Adenosine as a Non-Opioid Analgesic in the Perioperative Setting

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Adenosine as a Non-Opioid Analgesic in the
Perioperative Setting

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• -Ubiquitous metabolic intermediate in the body
• -Involved in nearly every aspect of cell
  function, including neuromodulation and
  neurotransmission
• -Adenosine A1 and A2 receptor
• widely distributed in brain and spinal cord
• ?novel non-opiate target for pain management

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• -Compared to placebo or remifentanil,
• an intraoperative adenosine infusion? stabilize
  core hemodynamics and reduce the requirement for
  anesthesia during surgery and improve
  postoperative recovery

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• -The safety profile has been well characterized
  based on use of currently approved adenosine
  products
• -Most common adverse events
• ?flushig, chest discomfort, dyspnea, headache,
• gastrointestinal discomfort, and
  lightheadedness
• generally well tolerated and transient

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• -Opioid remain the mainstay for postoperative
  analgesia, especially for major surgery
• ? however, pain is a multifactorial phenomenon
• that may not be adequately controlled with
  
• opioid monotherapy alone
• -Opoid dose-related adverse effect such as
  respiratory depression, nausea, vomiting, urinary
  retention, itching, and sedation

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• -To improve pain relief and reduce the incidence
  and severity of side effects, a multifactorial
  approach to postoperative analgesia should be
  used.
• -NSAIDs may cause bleeding, renal dysfunction,
  and cardiovascular adverse events.
• -Although COX-2 specific inhibitors do not
  increase perioperative bleeding,
• their cardiorenal side effects may be similar
  to that of traditional NSAIDs

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• -Adenosine
• 1) important neuromodulator and regulates
  neuronal and non-neuronal cellular function by
  actions on adenosine receptors
• 2) signaling molecule in immunity and
  inflammation acting as an endogenous
  antiinflammatory agent
• 3) acts as a neurotransmitter and
• regulates pain transmission in the spinal
  cord,
• and these receptors are a novel, nonopiate
  target
• for pain management

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• -Two formulations of adenosine are currently on
  the market for cardiovascular indications (
  Adenocard and Adenoscan)
• -Adenoscan 60- and 90-mL vials?perioperative
  setting
• -Adenocard conversion to sinus rhythm of PSVT(
  WPW syndrome)

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• -Clinical pharmacology of adenosine and its
  efficacy and safety when used as an adjunct in
  postoperative pain management

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Preclinical pharmacology

• -Studies using adenosine analogues with different
  efficacy for the A1 and A2 adenosine receptors?
  adenosine A1 receptor are involved in inducing
  the antinociceptive effects
• -The role of the A1 adenosine receptor in
  inhibiting spinal sensory transmission? confirmed
  by the inhibitory effect of A1 analogues on the
  C-fiber-evoked responses of wind up and post
  discharge of dorsal horn neuron

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Preclinical pharmacology

• - adenosine agonists dose dependently inhibit the
  slow ventral root potential ?C-fiber-evoked
  excitatory response associates with nociceptive
  information
• -The rank order of agonist potency? adenosine
  agonist inhibit sensory transmission by acting on
  A1 receptor

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Preclinical pharmacology

• -Four loose ligatures around the sciatic nerve,
  called the chronic constriction injury model in
  animal? adenosine reduced the scratch behavior
  in rat after both IV administration and IT
  injection dose dependent

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Preclinical pharmacology

• -This effect of adenosine was abolished by IT
  injection of the A1 receptor antagonist
  cyclopentylxantine
• -A neurotoxicological evaluation using
  morphologic measurement showed that chronic IT
  administration of R-PIA( R-phenyl-isopropyl
  adenosine) once daily for 14 days induced no
  neurotoxic changes in the rat spinal cord

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Preclinical pharmacology

• -Adenosine also interacts with other analgesics
• ?IV adenosine had an additive analgesic effect
• with morphine and ketamine in experimentally
• induced ischemic pain in healthy volunteers

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Efficacy in the perioperative setting

• -Published reports of
• randomized, controlled trials
• investigated perioperative adenosine
• administration for postoperative pain
• management
• were searched

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Efficacy in the perioperative setting
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Efficacy in the perioperative setting
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Safety of adenosinesafety of adenosine as an
analgesic in the perioperative setting

• -In the study invloving females who underwent
  breast surgery, 3 of 36 evaluable
  adenosine-treated pts. reported one or more of
  the following hematoma fever reoperation due
  to postoperative bleeding postoperative headache

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safety of adenosine as an analgesic in the
perioperative setting

• -In the study involving females undergoing
  abdominal hysterectomy,
  2 of 23 adenosine treated pts.
  experienced an adverse event transient
  atrioventricular block II or transient decrease
  in systolic blood pr. due to accidental overdose
• -In the study of pts. who underwent shoulder
  surgery, no adverse events were recorded

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safety of adenosine as an analgesic in the
perioperative setting

• -In 110 pts. who underwent surgery of the upper
  extremity with brachial plexus block and received
  IV adenosine in addition to local anesthetics, 4
  pts. Experienced an adverse event. ? headache
  (adenosine), faintness (adenosine),
  palpitation/tightness (adenosine), and itching
  (placebo)

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safety of adenosine as an analgesic in the
perioperative setting

• -In the study that compared IV adenosine to IV
  remifentanil in pts. who underwent a
  hysterectomy, 1 of 15 pts. in the adenosine group
  experienced severe bronchospasm shortly after
  initiation of infusion

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safety of adenosine in cardiac indication

• - events most commonly associated with Adenoscan
  were flushing(44), chest
  discomfort(40), dyspnea
  or urge to breath deeply (28), headache (18),
  throat, neck,
  or jaw discomfort (13), and lightheadedness/
  dizziness (12)

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safety of adenosine in cardiac indication

• -Adenoscan is contraindicated for
  known or suspected bronchoconstrictive or
  bronchoplastic lung disease
• -Warnings for fatal cardiac arrest
  life threatening ventricular
  arrhythmias, myocardial infarction,
  sinoatrial and AV
  block, hypo
  and hyperthension, and bronchoconstriction

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safety of adenosine in cardiac indication

• -In a multicenter study, information was
  collected from 9256 pts.? side effect were
  generally mild and well tolerated by most
  pts.(81), Severe bronchospasm in
  7 pts., no death, only one case each of
  myocardial infarction and pulmonary edema.
• -Transient AV block occurred in 8 of the pts.

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safety of adenosine in cardiac indication

• -In a controlled study that investigated the
  safety and feasibility of adenosine adjunct to
  primary PTCA in pts. with acute MI?
  administration of intracoronary adenosine was
  well tolerated.
  adverse cardiac events occurred in
  5 0f 27(19)pts. in adenosine group and 13 of
  27(48)pts. in saline group

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safety of adenosine in cardiac indication

• -It is important to emphasize that
  the safety of adenosine in the nonsurgical
  practice may not reflect its safety in the
  perioperative period.
• -Unlike nonsurgical use, there may be a number of
  drug-to-drug interactions between adenosine and
  inhaled anesthetics and opioid

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safety of adenosine in cardiac indication

• -With increased bronchotracheal stimulation
  during the perioperative period,
  the
  potential for bronchoconstriction may be higher
  than in a nonsurgical population? need to be
  investigated further

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conclusion

• -Adenosine appears to demonstrate opiod-sparing,
  anesthetic-sparing, and analgesic properties
• -Dose finding clinical studies are warranted to
  establish the optimal dose for achieving a
  balance between efficacy and side effects profile
  for adenosine use in the perioperative setting