What It is /Pain pathways new advances in understanding /How does it present / why its important to Rx appropriately
How does this effect pharmacology: The old & the new :
recognised drugs & ways of doing things
Recent innovations in pain management in response to new understandings of pain pathways
The old drugs a new,
Research has provided evidence base for the use of old know drugs in new innovative ways; we will briefly look at some of these concepts
We will look briefly at recent changes to clinical practice via modality of analgesic delivery or different ways we utilize the drugs we have on hand
New ones Of course there are always New drugs
And whatever else happens to work it way into the presentation
Slide (4) 2 WHATS PAIN
Definition:Technically Pain is:
Learnt application of the word through (early) life experiences to perceived situation by the individual
Unquestionably a sensation, in a part or parts of the body, but it is also always unpleasant and therefore also an emotional experience for most. But may/may not have pathophysiological cause! ………
It nevertheless elicits a pain response (International Association for the Study of Pain 1994)
However, many people may report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons.!
Subjectively: usually no way to distinguish individuals experience from that due to tissue damage. Thus . If they regard their experience as pain & its reported in the same ways as pain caused by tissue damage, it should be accepted as pain.
This definition avoids tying pain to stimulus. Activity induced in the nociceptor and the nociceptive pathways by a noxious stimulus is NOT pain, which is always a psychological state, even though we may well appreciate that pain most often has a proximate physical cause.
Acute pain: ‘pain of recent onset & probable limited duration (90D), usually has identifiable temporal & causal relationship to injury or disease’.
Chronic pain: ‘commonly persists beyond the time of healing of an injury & frequently there may not be any clearly identifiable cause’ ((Ready & Edwards, 1992)ANZCA 2010).
A continuum is now recognized between acute & chronic pain rather than distinct entities. Increased understanding of the mechanisms of acute pain has led to improvements in clinical management & in the future it may be possible to more directly target the pathophysiological processes associated with specific pain syndromes. ANZCA 2010
However in clinical practice pain is “whatever the experiencing person says it is, existing whenever he says it does." (by Margo McCaffrey in 1968).
I propose that the future spoken of in 2010 is here today with the easy access to the Acute Pain Management: Scientific Evidence, 3rd Ed 2010, Australian & New Zealand College of Anaesthetists & Faculty of Pain Medicine, and an increased understanding of the pharmacokinetics of analgesic drugs and there adjunctive’s
Slide 6) 3Statement of Evidence for clinical practice (ANZCA 2010)
specific early analgesic interventions reduce the incidence of chronic (persistent) pain after surgery. (level 11)
Persistent post surgical pain risk factors include: severity of pre & postoperative pain, intraoperative nerve injury & psychological vulnerability. (level 1V)
Pre-emptive vs preventive analgesia:i.e. Epidural, Ketamine, Gadapentin, Clonidine
ANZCA recommendations provide us a guide to effective management of pain.
1. Epidural prior to thorocotomy & continued post op. Thorocotomy incidence of chronic pain greatly reduced with 10% pt rating pain > 5/10 p10
2. Peri operative Gabapentin to pt having mastectomy Gabapentin pre mastectomy-neuropathic pain at 6 mths : placebo group 25% / treated group 5%.
Pre-emptive- Where a preoperative treatment is more effective than the identical treatment administered after incision or surgery.:
The timing of a single analgesic intervention (pre incision vs post incision), defined as pre-emptive analgesia, has a significant effect on postoperative pain relief with epidural analgesia. (level
1)There is evidence that some analgesic interventions have an effect on post operative pain and /or analgesic consumption that exceeds the expected duration of action of the drug defined as preventive analgesia. Eg Ketamine. (level 1) ANZCA 2010
So the evidence supports that pharmacology works and works well, so what are some of the wholes in the system
1 Lack of accurate preoperative work up,where appropriate pre emptive analgesia is known to be of benefit: i.e.
Epidural for amputations,
pregabalin for anticipated or know neuropathic pain,
conversion to methodone from Norspan 7/7 pre op,
appropriate education & assessment of patient to ascertain existing potential tolerance/ or sensitivty levels; expected or perceived pain levels currently experienced or expected
2. Inability to target specific types of pain appropriately (lack of adequate pain type assessment) & /or knowledge of targeted pharmacology (narcotic & adjunctive)
3. Time constraints, pre operatively, intra operatively and post operatively
Slide (7) 4
The WHO ladder illustrates the basic world standards for pain management. However it looks primarily at one the 4 element of the pain processing: Perception & thus in light of recent R&D is incomplete
Slide (8) 5 “You must unlearn what you have learned”
There are many things we must unlearn from old ways of using medications, expected delivery methods, expected hospitalisation times i.e. joint replacements . The list goes on
Personal Bias’s: Our individual conditioned response to a patient in pain – working out of our perception not theirs. Particularly with acute on chronic patients or those who use illicit substances as well. Judge not least you be judged” Patient respect to quality care mandated that we do not judge.
