This presentation will cover several areas starting theoretically and moving through to practical application



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Alpha- 2 agonist Clonidine

Action:The stimulation of damaged peripheral nerve terminals by ephedrine is described as Sympathetically maintained pain.



  • Clonidine reduces the release of ephedrine on to the peripheral nerve terminal.

  • Other actions unclear

Autonomic drugs which have proven beneficial in the treatment of neuropathic pain include the alpha–2 agonists: clonidine and alpha–1 antagonists (e.g. prazosin, terazosin).

The role of the alpha-2 adrenergic system in neuropathic pain has been studied using various pharmacological interventions and animal models.


In animal studies, alpha-2 adrenergic agonists produce analgesia by actions in the periphery, supraspinal central nervous system and in the spinal cord.clonidine is believed to produce analgesia at the spinal level, in part through stimulation of cholinergic interneurones in the spinal cord. This cholinergic mediation of analgesia, as reflected by cerebrospinal fluid acetylcholine concentration, is activated by intrathecal, but not IV, injection of clonidine.

However, clonidine has been shown to produce analgesia to experimental pain stumuli after systemic and epidural injection. However, clinical studies of systemic clonidine for analgesia have yielded conflicting results. Alpha-2 adrenergic agonists produce sedation and reduced blood pressure in addition to analgesia. Small doses (50 mg) of clonidine may reduce blood pressure more after an intrathecal than an IV injection.


Clonidine has also been shown to potentiate the neuropathic pain-relieving action of the NMDA antagonist MK–801 while preventing its neurotoxic and hyperactivity side-effects.Clonidine is available in several different dosage forms and can be administered orally, transdermally or spinally. Conversely, systemic dexmedetomidine, another alpha-2 adrenergic agonist, has been shown neither to prevent nor attenuate neuropathic pain behaviour in rats. Dexmedetomidine has an affinity for all three alpha-2 adrenergic receptor subtypes. The role of the different subtypes of alpha-2 adrenoreceptors remains unclear.
ArticleDate:20050907
SiteSection: Article All rights reserved © 2011. Designed by AnaesthesiaUK.

Clonidine, an a2-adrenergic agonist, has been shown to prolong the action of local anaesthetics especially when used in the intrathecal or epidural space. It activates a negative-feedback mechanism via its action on a2-receptors, which decreases catecholamine release. This modulates input at the dorsal horn. Clonidine also has cholinergic effects and increases the amount of acetylcholine available centrally. Its main adverse effects are hypotension, bradycardia and sedation. When combined with ropivacaine 0.1%, as little as 25 µg of clonidine in the epidural space has been associated with bradycardia and sedation. However, hypotension was significant only with doses of more than 75 µg epidurally.

Clonidine has also been shown to prolong local anaesthesia in peripheral blocks, probably by direct peripheral action. A recent study using only Clonidine for interscalene blocks showed significantly longer analgesia when compared with a group receiving Clonidine subcutaneously.3 The exact mechanism of peripheral action is unknown. Clonidine may act on peripheral a2-receptors or reduce the vascular uptake of local anaesthetic by its vascular adrenergic effects. Clonidine may exert a peripheral analgesic action by causing the release of enkephalin-like compounds. Doses up to 150 µg administered peripherally have minimal side-effects.



Anaesthesia UK : Local Anaesthetic Pharmacologywww.frca.co.uk/article.aspx?articleid=100505 -
 α2 Adrenergic Agonists ;Primarily preoperative and intraoperative use

Clonidine: α2 agonist, α2: α1 biding 220:1; PO, IV, TD, Neuraxial routes;Reduced postoperative opioid requirement

Side Effects: Sedation, Bradycardia, hypotension

Dexmedetomedine: Superselective α2 agonist: α2:α1 binding 1620:1;Supraspinal, Spinal & Peripheral action;

No respiratory depression;



Alpha- 2 agonist

  • The stimulation of damaged peripheral nerve terminals by ephedrine is described as Sympathetically maintained pain. Clonidine reduces the release of ephedrine on to the peripheral nerve terminal.

