Slide (4) 1 This presentation will cover several areas starting theoretically and moving through to practical application Quick over view from the experts on pain 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 And finally 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: Always subjective 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. Futher: 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 1 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 rd Management: Scientific Evidence, 3 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) 3 Statement 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.: Epidural. Wound infiltration with LA prior to incision Patient Education to reduce anxiety Pre-emptive vs preventive analgesia 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 2 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 DAspartate (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 ) 1.Molecular Mechanisms: peripheral sensitization - primary mediators –secondary mediators 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. 3 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 • • • • • Transduction – Noxious mechanical, chemical and thermal stimuli are converted to action potential Transmission – AP conducted through nervous system Modulation – Alteration of neural transmission along the pain pathway, principally at dorsal horn Perception – 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 4 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 :st nd A)Peripheral receptors; 2 distinct types responses to a painful stimulus 1 /2 . 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 nd The 2 is 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, nd pathways, perception of & Rx is very different. Visceral pain is predominantly of the “2 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 pain receptors. 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 highthreshold 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. st B. Neural pathways. 1 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. Local interconnections. Ascending pathways and descending (control) pathways are considered much later. Neural pathways; Spinal Cord mechanisms & long tracts; Brainstem, thalamus, cortex & other areas. Descending pathways. Ascending Pain Connections We now have sufficient resources to examine the various ascending pain pathways. First, the primitive spino-reticulodiencephalic 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 5 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 NMDAmediated "wind-up"). & Neurotransmitters 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. Specific neurotransmitters 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. GABA GABA is widespread in the brain and spinal cord. Together with its partner glycine, it has major inhibitory effects, dramatically evident in poisoning with strychnine, which antagonises glycine. Interneurones in laminae I, II and III are GABA-rich, and mediate gate control in the dorsal horn by synapsing on neurones that contain substance P. There are several distinct GABA receptors that work quite differently - the GABAA receptor is a "ligand-gated ion channel" that allows chloride ions to leak into the cell, while the GABAB receptor is a "seven-spanning" transmembrane structure that activates G proteins. Again, the clinical utility of this knowledge is small, as GABAB receptor agonists such as baclofen, which are analgesic at the spinal level in rats, have little effect in man, although they may potentiate the analgesia of morphine. Benzodiazepines modulate the GABAA receptor allosterically - but GABAA seems more important at supraspinal than spinal sites. Tachykinins It will probably be several years before newer agents such as neurokinin antagonists have been tested sufficiently for widespread clinical use, although (for example) NK-1 antagonists such as CP-96 345 have been shown to moderately decrease isoflurane MAC in tail-clamped rats (shudder!) when given intrathecally. Neurokinin receptors probably do mediate pain in the spinal cord - substance P binds to the NK-1 receptor while neurokinins A and B bind respectively to the NK-2 and NK-3 receptors. Collectively these substances are known as 'tachykinins'. The tachykinin receptors are G-protein coupled, and increase intracellular calcium levels, triggering gene transcription. E. Descending pathways. Descending modulation of pain sensation originates from three main areas: Brainstem, where the Periaqueductal grey matter (PAG) is particularly important. Fibres pass from PAG to the reticular formation of the medulla (the nucleus raphe magnus or "NRM", and the closely associated nucleus reticularis gigantocellularis pars alpha, and nucleus reticularis paragigantocellularis, all together called the ventromedian medulla or "VMM") where connections are serotoninergic, and from there axons descend in the "dorsolateral funiculus" of the spinal cord, to end up (surprise, surprise) on interneurones right next to the substantia gelatinosa (lamina II) in the cord. The synapses here are enkephalinergic. Stimulation of this system causes inhibition of incoming pain impulses. Thus, although serotonin applied peripherally augments pain, its action centrally is important in descending inhibition of incoming painful impulses! New evidence suggests that GABA is also important in inhibition of pain pathways by the VMM [Neuroscience Jul 1996 73(2) 509-18pp]. 