCA) regimens. The three

most commonly used drugs, fentanyl, morphine, and remifentanil, have been studied and

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compared for superiority of analgesia. One study may demonstrate little difference between

the analgesia provided by these agents12, whereas others find superiority of morphine
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(40mg) compared with fentanyl (600µgs) in postoperative pain scores, use of postoperative

analgesia, and in the quality of recovery13. The use of a continuous background infusion of
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morphine with a morphine PCA has not been shown to improve pain scores compared with

use of a morphine PCA alone, and may also increase its side effects.14
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Remifentanil, one of the newer opioids used in cardiac surgery, allows for earlier extubation
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compared with higher-dose morphine and fentanyl regimens, and has gained popularity as
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part of enhanced recovery programs. In regards to the quality of perioperative analgesia,

the literature has been divided when comparing remifentanil to older opioids. Möllhoff et al.
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(2001) compared fentanyl with remifentanil in 321 patients undergoing coronary artery

bypass (CABG) surgery.15 This randomized, double-blind study demonstrated the

superiority of a remifentanil infusion in blunting hemodynamic responses to sternotomy

and skin incision (but not tracheal intubation). Because of its short half-life, the use of

remifentanil perioperatively is associated with increased opioid requirement from the

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immediate postoperatively period through to an hour after extubation.15,11,16 Management

of postoperative analgesia needs to be carefully planned in these patients.

Methadone, a mu-receptor agonist, also has antagonist activity at the N-methyl-d-aspartate

(NMDA) receptor. Its long half-life initially hindered its use because of the risk of prolonged

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endotracheal intubation, but in smaller doses it allows for earlier extubation while still

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providing analgesia for up to 72 hours. It has received renewed interest in general

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anesthesia in the last few years, which has also translated into cardiac anesthesia and its

benefits in the postoperative course. In comparison with morphine (20mg), methadone

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(20mg) given intraoperatively, does not delay extubation, and leads to less total doses of

morphine, improved quality of analgesia and reduced incidence of postoperative nausea

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and vomiting (PONV).17 Similar results are seen with methadone (0.3mg/kg) when

compared to fentanyl (12µg/kg), where again postoperative morphine requirements and

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pain scores are reduced, and there is higher patient-perceived quality of analgesia.18 A

prospective, randomized, double-blind, placebo-controlled trial is underway, investigating

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the effects of pre-operative oral methadone on the postoperative consumption of opioid

(clinical trials registration number: NCT02774499).

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Intrathecal techniques of providing perioperative analgesia in cardiac anesthesia were first

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described in the 1980s by Mathews and Abrams.19 They used single shot spinal anesthesia
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with 1.5mg - 4mg of preservative-free morphine, and noted that all patients were able to

wake in the operating theatre with no pain, and with only 1 in 10 needing mechanical

ventilation postoperatively. With its low lipid solubility, intrathecal morphine provides

mainly postoperative analgesia, rather than any attenuation of stress response to intubation

and sternotomy, cardiopulmonary bypass. There is improved postoperative analgesia in

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patients managed with intrathecal morphine and an intravenous remifentanil infusion,

compared with sufentanil20 and fentanyl21,22. However, time to extubation is prolonged, and

there is a higher incidence of PONV and pruritus, seen in up to 20% of patients.23,24

Recent studies have tried to elucidate a minimally effective dose of intrathecal morphine;

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one that is still able to provide a profound analgesia whilst minimizing adverse effects such

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as pruritus, PONV, urinary retention and respiratory depression.25,21 Intrathecal doses as

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low as 300µg given before CABG have been shown to reduce total morphine consumption

postoperatively by 40%, with lower reported pain scores and greater respiratory

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functioning (measured by peak expiratory flow rate).26 Smaller doses of intrathecal

morphine (1.5µg/kg) in patients undergoing minimally invasive mitral and tricuspid valve
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repair demonstrated no delay in time to extubation and reduced use of additional opioids in

the postoperative period when compared with a PCA-only group.27 Other intrathecal
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opioids that have been investigated including fentanyl (10µg/kg) combined with morphine,

sufentanil (1µg/kg) and meperidine/pethidine (1.5mg/kg), demonstrated no evidence of

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superiority over morphine alone.28,29,30

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Epidural techniques in cardiac surgery were first describes by Hoar et al. in 1976 as a

method to reduce hypertension post myocardial revascularization.31 The potential benefits