  • Other actions unclear

  • Clonodine)(Have sedative, anxiolytic, analgesic and haemodynamic-stabilising effects. They act on alpha2 adrenoreceptors in the CNS to reduce noradrenergic activity, and also on receptors in other tissues. The main site of analgesic action is thought to be the spinal cord. Stimulation of imidazoline receptors results in a central hypotensive and antiarrhythmic action.)


Alpha-2 agonists Key message

1. The use of systemic alpha-2-agonists consistently improves perioperative opioid analgesia but the frequency and severity of side effects may limit their clinical usefulness (U) (Level II).


Magnesium,
Magnesium :30–50 mg/kg,

    • followed by 7–15 mg/kg/h IV

    • In the Peripheral Nervous System it interferes with the release of neurotransmitters at all synaptic junctions & potentiates the action of local anesthetics(3)

  • Peripheral nervous system: interferes with the release of neurotransmitters at all synaptic

  • junctions & potentiates the action of local anesthetics.[40]

  • At the neuromuscular junction, magnesium concentrations of 5 mmol/L cause significant

  • presynaptic neuromuscular blockade and enhance the action of the nondepolarizing muscle relaxants.[40]

  • It can precipitate severe muscle weakness in patients with Eaton-Lambert syndrome, patients with myasthenia gravis, or patients pretreated with a small dose of a defasciculating agent.[40] Magnesium prolongs the action of depolarizing neuromuscular blocker drugs (e.g., succinylcholine); administration before the use of succinylcholine prevents the release of potassium provoked by the neuromuscular blocking drug (see  Chapter 29).

  • Magnesium has several important pharmacologic actions.

  • Its route of elimination is renal, and any patient who is oliguric or in a reduced urine output state requires downward dosing adjustment of magnesium therapy.

  • Magnesium should be regarded as a cardiovascular drug, first and foremost, with calcium antagonistic and antiadrenergic properties that may be accompanied by minimal myocardial depression.[40]


Magnesium :30–50 mg/kg,

    • followed by 7–15 mg/kg/h IV

    • In the Peripheral Nervous System it interferes with the release of neurotransmitters at all synaptic junctions & potentiates the action of local anesthetics(3)

  • Peripheral nervous system: interferes with the release of neurotransmitters at all synaptic

  • junctions & potentiates the action of local anesthetics.[40]

  • At the neuromuscular junction, magnesium concentrations of 5 mmol/L cause significant

  • presynaptic neuromuscular blockade and enhance the action of the nondepolarizing muscle relaxants.[40]

  • It can precipitate severe muscle weakness in patients with Eaton-Lambert syndrome, patients with myasthenia gravis, or patients pretreated with a small dose of a defasciculating agent.[40] Magnesium prolongs the action of depolarizing neuromuscular blocker drugs (e.g., succinylcholine); administration before the use of succinylcholine prevents the release of potassium provoked by the neuromuscular blocking drug (see  Chapter 29).

  • Magnesium has several important pharmacologic actions.

  • Its route of elimination is renal, and any patient who is oliguric or in a reduced urine output state requires downward dosing adjustment of magnesium therapy.

  • Magnesium should be regarded as a cardiovascular drug, first and foremost, with calcium antagonistic and antiadrenergic properties that may be accompanied by minimal myocardial depression.[40]

 Magnesium: 30–50 mg/kg,



    • followed by 7–15 mg/kg/h IV

    • In the Peripheral Nervous System it interferes with the release of neurotransmitters at all synaptic junctions & potentiates the action of local anesthetics(3)

  • Peripheral nervous system: interferes with the release of neurotransmitters at all synaptic

  • junctions & potentiates the action of local anesthetics.[40]

  • At the neuromuscular junction, magnesium concentrations of 5 mmol/L cause significant

  • presynaptic neuromuscular blockade and enhance the action of the nondepolarizing muscle relaxants.[40]

  • It can precipitate severe muscle weakness in patients with Eaton-Lambert syndrome, patients with myasthenia gravis, or patients pretreated with a small dose of a defasciculating agent.[40] Magnesium prolongs the action of depolarizing neuromuscular blocker drugs (e.g., succinylcholine); administration before the use of succinylcholine prevents the release of potassium provoked by the neuromuscular blocking drug (see  Chapter 29).

  • Magnesium has several important pharmacologic actions.

  • Its route of elimination is renal, and any patient who is oliguric or in a reduced urine output state requires downward dosing adjustment of magnesium therapy.