6 Slide (13) 10 Diagram at the neural level Busy diagram but just know that there is lots of neurotransmitters & receptors that makes the process of effective targeted pain management complicated but also gives lots of options for onging pain management Molecular Mechanisms: peripheral sensitization - primary mediators –secondary mediators NMDA receptor and central sensitization (CS): Clinical wind up occurs from the processes of N-Methyl D-Aspartate (NMDA) activation, wind up CS, 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 Transcription-dependent sensitization(TDS) activation of NMDA wind up and early LTP of pain are transcriptionindependent 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. 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 (14) 10 Practical concepts in pain: Not controlling post operative pain has negative effcts benefits; Not controlling post operative pain has negative benefits; Physiologically and psychological aspects of patient experience of pain are considered together left as to right hands. Then next slide provides a summary of these effects Exacerbations of acute A on C, 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), & transcriptiondependent sensitization Advances in molecular mechanisms knowledge have led to the development of multimodal analgesia & new pharmaceutical products to treat postoperative pain. R&D New pharmacological products to treat postoperative pain include extended-release epidural morphine & analgesic adjuvants such as capsaicin, ketamine, gabapentin, pregabalin dexmetomidine, and tapentadol. Newer postoperative patient-controlled analgesia (PCA) in modes such as intranasal (ie fentanyl), regional, transdermal, and pulmonary (USA) presents another c interesting avenue of development .( N. Vadivelu, S. Mitra, & D. Narayan, (2010) Recent Advances in Postoperative Pain Management ,Yale J Biol Med. Mar 2010; 83(1): 11–25. Published online Mar 2010) Molecular Mechanisms: peripheral sensitization - primary mediators –secondary mediators NMDA receptor and central sensitization (CS): Clinical wind up occurs from the processes of N-Methyl D-Aspartate (NMDA) activation, wind up CS, 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 Transcription-dependent sensitization(TDS) activation of NMDA wind up and early LTP of pain are transcriptionindependent 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 7 independent localized - includes the late phase of LTP, & 2 activity independent widespread - Late phase LTP seen mainly in the hippocampus and other cortical areas. 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 (15) 11 Controlling post operative pain has negative effects: Physiologically & Psychological effects Diaragm Slide (16) 12 Practical concepts in Pain: cont’d Practical concepts in Pain: So what do we actually see and what seems to work 1.Patient comfort/Functional ability/activity = Patient expectations: Fact or Fiction + +2 Basic Pain Assessment (thorough + 3 Present / Past History) + 4 Positioning + 5 Pharmacology We will look at each of these in turn The purpose of pain management is to allow the patient to be comfortable at rest & to a greater degree whilst activity also. After all no one has time to lie around in our modern busy hospitals! Slide (17) 13 Patient comfort What is patient comfort? As with the subjective nature of pain perception, patient comfort level is also a subjective assessment being a balance between pain registration (their score & FAS);what’s perceptually emotionally, physiologically & pharmacologically achievable in a given situation for the individual. I often call these situations patchwork quilts or coats of analgesia that adequately covers the painful stimulus allowing patients to attend activities of daily living comfortably. It is a process that is expected to improve over time as healing continues the need for analgesia reduces but at all time a patient ideally can preform their activity of daily living, initially with assistance possibly but ultimately unadded as far as practicable Thus, the more complex the situation the more effective pre operative education and pain management will enhance post operative