Clinical Application: Acute Pain

16 May

IT administration of clonidine with local anaesthetic (LA) improves the quality and duration  of the LA block but may cause greater  hypotension  (Bonnet et al. 1989). Similarly, epidural clonidine (1–4 μg kg−1) with LA improves the quality and duration  of the block but does not increase hypotension. Caudal administration (0.75–3 μg kg−1) with LA increases anaesthesia duration  two- to threefold (Lee and Rubin 1994). This may be of especial utility in paediatric anaesthesia,  as children  appear  less susceptible to adverse haemodynamic

changes (as blood pressure is less dependent on sympathetic tone at this age). Clonidine is also efficacious for labour analgesia (epidural doses of 1 μgkg−1) with the epidural combination of 75 μg clonidine and 50 μg fentanyl more than doubling the duration  of analgesia produced  by bupivacaine alone (Celleno et al. 1995). Furthermore,  clonidine  is a commonly  employed adjuvant  for brachial plexus blocks as it significantly prolongs the duration  of anaesthesia

provided (Bernard and Macaire 1997).

Clinical Application:  Chronic Pain

Epidural administration of clonidine has been associated with significant anal- gesia for deafferentation pain post spinal cord injury (Glynn et al. 1986), spas- ticity (Rémy-Néris et al. 1999), chronic arachnoiditis  (Glynn et al. 1988) and for chronic sharp and shooting pains (Byas-Smith et al. 1995). Furthermore,

in the treatment  of intractable  cancer pain, epidural clonidine (100–900 μg)

produces a dose-dependent analgesia lasting up to 8 h (Eisenach et al. 1989).

Two weeks of analgesia is also produced  by continuous  epidural infusion of

30 μg h−1  during which time the initial sedative effect disappears  (Eisenach et al. 1995). Clonidine is now regarded a second line pharmacotherapy for the

treatment of cancer pain as an adjunct or an alternative to opioids.

Conclusion: α2 Adrenergic Agonists

In both the acute and chronic pain settings, α2 adrenergic agonists remain rela- tively underused. With the expanding role of dexmedetomidine in the intensive care setting (Coursin et al. 2001) further information  about the analgesic ac- tion of this class of agents will become available. A recent study of the systemic administration of dexmedetomidine  in human  volunteers  found significant analgesia against thermal-induced pain (Cortinez et al. 2004), although the modality of experimental pain influences the estimation of analgesic efficacy in this type of study (Maze and Angst 2004). In addition, a recent randomised controlled trial of 34 post-operative  patients showed that Dex provided more efficacious analgesia than morphine (Arain et al. 2004). However, as described above (Sect. 2.3), regional rather than systemic approaches appear more effi- cacious, although further clinical studies are required to quantify the systemic

analgesia afforded by α2 adrenoceptor  agonists. Preclinical investigation into the downstream effectors beyond surface receptor signalling may facilitate the development of a new class of drugs to allow more effective pain relief.

Cholinergic Agents

As discussed in Sect. 2, the intrinsic antinociceptive system involves cholinergic signalling to modulate pain responses. Acetylcholine release induced by DINs or exogenous sources such as α2 adrenoceptor  and opiate agonists induces an antinociceptive effect (Chen and Pan 2001). Recent interest in this class of

agents has been sparked by a series of interesting discoveries using genetic and pharmacological approaches.

Cholinesterase inhibitors have been used in anaesthesia for many years and their analgesic potential was highlighted over 70 years ago; recently their IT administration for analgesia has gained deserved interest (Hood et al. 1997). In human volunteers, neostigmine was shown to have an analgesic effect when given intrathecally and to potentiate systemic alfentanil analgesia. This effect was correlated with increased CSF acetylcholine.

Nicotinic acetylcholine receptor (nAChR) and muscarinic acetylcholine re- ceptor (mAChR) agonists are antinociceptive (Traynor 1998; Eisenach 1999). Cholinergic agonists have similar efficacy to morphine; they lack the long-term addiction and withdrawal side-effects (Bannon et al. 1998; Swedberg et al. 1997) and thus may have utility in both acute and chronic pain settings. Furthermore, intranasal  nicotine has recently shown potency as a post-operative  analgesic (Flood and Daniel 2004).