  • Magnesium should be regarded as a cardiovascular drug, first and foremost, with calcium antagonistic and antiadrenergic properties that may be accompanied by minimal myocardial depression.[40]


Calcitonin

Calcitonin is a 32 amino acid peptide hormone that regulates calcium homeostasis in

vertebrates. It also has analgesic properties, primarily through receptor-mediated modulation of serotonergic activity in pain pathways of the central nervous system. Salmon calcitonin synthetic form has greater potency

The adverse effects of calcitonin therapy such as

sedation, nausea, skin flushing and diarrhoea may reflect increased serotonergic activity. In rodents, the 5HT3 antagonist tropisetron reduced its analgesic efficacy, which may be relevant in humans during the treatment of nausea and vomiting (Visser, 2005). Salmon calcitonin, (IV, SC, IM, IN or rectal) reduces acute pain at rest and on movement and improves mobilisation (in 7 to 28 days) in patients with osteoporotic vertebral fractures and side effects are usually minor and mainly gastrointestinal (Blau & Hoehns, 2003 Level I; Knopp et al, 2005 Level I).

IV (and likely SC) salmon calcitonin is effective in the treatment of acute phantom limb pain (Jaeger & Maier, 1992 Level II). However, it was not effective for chronic phantom limb pain (Eichenberger et al, 2008 Level II).

Bisphosphonates

IV pamidronate (3 daily doses) reduced pain associated with acute osteoporotic vertebral fractures for up to 30 days post-treatment (Armingeat et al, 2006 Level II).

Bisphosphonates reduced sub-acute bone pain associated with metastatic carcinoma of the breast (Pavlakis et al, 2005 Level I) or prostate (Yuen et al, 2006 Level I) and in multiple myeloma (Djulbegovic et al, 2002 Level I).

Salmon calcitonin and bisphosphonates ANZCA’s Key messages

1. Bisphosphonates reduce bone pain associated with metastatic cancer and multiple myeloma (N) (Level I [Cochrane Review]).

2. Salmon calcitonin reduces pain and improves mobilisation after osteoporosis-related vertebral fractures (S) (Level I).

3. Salmon calcitonin reduces acute but not chronic phantom limb pain (N) (Level II).

4. Pamidronate reduces pain associated with acute osteoporotic vertebral fractures (N) (Level II).

 

Cannabinoids Key message

1. Current evidence does not support the use of cannabinoids in acute pain management

(S) but these drugs appear to be mildly effective when used in the treatment of chronic neuropathic pain, including multiple sclerosis-related pain (N) (Level I).

 

 

Neuraxial Analgesia: Epidural Analgesia



Superior to systemic opioids; Efficacy determined by:Catheter-incision site congruency;Choice of analgesic drugs; LA+Opioid;Rates of infusion;Duration of epidural analgesia; At least 2-4 days; Type of pain assessment:Dynamic Vs Rest

Peripheral Regional Analgesia

Pain control superior to systemic opioids; Fewer side effects compared to systemic opioids; Fewer neurologic and infectious complications compared to neuraxial block; Prolonged duration; Single injection and continuous catheter techniques

 

Indications of peripheral Nerve Blocks:

 Pain control superior to systemic opioids; Fewer side effects compared to systemic opioids; Fewer neurologic and infectious complications compared to neuraxial block; Prolonged duration; Single injection and continuous catheter techniques



Peripheral Nerve Block

Indication: Lumbar plexus; Surgery of knee; Femoral Nerve; TKA, ACL repair, femoral neck fracture, saphenous vein stripping, muscle biopsy of anterior, medial or lateral thigh; Sciatic Nerve; AK amputation (combined with lumbar plexus block

Ankle replacement, arthrodesis; Calcaneal osteotomy; Achilles tendon repair; Popliteal Fossa; BK amputation (combined with saphenous nerve block); Ankle surgery: Triple arthrodesis, Achilles tendon repair; Foot surgery: Bunion surgery, transmetatarsal amputation



Paravertebral Block: Suited for thoracic, breast surgery, VATS, cholecystectomy, nephrectomy etc

Used to treat rib fracture pain; Potential space, contains anterior and posterior ramus of the spinal nerve root with white and grey rami communicantes; Single injection or continuous catheter technique; Comparable to thoracic epidural blockade