outcomes Effective pre operative education which may include training in relaxation & breathing techniques in combination with realistic evidence based patient targeted ouitcomes education can be very beneficial in the postoperative recovery phases. This may mitigate pain registration & adverse outcome, thus enhance recovery time. Hip surgery expectation up same day dressed in street clothes home day 1 that what’s educated and that what patient expect and in the main that’s what happens 8 Slide (18) 14 1. Comprehensive assessment of pain. 2. Past history / present comorbitities& projected outcomes are considered together as they are always interconnected & individualised to the patient & particular situation at hand. Standardised Scoring system: i.e. numerical; visual analogue scale; Wong baker; Behavioural rating scale + Functional Activity Score (FAS), BHS has a standard assessment & measurement th of acute pain chart at each patient bed., pain is considered the 5 basic observation & as such is recorded on RORC, & all other ORC type charts.& there a few of them! Direct Pain type Rx: Recognition of the 8 pain types (BHS we use a table of the 8 pain types with descriptor information & suggested pharmacological treatments available; & we also refer to ANZCA 2012 for specific condition treatment regimes if patients are unable to give accurate pain type descriptions. Note chronic pain patients & possibly those with cognitive impairment may have difficulty localizing to pain; actual pain descriptors as part of their coping mechanism - psychological aversion to the pain stimulus – they just don’t want to look at or concentrate on the pain experienced when its intense.. They may be more able to describe when some level of control achieved. Thus as a nurse it is important to be vigilant to the nonverbal cues, frequency, intensity & or alteration to pain experienced, patient spontaneous descriptors & any alteration in non verbal pain stimulus registration post Rx’s. In addition, having a grasp of the onset /peak action times of drugs given (route specific) will allow more accurate assessment and negate ‘wind up tiggers’.(asking if improved when inadequate time elapsed for response registration. i.e bolusing APP /epidural) Slide (19) 15 Comprehensive assessment of pain BHS tool Slide (20) 16 1. Comprehensive assessment of pain 2) Past history / comorbitities cont’d What are the elements of a comprehensive pain assessment these can also be stated as: Patient individual interpretation of their 3 P’s Present, Past and projected situation, will colour their end interpretation of a pain response & subsequent response to management, Thus, it is important to individualise the experience & normalise to expected outcomes (this may be the general population or in complex case specific to the individual) Anatomically: loss of perceived vital organ/ or actual loss of vital organ; amputations pt happy for same (glass half full) – unhappy about same – (half empty), back surgery working /retired etc Physiologically: individuals ability to tolerate/metabolise medications will effect what’s used; ability to effectively heal or rehabilitate will effect expected & actual pain management plans & outcomes Psychologically: in combination with the above & taking into consideration the patients congnitive resilence & or capacity to understand the surgical process & outcomes The American Academy of Pain Medicine (AAPM), American Pain Society (APS), American Society of Addiction Medicine (ASAM), & NAABT recognizes these definitions below as the current accepted definitions. I. Addiction: Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, & environmental factors influencing its development & manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. 9 II. Physical Dependence: Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, &/or administration of an antagonist. III. Tolerance: Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Physical dependence & tolerance are normal physiology. Addiction is a disorder that is damaging & requires treatment Present / Past History (previous pharmocology exposure (always be mindful of self medicating with drugs Script/elicit/alcohol all will effect “tolerance” /treatment options, conversely analgesic naive patient may have little requirement (codeine % Caucasian population don’t possess enzyme required to convert codeine to morphine so passes through system with no effect; past pain levels + Positioning + Pharmacology = Patient comfort/Functional ability Analgesia is titrated to patient’s report of pain and functional ability. . Slide (21) 17 How does the patient describe the pain chart? Slide (22) 18 3 .Patient expectation: Fact or fiction Patient expectations: No doubt that appropriate pre operative education (ideally pre anaesthetic clinic staff with specialised