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that epidural techniques brings to cardiac surgery have been reviewed by Landoni and
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colleagues, and include: reduction in mortality, blunting the stress response to surgery,

coronary artery dilatation and improved myocardial perfusion, immunomodulation,

reduced total doses of general anesthesia and opioid use, early extubation and

physiotherapy.32 In regards to postoperative analgesia, thoracic epidural infusions

(ropivacaine 1%+ fentanyl 100µg bolus + 15-25 µg/h infusion) have been found to be

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superior when compared with morphine PCA alone. This superiority was not demonstrated

with patient-controlled thoracic epidural boluses (bupivacaine 0.5% + 2 μg/ml fentanyl plus

2 μg/ml adrenaline).33,34 Despite these potential benefits, the 2011 joint American College of

Cardiology Foundation (ACCF) and the American Heart Association (AHA) guidelines on

CABG surgery determined that the effectiveness of high thoracic epidurals for routine cases

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remains uncertain.35

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The use of neuraxial techniques in cardiac surgery has been controversial as systemic

heparinization is required which can expose patients to a ten-times increase risk of the rare

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and devastating complication of peridural hematomas.36 A recent meta-analysis estimated

the risk of epidural hematoma associated with the use of high thoracic epidural in cardiac
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surgical patients at 1:3552. Interestingly, this is not significantly higher than the risk

presented when used in major non-cardiac surgery where full anticoagulation is not
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required. Intrathecal needles are less traumatic than epidural needles, reducing the risk of

peridural hematomas. Intrathecal opioid analgesia may be considered a safer option

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compared with epidurals in patients undergoing heparinization, but is limited in the ability

to titrate to effects, increased cardiovascular instability and duration of analgesia only up to

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24 hours. Where neuraxial routes are used, the patient should be monitored for

neurological complications, ideally in a center that can provide both cardiac and
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neurosurgical services. The selection of patients requires a thorough understanding of the

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benefits in providing opioid and local analgesia via neuraxial routes versus the risk of

peridural hematomas with increased resources for perioperative management.

Once the patient can tolerate oral fluids, an early transition to immediate-release oral opioid

formulations provides greater baseline analgesia, significantly reduces total opioid

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consumption, and is less expensive.37 The available oral opioids include oxycodone, oral

morphine, codeine, tramadol, and tapentadol. They differ slightly in analgesic efficacy and

incidences of side effects, including PONV, constipation, dry mouth, pruritus, bladder

dysfunction and drowsiness. Tramadol is a centrally acting µ-opioid receptor agonist with

other modes of actions to inhibit reuptake of norepinephrine/noradrenaline and serotonin.

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Tapentadol is a newer agent with more potent µ-opioid activity, weaker serotonin-reuptake

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inhibition, and no known active metabolites. In cardiac surgical patients, tapentadol has

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demonstrated greater analgesic efficacy and reduced incidence of PONV when compared

with tramadol.38 The combination of oral opioids with peripherally acting compounds

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(methylnaltrexone, alvimopan) has been shown to reduce constipation in moderate-to-

severe non-cancer pain, but there is limited evidence in the acute perioperative setting.39
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Transdermal fentanyl patches have a 48-hour delay before maximum plasma concentration
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is achieved and prolonged half-life even after the removal of the patch.40 They are registered

for use in chronic pain, and despite anecdotal use there is no evidence in cardiac patients for
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their use in acute post-surgical pain. They are generally contraindicated because they are

slow, difficult to titrate and increased risk of respiratory depression post-operatively.41

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Controlled-release and compound opioid analgesics (e.g. with acetaminophen

(paracetamol), aspirin, non-steroidal anti-inflammatory agents (NSAIDs), or caffeine)

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reduce the capacity for effective titration of the individual components to pain, may prolong
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the use of opioids, exhibit more side effects, and are not recommended.42

Some of the variability in opioid effects that we see between patients can be accounted for

by pharmacogenetics, age, patient-related factors (such as renal and liver dysfunction) and

interactions with other medications. In regards to age, a small pharmacodynamics and

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pharmacokinetic study of opioids compared patients of over 75 years old with those less

than 60 years old. They identified that the plasma concentration of intravenous fentanyl

was higher in the former group, but levels of intravenous oxycodone were similar to the

middle-aged patients. Clinically the elderly patients had less pain but were more sedated

after doses of oxycodone.43 In the presence of hepatic and renal dysfunction, opioids should

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be cautiously titrated to effect (see Table 1).1,2 The metabolites of morphine from liver