Cholinergic Receptors and Substrates

Nicotinic cholinergic receptors  are ligand-gated  ion channels  formed from pentamers  of α subunits  (containing  the ACh binding  site) with β, γ, δ or ε subunits. Neuronal nAChR are considered more diverse than their muscle equivalents, with α2–10 and β2–4 subunits  cloned in neurons.  α2–4 and 6 can form heteromeric  channels with β2–4 subunits; α7–9 form homomeric channels. In the rat brain, messenger RNA (mRNA) for α4, α7 and β2 subunits are widely expressed, though the β2 subunit is less abundant  in the brain of

primates (Tassonyi et al. 2002; Gotti et al. 2004). nAChR are excitatory in nature and likely influence learning, memory, arousal and analgesia.

mAChR are G protein-coupled channels which are either excitatory (M2 and 4) or inhibitory (M1, M3, M5) in nature. Even-numbered channels inhibit adenylyl cyclase via Gi/Go while odd-numbered channels, coupled to Gq/G11,

activate phospholipase C (Caulfield and Birdsall 1998). Similar to α2 adreno-

ceptors,  M2 receptor  activation  also activates  GIRK channels  (Fernandez-

Fernandez et al. 1999).

Pharmacogenetic Studies

Investigation  of the receptor  subtypes  involved has been furthered  greatly by the use of genetic manipulation.  Knock-out  mice lacking the α4  or β2 nAChR subunit showed reduced nicotine-elicited  antinociception  in the hot plate test (Marubio  et al. 1999). In addition,  morphine  antinociception is reduced  in M4  and  M4/M2 knock-out  mice (Duttaroy  et al. 2000). Similar

to α2 adrenoceptor  agonists, M2 and M4 receptors are coupled to Gi proteins

and are inhibitory in nature, and dual knock-out of both receptors abolished

the antinociception induced by oxotremorine, a muscarinic agonist (Duttaroy

et al. 2002). Sole knock-out of the M2 receptor reduced antinociception (but to a lesser extent than dual knock-out) and also reduced the inhibitory action of muscarine on CGRP release from peripheral nerve endings (Bernardini et al.

2002). The antinociceptive action of oxotremorine,  the muscarinic agonist, is reduced in mice with a GIRK-2-null mutation,  indicating  primarily a post- synaptic action of this drug via GIRK channels. As M2 channels are known to

activate GIRK channels and knock-out of either reduced muscarinic receptor antinociception,  it is likely that M2 and GIRK channels mediate muscarinic antinociception,  at least in mice. Therefore  the likely cholinergic receptor subtypes modulating pain are the nAChR α4 or β2, and mAChR M2 and M4.


Anti-cholinesterase Inhibitors

Potentiation  of endogenous acetylcholine by the IT use of anti-cholinesterase inhibitors has recently gained renewed interest after recent clinical trials. Act- ing via both muscarinic  and nicotinic receptors,  acetylcholine is known to play a role in both endogenous  and exogenous analgesia. Neostigmine (IT)

potentiates opioid and α2 adrenoceptor  agonist-induced  analgesia (Detweiler et al. 1993; Hood et al. 1997). Clinically the combination  of neostigmine  IT and opioid analgesia has been used successfully in gynaecological and obstet-

ric anaesthesia; particular  utility for mobile epidurals has been noted (Lau- retti et al. 1998; Roelants and Lavand’homme 2004). However, nausea remains a limitation of this novel strategy and further investigation is required to fully

describe the extent of this side-effect.