staff) is of great benefit to patients understanding of what’s a reasonable expectation: 1 Thoughts : Understanding the Pt knowledge/ expectation from past experience/exposure or others feedback, that may or will impact of current presentation allows for effective remodeling (education on new ways of doing things) so that patient’s knowledge and thus expected outcomes hence are in keeping with current practice. - i.e (recent in particular Ortho: THR educ), debunk misconcept’s of patient being ill needing to lie in bed, or the magnitude of the surgical assault/ thus expected outcome i.e. lap choly/ open choly expected pain differences; adbo surgery: spinal /general anaesthesia or open / laparoscopic procedures 2. Actions : clear expectations of what physical activity &/ or how quickly there is expected to be a return to ADL’s discussed pre operatively and reinforces post operatively, this includes length of hospital stay 3. Reality: glass half full not half empty, encouragement that is empathetic and sincere ensuring that all adjunctive therapies and supports are instigated in a timely manner. True these patient are in their initial post operative stage one would hope that much of this has already been attended too, but if not there may be a need for organizational change Comprehensive Pain Assessment: This requires a detailed actual assessment of the descriptive type, location, intensity, duration, new or old & importantly any known relieving strategies by the patient or staff. 10 In combination with relevant past history. Understanding a patient history of the pain experience and what previous medications strategies or other relieving techniques may be beneficial. Likewise Acute on Chronic pain operative site may be insignificant to pre operative complaint or post operative pain insignificant to preoperative despite operative procedure (arthritic pains Co Morbidities liver/ kidney (metabolism), diabetes,(neuropathies) paraplegias past injury relevant and/ or contributory pain tolerance issues, Importance of support: Both Physical and Psychological will help shape a patients perception of the pain experience Positioning/Reassurance: One of the simplest and most effective things – ensure good body alignment and reduced tension of the operative site – if appropriate provide counter tension (towel over abdomen – and be able to explain its benefits to the patient – increase likelihood of patients using techniques. Pharmacology choice appropriate to pain type (8). Not all responsive to narcotic some responsive to adjunctive type pharmacology ie neuropathic pain Acute Pain Management ANZCA, The importance of adjunctive therapy: allow for a broader coverage of pain receptor sites and thus greater opportunity to minimise the pain signal registration for the individual in response to smaller dosing of any one particular drug . Has the side benefit of reduce side effects and tolerance response in . Other aspects: Supportive therapies, counselling Slide (23) 19 3.Patient expectation: Fact or fiction cont’d Past injury/scaring or chronic pain, Rx for same (tolerance) Elicit drug / Alcohol use (tolerance) Renal/Liver impairment effects pharmacology metabolism & excretion (consideration particularly in the elderly) pt age/metabolic capacity. As a rule of thumb in the young and the elderly it ideal to use drugs with less active metabolites therefore less risk of accumulative effect or side effects. In addition the dosing requirements is usually less than for adult patients, although children dosing is usually up to age 8-10years onset of elderly dosing is dependent on co morbidity states but generally considered around age 70 Slide (24) 20 4. Positioning Positioning: importance of support & reassurance this allows patient to have some control over their body even if only perceived ie towel to counterbrace abdomen when coughing (helpful to explain mechanism - increases compliance if patients understand why) Optimized supportive patient position will greatly assist pain management, it’s simple and often overlooked. Abdominal surgery knee’s up takes tension of the abdominal muscles. Elevation of limbs reduces swelling Sitting as upright as possible takes weight off the diagram. Limbs supported in position of comfort Other supportive devices Occasional with effective communication of expected outcomes considerate of patient pre condition and utilizing optimized positioning is significant enough to control pain Slide (25) 21 Slide (26) 22 5.Targeted Pharmacology 11 Targeted Pharmacology 1. ANZCA: Appropriate to pain type, & importance of adjunctive therapy ‘a little bit of a lot reduces side effects & increase relieve’. 