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biotransformation are renally excreted and can accumulate in patients with reduced renal

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function. Importantly, the major metabolites, morphine-3-glucuronide and morphine-6-

glucuronide, have activity at opioid receptors which provides analgesic effects but also

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respiratory and CNS depression. Fentanyl, sufentanil, alfentanil, and methadone have no

active metabolites from biotransformation, and dose reductions are recommended for those
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with renal impairment. Approximately 10% of oral codeine is metabolized to morphine,

providing most of its clinical effects. Oral codeine is not metabolized in a predictable way in
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a fifth of patients because of genetic polymorphism in the cytochrome P450 enzyme,

CYP2D6, and may not provide reliable analgesia; it is not recommended for use in those
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with renal impairment. The rapid metabolism of remifentanil by blood esterases means that

its metabolism and elimination are not dependent on renal or liver function, and may be a
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better choice in patients with respective dysfunction.

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Doses and Fast Track Cardiac Anesthesia

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High-dose opioid techniques with morphine or fentanyl led to delayed recovery, respiratory

depression, prolonged ventilation, increased ICU stays, costs, and potential for

postoperative complications. In the latter part of the twentieth century, as the demand for

cardiac surgery increased, the fast-track model of perioperative care expanded to include

cardiac surgery and specific cardiac recovery or cardiothoracic intensive care units were

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developed.

Although there is no standard definition of FTCA, the recent Cochrane review into the safety

and effectiveness of FTCA defined it as liberation from mechanical ventilation within 8

hours of cardiac surgery.44 Indeed many centers now refer FTCA to mean extubation within

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1-6 hours and ultra-FTCA where the patient bypasses an ICU admission completely. Despite

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low quality of evidence available, the Cochrane review demonstrated FTCA to be a safe

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technique, with similar rates of mortality and postoperative complications compared with

conventional (i.e. late) extubation, with decreased time spent in intensive care, however

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overall hospital length of stay was unchanged.44,45 The benefits from FTCA to patients of low

to moderate operative risk include faster times to extubation and time spent in intensive
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care without risk to morbidly and mortality, and the hospital will benefit from improved

patient flow, as there is a general push for ICU resources. Predictive factors for fast track
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failure include age, female sex, prolonged surgery, and prolonged cross-clamp time.46
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‘Low’ fentanyl dosing (12µg/kg) significantly decreases time to extubation compared with

high-dose fentanyl (24µg/kg), and smaller dose opioid regimens have been adopted over
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the last decade aiming to maintain analgesic efficacy.47 Use of sufentanil and alfentanil

intraoperatively have demonstrated faster liberation from mechanical ventilation, though

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no change in time spent in ICU, when compared with patients on fentanyl regimes.11,48,49 The
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introduction of remifentanil was praised as it was thought to have the ability to deliver a

high dose of opioid analgesia intraoperatively, without an prolonging liberation from

mechanical ventilation. However, earlier studies demonstrated no superiority47,50,51 and

even inferiority15,52,53 of remifentanil compared with other opioids. A meta-analysis by

Greco and colleagues later showed significantly faster extubation and recovery times in

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remifentanil groups when compared with fentanyl or sufentanil in cardiac surgical

patients.54 Median anesthetic costs may be higher in those patients managed with

remifentanil for FTCA but generally ICU stay, hospital stay and total costs are similar

amongst remifentanil, fentanyl, and sufentanil use.11,47,54,55

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Epidurals have also been investigated with respect to possible benefits in FTCA. Compared

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with controls, cardiac patients managed with epidurals have a shorter time of mechanical

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ventilation, decreased sedation scores and improved spirometry in the early postoperative

period, and reduced mortality (NNT=70).22,32

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Opioid-Induced Hyperalgesia and Chronic Neuropathic Pain

After improvements in cardiac surgical outcomes over the past decade, the focus has now
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turned to more patient-centered outcomes, such as disability and chronic pain. Up to 40% of

patients can have symptoms of chronic pain when measured at one year after cardiac
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surgery.56 A little understood paradox that arises from opioid administration is opioid-

induced hyperalgesia (OIH), which is described by decreased pain thresholds (hyperalgesia)

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or painful responses to previously non-nociceptive stimuli (allodynia) after exposure to

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opioids. All the opioids have been shown to trigger this dose-dependent hyperalgesia, but

especially evidence with the short-acting agents, fentanyl and remifentanil.57

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In CABG patients, the use of high dose fentanyl (induction with 40-70µg/kg + 5-