Slide (9) 6 Acute pain exacerbations may result in neural sensitization & release of mediators both peripherally & centrally
Recent advances in postoperative pain management aims to limit this process & are loosely grouped in the following areas:
Molecular Mechanisms: Extremely complex evolving concepts: a increased variety of receptors; neurotransmitters (inhibitory/excitatory) ; at an increased number of levels from the site of injury (or not) – through to intricate parts of the brain. Impulse's going up the ascending pathway through the dorsal horn/spinal cord to the relevant areas in the brain where a variety of registrations occur & then send stimulus signals down the descending pathway to the site of perceived stimulus. Exacerbations of acute; acute on chronic or chronic pain can lead to neural sensitization & release of mediators both peripherally & centrally. N-Methyl D-Aspartate (NMDA) activation results in ‘clinical wind up: central sensitization (wind up), long-term potentiation of pain (LTP), & transcription-dependent sensitization.
Pharmaceutical products Advances in molecular mechanisms knowledge have led to the development of multimodal analgesia & new pharmaceutical products to treat postoperative pain.
Routes and modes of delivery: R&D to develop longer lasting drugs, those with different property combinations, or differing routes of administration
Other modes of analgesia, (adjunctives): New types, use of established drugs in new ways LA, gabapentin etc
Organizational and procedural aspects: New ways of stream lining procedures, new education programs to psychologically modulate patient perceptions
Molecular Mechanisms (extremely complex, for me @ least )
N-Methyl D-Aspartate (NMDA) receptor & central sensitization (CS): Clinical wind up occurs from the processes of (NMDA) activation,
wind up CS,
2.Long-term potentiation of pain (LTP), early LTP (reversible ) unrelieved will progress to late irreversible memory pathway's in the brain in response to perceived pain registration regardless of presence of pain stimulus
3. Transcription-dependent sensitization(TDS) activation of NMDA wind up and early LTP of pain are transcription-independent processes. TDS is mediated by inflammation & related alterations in the dorsal root ganglion, the dorsal horn, & irreversible structural modifications in the central nervous system. TDS : 2 forms: 1. activity independent localized - includes the late phase of LTP, & 2 activity independent widespread - Late phase LTP seen mainly in the hippocampus and other cortical areas.
4. Common mechanisms of pain and memory: neurokinin (NK1);COX-2 & NMDA receptor are involved in CS, but not involved in hippocampal LTP memory The common mechanisms in hippocampal early phase LTP & CS are phosphorylation of synaptic receptors and the insertion of AMPA receptors into the post-synaptic membrane. There is only synaptic strengthening in hippocampal LTP, while CS also can cause neuronal network changes & other cellular mechanisms. Necessary then to avoid the interruption of memory formation & cortical function while treating CS since the process of LTP is present in CS as well as in memory mechanisms in the cortex .
Slide (10) 7 Pain Processing Element
Noxious mechanical, chemical and thermal stimuli are converted to action potential
AP conducted through nervous system
Alteration of neural transmission along the pain pathway, principally at dorsal horn
Final common pathway. Integration of painful input into somatosensory and limbic cortex.
Traditional analgesic approaches may target only perception
Slide (11) 8 This diagram details the Pain Processing Element highlights the wide range of possible site for adjunctive therapies pharmacology activity
Slide (12) 9 Diagram of pain pathways
Rational: Pain management pharmacology i.e. targeting ‘pain processing’ mechanism with specifically targeted drugs allows accumulative synergistic effect of pharmacology. ‘a little bit of a lot lessens the load’ . This reduce the risk of both ongoing pain sensation with it physiological & psychological effects. But potentially more importantly the risk of ‘wind up’ formulation & minimize adverse effects in critical structure including but not restricted to: NMDA; receptors, PAG & RVM centres in the Brain.