No hypotension, PONV, urinary retention

Other Techniques: Rectus Sheath Block; Transversus abdominis plane block; Placement of continuous wound catheter

Continuous intra-articular infusion of LA; Periarticular soft tissue injection of LA; Intrapleural or Intraperitoneal Analgesia

 

Complications: Intravascular injection (lIntralipid); Unintentional neuraxial spread; Scalene block; Lumbar plexus block

Paravertebral block; Nerve Damage; Incidence 1:10000 – 1:30000; Significant nerve damage 1:1 00 000

Direct injury, hematoma, infection, ischemia; >90% recover within 1 week; 92 -97% within 4-6 weeks, 99% within 1 year

Definition: Any technique of pain management that allows the patients to manage their own analgesia on demand

Compensates for interpatient and intrapatient variability in analgesic needs, variability of serum drug levels, administrative delays


Local anaesthetics

  • Local anaesthetic agents produce reversible conduction blockade of impulses along central and peripheral nerve pathways by altering membrane permeability to sodium ions.

  • Preferentially block smaller diameter nerve fibres.

    • C fibre

    • A delta and Sympathetics

    • A beta - touch and pressure

    • A alpha- motor function of skeletal muscles

  • To prevent conduction 3 nodes in succession must be blocked.


Long acting Local Anaesthetic Agents (Amide Group)

  • Bupivacaine (Marcaine) S/P small cardiotoxic window

  • Ropivacaine (Naropin)

  • Levobupivacine (Chirocaine)

  • Short acting LA: Lignocaine

Amide group

Ropivacaine :pure S (-) enantiomer :low lipid solubility



  • Toxicity CVS and CNS occurs at plasma levels greater than 4 mcg/kg.


Chirocaine (Levobupivacaine): High Lipid solubility

  • Toxicity CVS and CNS occurs at plasma levels greater than 2 – 3 mcg/kg

Bupivacaine: racemic mixture; high lipid solubility

Toxicity: CVS and CNS occurs at plasma levels greater than 1.5 – 2 mcg/kg



Side effects of Local Anaesthetics

  • Hypotension due to peripheral vasodilatation

  • Motor blockade

  • CNS toxicity - tingling of lips, tinnitus, nystagmus, convulse.

  • CVS toxicity - bradycardia, heart block, cardiac arrest.

  • .

References:

Australian Medicines Handbook Pty Ltd. Last modified by AMH: July 2011.

MIM’s online 2010

Oxford Medicine online data base Anesthetics, 2010

\ Systemic Medications: Opioids


  • Opioid Receptors: ì, κ and δ receptors

  • Location of receptors:

    • Periphery following inflammation

    • Spinal cord dorsal horn

    • Supraspinally in the brainstem, thalamus and cortex

    • PAG, nucleus raphe magnus and RVM in descending pathway

Mechanism of Action:

  • Spinal

    • Inhibition of Ca++ influx presynaptically

    • Enhacing K+ efflux postsynaptically

    • Activation of descending inhibitory GABAergic circuit

  • Peripheral

    • Inhibition of release of pro inflammatory and pro nociceptive substances

Adverse Effects & Problems:

  • Respiratory Depression

  • Nausea and Vomiting

  • Sedation

  • Urinary Retention

  • Euphoria/Dysphoria

  • Constipation

  • Tolerance

  • Dependence and Addiction



Transdermal Fentanyl Delivery System (Ionsys)

  • Needle free, patient activated system for in-hospital use

  • Iontophoresis

      • Low intensity electrical field used to transport fentanyl across skin into circulation

  • Each double click delivers 40mcg over 10 min

  • For us in adults > 18 years

  • Used for 24 hours or 80 doses

Pethidine:

Phenylpiperidine derivative μ and κ receptor agonist.

Also has Na+ channel blocking and Atopinergic action



Routes

IM, IV, PO

Duration of Action

2-4 hours

Side effects

CNS excitation- seizures, myoclonus due to nor-pethidine toxicity

Interaction with MAO inhibitors, antidepressants



Dose

100mg IV/IM q 4 hr

300 mg PO q 4 hr



Watch for

Nausea,vomiting, euphoria, ventillatory depression

sedation




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