10µg/kg/hr) compared with lower doses (induction 2µg/kg + 1-3µg/kg/hr) was associated

with greater tactile allodynia and thermal hyperalgesia that returns to baseline by Day 7

postoperatively.58 With regards to remifentanil, there is growing evidence for this dose-

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dependent relationship with OIH.59 Several systematic reviews based on general and

thoracic surgical populations, demonstrating an association between acute remifentanil

exposure and OIH (especially with doses higher than 0.1 µg/kg/min).60,61,62 In the cardiac

surgical population, there are no differences in early (up to 48 hours) postoperative opioid

consumption between placebo or a low dose (0.1μg/kg/min) remifentanil infusion with

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those of higher infusions (0.3 μg/kg/min).63,64

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When we investigate beyond a few days postoperatively, the evidence for the potential for

remifentanil to cause OIH becomes clearer. Richebé et al randomized a group of 40 cardiac

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patients to two infusion algorithms of remifentanil: one with a continuous infusion (0.3

µg/kg/min) compared with using a target-controlled infusion mode (target of 7 ng/mL),

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resulting in different cumulative doses of remifentanil (5.33mg versus 3.66mg,

respectively). They found that the group with higher overall remifentanil dose had greater
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hyperalgesic responses in the first postoperative week.65 Gulik et al reported an incidence of

chronic pain at one year of 20% in a cohort of ninety patents, and with a significant dose-
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dependent relationship of intraoperative remifentanil.66 The REFLECT study

(ClinicalTrials.gov identifier: NCT02031016) is an ongoing prospective randomized trial,

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aiming to identify the influence of perioperative remifentanil on long-term pain outcomes

specifically in cardiac surgical patients.

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Cardioprotection

Cardiac surgery can produce both ischemia and reperfusion injury to the myocardium,

which can lead to arrhythmias, myocardial dysfunction, and damage; there are

pharmacological methods to protect against this injury. Benefits of conditioning the heart to

ischemia were first demonstrated in the sentinel work by Murry and colleagues in 1986,

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endogenous cardiac opioid receptors were later shown to play a role by the work of Schultz

et al.67,68 This led to the increasing study of receptor subtypes responsible and the potential

for exogenous opioid use in preventing ischemia reperfusion injury.

Although there are numerous animal and in vitro models to support a role of opioids in

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cardioprotection, the body of evidence in humans is not as strong. Clinically, investigations

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have utilized postoperative infarction rates and markers of cardiac insult (such as CK,

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troponin-I, B-type natriuretic peptide, ischemia-modified albumin, and heart-type fatty

acid–binding protein) as a surrogate for cardiac protection. Fentanyl47, remifentanil69,

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sufentanil70, morphine71 and methadone72 have all been shown to decrease postoperative

markers of cardiac insult in a dose-dependent response and which can be blocked by

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selective opioid antagonists.73,74 Morphine has the additional benefit of immunomodulation

properties.
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Though opioids are praised for their cardiostability, the cardiac effects of opioids need to be
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brought to attention in patients with unstable cardiac function. For example, the use of

opioids perioperatively may increase PaCO2 in spontaneously breathing patients. Whilst

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that has coronary vasodilatory effects it also direct cardiodepressive actions, and in post-

coronary artery bypass graft patients has been shown to cause pulmonary vasoconstriction
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resulting in right ventricle afterload stress and reduced ventricular function.75,76

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Cardiac surgery is complex, heterogeneous and dynamic, so teasing out a cardioprotective

effect of exogenously administered opioids in cardiac patients remains a difficult task.

While there is some evidence for a role of opioid receptors in cardioprotection, there is little

to suggest superiority of one agent or dose (in humans) over another. Similarly, the putative

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mechanisms of cardioprotection by other mechanisms such as volatile anesthesia (e.g.

attenuating calcium overload, anti-inflammatory and antioxidant effects, pre- and post-

conditioning-like protection) have proved challenging to demonstrate in clinical studies.77

The Global Opioid Crisis

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There is a growing public health concern in regards to iatrogenic opioid dependency, with

now almost 1 in 25 adults in the USA regularly using prescription opioids.78 This opioid

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crisis is now declared a ‘health emergency’ in many countries around the world.