NMDA = N-methyl-d-aspartate; PAG = periaqueductal gray; RVM = rostral ventromedial medulla (brain stem)
Pain Pathway understanding, although the "gate control" theory of pain basic idea still has merrit: incoming pain stimuli can be "gated" (shut off) by other stimuli, because many nerve cells talk to one another in the dorsal horn of the spinal cannel as important fibers coming from the periphery into the dorsal horn send impulses brain ward that are then interrupted and relayed back to source (overs implication) recent R&D has details are far more intricate detailed process which continues to evolve as neuroscience understanding advances
Tiny unmyelinated 'C' fibres: important carriers of the long-lasting burning pain that makes a surgical wound (for example) such an unpleasant experience. There is controversy about where these fibres terminate - in primates many terminate in the deep dorsal horn and even the ventral horn, although conventionally lamina II has been said to be their destination (Willis and Westlund).
Thin myelinated 'A delta' fibres, concerned with more accurate localisation of pain, and terminating mostly laterally in laminae I and V.
Rather chunky 'A beta' fibres that carry information about vibration and position sense from the periphery to the cord.
Unpleasant stimuli entering via the C fibres can be suppressed by concurrent stimulation of A delta fibres (high amplitude low frequency stimulation, for example by acupuncture) or by impulses passing through A beta fibres. Examples of the latter include TENS (transcutaneous electrical nerve stimulation) and the simple expedient of rubbing the skin, which is well known by mothers to decrease perception of pain!
Pain pathways components :-
A)Peripheral receptors; 2 distinct types responses to a painful stimulus 1st /2nd. 1st pain is well-localised to part of body surface & brief, described as sharp, and "pricking“ .The receptors are high threshold mechanoreceptors . There appear to be specific "nociceptors" which mediate pain, and ONLY pain
The 2ndis more diffuse & protracted & due to stimulation of receptors that exist in many tissues (but not in, paradoxically, the brain). Described often as dull (i.e. not sharp) and aching - being poorly localised. Receptors are termed polymodal nociceptors. Pain tends to last beyond the termination of an acute painful stimulus. Sources, pathways, perception of & Rx is very different. Visceral pain is predominantly of the “2nd pain" type. Although
Visceral pain can however sometimes be referred to a region of the body surface (for example, shoulder tip pain with sub-diaphragmatic irritation). See [Cervero, F. Physiological Rev 1994(74.1) 95-129pp] for a review of the sensory innervation of the viscera.
Evidence that neurotransmitters such as substance P (=sP),vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide are important mediators, either as neurotransmitters, or sensitisers of visceral painreceptors. Prostaglandins, histamine, serotonin, bradykinin, ATP, potassium, and H+ ions also appear important in this regard, especially serotonin, which appears to act mainly on 5HT3 receptors.
Pain perception, thresholds for feeling pain are remarkably constant from individual to individual. i.e. Peripheral receptor stimulation of sufficient intensity will reproducibly cause pain at the same level in most people. The response of the individual, & his tolerance of the pain, will however differ markedly between individuals.
Of great interest is "Neurogenic Inflammation". Here, stimulation of C fibres causes a local reaction:vasodilatation & increased capillary permeability; due to retrograde transport & local release of sP and calcitonin gene-related peptide. Resulting in potential release:, K+, H+, acetylcholine, histamine and bradykinin & these cause prostaglandin & leukotriene production (which may end up sensitizing high-threshold mechanoreceptors)! Neurogenic inflammation may spread to surrounding tissues antidromically!!
Peripherally acting analgesia include: NSAID, corticosteroids, LA (which may theoretically inhibit neurogenic inflammation if given early enough, an area of great controversy), & even novel drugs such as substance P antagonists (One such antagonist that does NOT appear to work very well is capsaicin, but opioids, serotonin antagonists, baclofen & clonidine may also inhibit sP release).
Of note is the recent identification of two different types of cyclo-oxygenase, with the potential for developing more specific NSAID’s, with (perhaps) fewer side-effects.
B. Neural pathways. 1st pain: responses are conveyed from the periphery to the dorsal horn of the spinal cord in small myelinated fibres (A delta) while 2nd pain is conveyed in non-myelinated C fibres. Important, especially when considering the "gate control theory" detailed below. Also of importance to this theory are afferent stimuli coming in large myelinated fibres (A beta fibres), from peripheral vibration / pressure / touch receptors.
Neurogenic pain, originating in damaged or abnormal C fibers, thus may respond to membrane- stabilizing drugs such as anticonvulsants (e.g. carbamazepine).
C. Spinal cord pathways.
Complex. We will consider: initial connections : laminae in the spinal grey matter close to where the fibres enter the spinal cord.
Ascending pathways and descending (control) pathways are considered much later.