Nicotinic Agonists

Recent interest in nAChR agonists as analgesics was prompted by epibatidine, a compound  isolated from the Ecuadorian  tree frog, Epipedobates tricolor. Epibatidine is 200 times more potent than morphine  but has a narrow ther- apeutic window with significant toxicity problems, including cardiovascular and motor effects (Decker and Meyer 1999). Newer compounds such as ABT-

594 (Bannon et al. 1998) have an improved safety profile but similar efficacy. Importantly,  ABT-594 also lacks the withdrawal side-effects and physical de- pendence of opioid analgesics, at least in rats. In a series of studies, Bannon and colleagues investigated  the systemic efficacy of ABT-594 in models of thermal, inflammatory and neuropathic  pain; the compound proved superior to morphine.  The neuroanatomical locus for this effect is still under discus- sion but activation of the LC and serotonergic neurons  in the nucleus raphe magnus which in turn activates DINs is likely to mediate the systemic anal- gesia of nAChR agonists (Bannon et al. 1998; Bitner et al. 1998). Consistent

with this concept, intracerebroventricular pre-treatment with an α4 antisense

oligonucleotide attenuated  systemic nAChR agonist analgesia. At the level of the spinal cord, serotonin release contributes to nAChR agonist analgesia likely via activation of non-α4β2 nAChR. Activation of these receptors likely acts via

’volume transmission’ whereby pre-synaptic  nAChR increase  serotonin  re- lease rather  than directly stimulate neuronal  firing (Cordero-Erausquin and Changeux 2001). nAChR agonists also activate noradrenergic  and muscarinic

DINs (Rogers and Iwamoto 1993) when administered  systemically. Significant controversy still plagues the analgesic effects of nAChR agonists administered intrathecally with both pro- and antinociceptive actions reported (Rueter et al.

2000); therefore, further study is required before use of these compounds  for

regional analgesia. Systemic administration of nAChR agonists likely induces analgesia predominantly through  supraspinal  mechanisms  with subsequent activation of DINs.


Muscarinic Agonists

Activation of muscarinic  receptors  induces antinociception  in various pain paradigms including thermal, inflammatory and neuropathic pain (Wess et al.

2003; Kang and Eisenach 2003; Shannon et al. 2001). Both central and periph- eral mechanisms of mAChR agonist analgesia exist. Central effects are likely targeted to the dorsal horn of spinal cord where M2 receptors predominate.

Peripheral  activation of M2 receptors  likely contributes  to analgesia via re- duced CGRP release. However, peripheral mechanisms lead to some concern about autonomic effects of these ligands which will require careful evaluation;

mAChR agonists may lend themselves to regional techniques rather than sys- temic approaches  (potentially in contrast to nAChR agonists). Furthermore, as there is little evidence for supraspinal  effects of muscarinic agonists there

may be little need to employ systemic administration.

As vedaclidine exhibits the typical antinociceptive profile of a muscarinic agonist and activates M2 and M4 receptor subtypes but inhibits the odd num- bered receptors (Shannon et al. 2001), it is likely that the inhibitory action of the even-numbered  channels is the predominant antinociceptive  mediator.  Fur- thermore, consistent with pharmacogenomic data, muscarinic antinociception is pertussis toxin sensitive, which indicates the role of inhibitory G protein sig- nalling, likely via M2 and M4 receptors. Further evidence that even numbered channels mediate muscarinic agonist antinociception  is that M2 receptors are known to couple to GIRK receptors and GIRK-null mutants  exhibit reduced muscarinic antinociception. This also indicates a post-synaptic mechanism of action; however, muscarinic antinociception  is also reduced in the presence

of the γ-aminobutyric acid (GABA)B receptor antagonist CGP55845, which is thought to represent a pre-synaptic effect of augmented endogenous GABA re-

lease inhibiting neurotransmitter release (Li et al. 2002). Antagonists of the M2, M3 and M4 receptor subtypes inhibit this GABA release (Zhang et al. 2005). In

addition, as M4 receptors play a crucial role in the potency of α2 adrenoceptor agonists against neuropathic  pain (Kang and Eisenach 2003), targeting this receptor subtype may prove useful for problematic pain management.

Conclusion: Cholinergic Agents

Cholinergic agents represent  a novel and potent class of new analgesics. We await the results of clinical trials to investigate their role in clinical medicine, but we hope they will enjoy clinical utility as independent and adjunctive anal- gesic therapy. Further investigation into the neural substrates and the receptor subtypes involved will allow further development of cholinergic strategies to combat pain.

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