Approximately 3.3% of previously opioid naïve patients continued to use opioids for more

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than 90 days after cardiac surgery.79 Prescribed opioids may stay at home unlocked and

unchecked, continuing to a reservoir of opioid tablets in the community which contributes

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to the continued supply and use of drugs of addiction in the community, and may lead to

death. Alongside improved legislation and education, attention has also shifted to
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responsibility of the doctors in the postoperative period to cease opioids or limit the
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unnecessary over-prescription of opioids after discharge.

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Preoperative pain and analgesic intake is a risk factor for higher postoperative pain scores

after major surgery. The management of patients in these groups needs special attention,
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and may include liaising with their pain specialist, or linking them up with one in the early

preoperative period.80 The transition from acute pain management to an analgesic regime at
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discharge needs to be carefully considered, managed and monitored, and the benefits of a

multimodal approach to analgesia with early deprescription of opioids encouraged.

We must continue to develop new and innovative approaches to maximize perioperative

analgesia while reducing the unwarranted use of opioids postoperatively. These approaches

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include multimodal therapy, opioid free anesthesia, and pharmaceutical opioid

developments. To allow for reduced dosing of opioids, multimodal therapy included the

addition of simple analgesics, and also regional techniques or local anesthetic patches,

where appropriate.81 For example, acetaminophen given immediately after induction of

anesthesia and 6-hourly for the first 24 hours has been shown to significantly reduce

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postoperative opioid requirement and patient satisfaction (but not opioid-related side

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effects).82 NSAIDs have traditionally been withheld in patients undergoing major surgery,

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including cardiac surgery, because of the possible adverse hematological, gastrointestinal

and renal effects. Yet numerous studies have demonstrated safety and analgesic efficacy,

US
with a single-dose of NSAID reducing postoperative opioid requirements.83,84,85 Low dose

ketamine infusions (for 48 hours postoperatively) have demonstrated to reduce total opioid
AN
consumption but not PONV in patients undergoing CABG.86 The newer opioid agents

including tramadol and tapentadol have also been examined in cardiac surgical patients in
M

combination with morphine, and have demonstrated benefits in reducing total morphine

requirements and PONV.38 For example, compared with morphine PCA alone, the addition
ED

of regular tramadol and acetaminophen postoperatively improves analgesia and can reduce

the total morphine requirement by 50% after CABG.87

PT

In an effort to completely eliminate the use of opioids, some non-cardiac surgical specialties
CE

use ‘opioid free anesthesia’ as an adjunct to fast-track anesthesia. Drugs used may include
AC

dexmedetomidine, clonidine, ketamine, gabapentinoids, esmolol, tricyclic antidepressents,

and lignocaine (detailed evidence for the use of these multimodalities is beyond the scope of

this review).

Drug developments are also pursued in an attempt to limit the problem of opioid-related

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side effects and substance abuse. Recent studies have shown that the β-arrestin pathway

mediates many of the undesirable effects of traditional opioids such as constipation,

respiratory depression, and the development of tolerance.88,89 This has led to the

investigation of naturally occurring selective μ-opioid receptor agonists, such as

mitragynine, an active alkaloid in the plant Mitragyna speciosa, commonly known as

T
kratom. This discovery has also fuelled the development of novel drugs that do not engage,

IP
or weakly engage, the β-arrestin pathway. Intravenous oliceridine and an oral form in

CR
development (TRV734) are G-protein biased μ-opioid receptor ligands, the former of which

is currently in Phase 3 clinical trials. In preclinical studies, they have been shown to be

US
faster acting and more potent than morphine, whilst reducing respiratory depression and

gastrointestinal dysfunction.90 PZM21 is another novel opioid that has been developed
AN
specifically from computer modeling, working backwards from the μ-opioid receptor to

create a specific ligand.91 Abuse deterrent technologies on the market to limit the extraction
M

of active opioid compounds include alterations in the delivery system, for example

resistance to crushing, extraction and heating. The combining agonist and antagonist in one
ED

formulation (e.g. with naltrexone) may assist patients at risk of abusing opioids by

decreasing an opioid-mediated euphoria.

PT
CE

Summary:
AC

The literature has been reviewed in regards to the differences amongst the current opioids

in use, looking specifically at a few outcome variables that are specifically important in

cardiac anesthesia such as postoperative analgesia, extubation times and FTCA, chronic

pain, and cardioprotection. Opioids have been and continue to be the primary mode for

analgesia in cardiac surgery.