We now have sufficient resources to examine the various ascending pain pathways. First, the primitive spino-reticulo-diencephalic connections Next, we examine the phylogenetically more modern pathways from cord to lateral thalamus and thence to the S I cortex. These pathways are discriminative pain pathways, and have little to do with perception of pain as a 'sore' stimulus! These pathways have few or no opioid receptors - morphine (for example) will have no effect on such pathways
Descending Pain Connections
As important as the ascending pathways are fibres that descend from brainstem to spinal cord to modulate the incoming signals. Notable neurotransmitters mediating this anti-nociceptive effect include noradrenaline (norepinephrine), especially in the locus coeruleus, and serotonin in the raphe nuclei. Opioid receptors are prevalent here. Some descending connections are: Descending connections that modulate incoming pain impulses.
Incoming painful stimuli are transmitted (A) to the dorsal horn, and from there (B) to the periaqueductal grey (PAG). Descending impulses pass (C) to the raphe nuclei, especially the nucleus raphe magnus, in the upper medulla, and thence back to the dorsal horn via reticulospinal fibres (D).
The above shows only the serotonergic descending fibres. Other pain-suppressing impulses pass from the PAG to the locus coeruleus, and from there to the dorsal horn.
Pain in the periphery - the nociceptor
The above connections are awfully complex. One might think that once we moved out to the periphery, things might become more simple. Not so! Most tissues are well provided with specific pain receptors called nociceptors. Formerly it was thought that painful stimuli were detected through 'overstimulation' of receptors for other modalities. This is incorrect. The quality of the pain perceived on stimulation of nociceptors seems to depend on the site of stimulation, and the nature of the fibres transmitting the sensation. Even in the periphery, there is a distinction between the sharp immediate pain ("first pain") transmitted by A delta fibres, and the prolonged unpleasant burning pain mediated through the smaller unmyelinated C fibres.
Nociceptors have numerous different receptors on their surfaces that modulate their sensitivity to stimulation. These include GABA, opiate, bradykinin, histamine, serotonin and capsaicin receptors, but the various roles of these receptors are poorly characterised.
The most fascinating aspect of pain perception in the periphery is that normally most nociceptors lie dormant. Inflammation sensitizes this vast population of nociceptors, making them far more sensitive to stimulation (hyperalgesia). Hyperalgesia may be primary (felt at the site of stimulation, related to sensitization of the neurones innervating that area) or secondary (felt at a site remote from the original injury, and probably related to NMDA-mediated "wind-up").
A plethora of neurotransmitters mediates transmission of the sensations of pain in both brain and spinal cord. The list is intimidating, and grows daily. We can try and 'lump' these neurotransmitters into various groups:
Excitatory neurotransmitters: Important are glutamate and the tachykinins, agents that act at the various neurokinin receptors including as substance P ('P is for pain'), neurokinin A and neurokinin B. Other substances that transmit pain impulses from incoming nerves in the dorsal horn including calcitonin gene-related peptide, vasoactive intestinal polypeptide, somatostatin and bombesin.
Inhibitory neurotransmitters: There are several inhibitory neurotransmitters, but in the central nervous system, gamma amino butyric acid (GABA) appears to reign supreme. Over forty percent of inhibition in the mammalian central nervous system is GABAergic.
Neurotransmitters involved in Descending Pain Regulation: Here, the alpha-2 stimulatory effects of noradrenaline (norepinephrine) and the effects of serotonin are prominent. Opiates relieve pain by stimulating mu and delta receptors at a host of sites.
Glutamate A brief Medline search for articles using the abbreviation "NMDA" in the past ten years will garner about twelve thousand references. This attests the fanatical interest researchers have in this, the hottest of the glutamate receptors, but one mustn't forget that there are at least two others, the "AMPA" receptor and the obscure and devious metabotropic receptor. The NMDA receptor mediates a host of spinal responses to severe painful stimulation, but there are several catches to understanding how it works. Normally, the receptor is inactive as it is physiologically choked by a magnesium ion sitting in its ion channel. In order for this ion to be removed, adjacent peptide receptors have to be stimulated - the Mg++ then pops off, and an emphatic painful response occurs. Neurophysiologists have known about this phenomenon for ages, gracing it with the label "wind-up" - as the frequency of C-fibre stimulation increases there is a dramatic and long-lasting central response, with some populations of spinal neurones becoming more and more sensitive to stimulation.
Consequences of glutamate receptor activation include production of c-fos (discussed below) and spinal production of prostanoids and the ubiquitous Dr NO, nitric oxide. Unfortunately all this knowledge benefits clinicians surprisingly little, as drugs that antagonise the effect of glutamate at the NMDA receptor tend to induce psychosis in humans, but the combination of low dose NMDA antagonists with opioids may be supra-additive with fewer side effects.