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Intravenous opioids allow for titration to effect with a greater safety profile intraoperatively

compared with other routes. Short-acting intravenous opioids or restrained dosing of

longer acting ones such as morphine and methadone, play a key role in providing safe and

effective FTCA. As patients’ pain intensity decreases over the first few postoperative days,

T
early transition from intravenous opioids to immediate-release oral formulations, then

IP
cessation of oral opioids at the earliest appropriate time is warranted to reduce the

CR
incidence of opioid-related side effects and dependence. Non-opioid adjuncts facilitate the

reduction and cessation of opioids in this period.

US
Neuraxial techniques with opioids have proven benefits, from shorter times to liberation
AN
from mechanical ventilation, decreased sedation scores and mortality benefits. However,

there is the potential for peridural hematoma, and current guidelines still remains uncertain
M

about the effectiveness of high thoracic epidurals for routine CABG cases.
ED

A caveat to the use of opioid agents is the dose-dependent relationship with OIH and

development of chronic neuropathic pain. We should aim for use the minimally effective
PT

doses of these agents that adequately controls responses to intraoperative stimuli and

postoperative pain, while decreasing exposure to higher opioid doses. Since the
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identification of endogenous cardiac opioid receptors, we have sought for a cardioprotective

AC

effect of exogenously administered opioids. There are demonstrated reductions in markers

of cardiac insult with all opioid agents, but determining a superior dose or agent in cardiac

patients remains enigmatic.

Over the last six decades, the field of cardiac surgery has undergone immense evolution.

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Alongside the development of cardiac surgical techniques and cardiopulmonary bypass,

other technological innovations and anesthetic drugs have allowed this subspecialty to

flourish, with improvements in safety and outcomes.92 The days of using high-dose opioids

to provide anesthesia during cardiac surgery have passed. A multimodal approach to

analgesia in cardiac surgical patients should be universally employed, with minimally

T
effective doses used, effectively controlling pain, but reducing overall side effects, improving

IP
patient centered outcomes and quality of recovery. These endpoints should be routinely

CR
measured and through audit and research we should strive for continuous practice

improvement.

US
AN
M
ED
PT
CE
AC

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TABLE 1: Pharmacokinetic data of opioids and recommendations for use in renal

and hepatic impairment.
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Potential Recommen
Volume effects due dations for
CE

Hal
Year of to use in:
f-
Opioid Introdu Route distribut accumulat
life Renal Hepatic
ced ion ed
(h) Impairme Impairme
(L/Kg) metabolite
AC

nt nt
(s)
CNS
depression,
2-4 2.7-5.3 hepatic Not Not
PO*/IV/EP encephalop recommen recommen
Morphine 1804 I/IT athy ded ded
Neuroexcit
ation and Not
3 3-6
CNS recommen
Codeine 1832 PO depression ded 0

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Prolonged
effects and
3.2 2.6
PO*/IV/EP CNS Dose
Oxycodone 1917 I depression reduction 0
Neuroexcit
ation and
2.5 4
Hydromorphon CNS Dose
e 1922 PO/IV* depression reduction 0
Not
8-
1-8 Dose recommen
60
Methadone 1938 PO/IV* 0 reduction ded

T
Neuroexcit Not
Meperidine/Pet PO/IV*/EP 4 3-5 ation and recommen

IP
hidine 1939 I/IT seizures ded 0
Cardiac and Not
6-

CR
Dextropropoxy 16 hepatotoxic recommen
12
phene 1955 IV/PO* ity ded 0
3.6 Dose Dose
3-8
Fentanyl 1960 IV/EPI/IT 5 0 reduction reduction
Dose
Sufentanil

Alfentaniil
1974

1976
IV

IV
2.7

2
US
1.5-
1.7

0.4-1
0

0
Neuroexcit
reduction
Dose
reduction
Not
0

0
Not
AN
6.3 2.6-2.9 ation and recommen recommen
Tramadol 1977 PO*/IV seizures ded ded
Buprenorphine 1981 PO*/IV 37 430 0 0 0
0.0 Dose
M

0.2-0.3
Remifentanil 1996 IV 6 0 0 reduction
Neuroexcit Not
4 540 ation and recommen
Tapentadol 2008 PO/IV* seizures 0 ded
ED

Not all routes of administration are listed. Where multiple routes are listed, the
pharmacokinetic data refers to the corresponding stared route. 0 = No significant
PT

metabolites, nil effects, or no changes recommended, PO = per oral, IV =

intravenous, EPI = epidural, IT = intrathecal.
CE
AC

31