2. Begin to make your patchwork quilt 1. Deliver pre/intr & post opearatively; as able, consider drug route onset/peak action for effect & efficiency (APP, IV vs Oral) 2. Note: use of narcotic of morphine being questions due to onset/peak/metabolism time considerations 3. Dosing considerations Age/ Gender/ tolerance/ sensitivity (1,5) 4. Dose x Pt specific Wt x 24hrs (6 The general (although this is a complex situation to which generalization fit poorly) trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, & also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight Obese patients drug dosing is difficult, as dosages based on pharmacokinetic data obtained in normal-weight individuals could induce errors. Physiopathological modifications in the obese can affect drug tissue distribution & elimination. Body constitution is characterised by a higher percentage of fat & a lower percentage of lean tissue & water. Despite cardiac output & total blood volume increasing, the blood flow per gram of fat is less than in nonobese individuals. Histological hepatic alterations are commonly reported in morbidly obese individuals. A higher glomerular filtration rate is also observed. Most of the pharmacokinetic information concerning obesity deals with distribution. Published data concerning molecules with moderate and weak lipophilicity are homogeneous. In obese compared with normal weight individuals, the total volume of distribution (Vd) is moderately increased (aminoglycosides, caffeine) or similar (H2-blockers, neuromuscular blockers), but the Vd corrected by kilogram of actual bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight. For highly lipophilic drugs, despite this common characteristic, discrepancies in distribution in obesity exist between drugs belonging to different pharmacological classes. Some drugs show a clear augmentation of Vd and elimination half-life (benzodiazepines, carbamazepine, trazodone, verapamil, sufentanil), indicating a marked distribution into adipose tissue. For others, Vd and Vd/kg are decreased (cyclosporin, propranolol), suggesting that factors others than lipid solubility intervene in tissue distribution. The general (although this is a complex situation to which generalization fit poorly) trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, & also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Usually CL is identical in obese & nonobese individuals, sometimes it is increased in obesity ( prednisolone, some benzodiazepines). With some drugs a significant reduction in CL is observed in obese individuals (methylprednisolone, propranolol). Renal clearance of aminoglycosides and cimetidine increases in obese individuals. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in CL. In some cases (atracurium, prednisolone) dosage adjustment does not follow these recommendations, owing to pharmacodynamic 12 data. (Clinical Pharmacokinetics August 1993, Volume 25, Issue 2, pp 103-114 Date: 04 Nov 2012 Clinical Pharmacokinetics of Drugs in Obesity Georges CheymolSummary Slide (27) 23 Pain window diagrams Slide (28) 24 Tree of analgesia So how do we know what drugs to use: understanding the different pharmogenics of each sub group of analgesia and their sites of action in the pain pathways will help. However this is a very complex process as new areas of pain pathway sites of actions are being discovered almost daily. Nevertheless drawing a line in the sand & starting somewhere is required. This knowledge is then coupled with either an understanding of the ascending and descending and brain registration areas functions in pain pathway interruption and modulation. In the late 1960’s the was the Gate Theory – today this has grown markedly . (Far to broad a topic to cover in this presentation. However the ANZCA Acute pain management book has done a lot of the leg work if you can achieve an effective thorough pain assessment. Lipid soluble narcotics (hydromorphone (Dilaudid), fentanyl) Water soluble narcotics (preservative-free (PF) morphine, Duramorph Why Use Opioids • Mode of Action: – Mimic action of endorphins. – Attach to receptor sites to produce analgesia. – Majority of receptor sites are found within the substantia gelatinosa of the dorsal horn (spinal cord). – Inhibit the release of substance P a neurotransmitter required for nociceptive transmission. • Opioid Recptors Receptor Action Mu 1 Analgesia, euphoria and dependence Mu 2 Respiratory depression, bradycardia, purities, miosis, nausea and vomiting, inhibition of gut motility Kappa Analgesia, sedation, miosis Delta Analgesia, dysphoria sigma Dysphoria, hallucinations, mydriasis Achieving analgesia in the recovery room Opioids and Adjunctive therapy • Maximize regional analgesia • Analgesia is titrated to patient’s report of pain and functional ability. • Analgesia frequently achieved with opioid loading doses(s) with consideration given to: – sedation score, respiration rate, BP, and age • Use Adjunctive: paracetamol, NSAID, Tramadol, and ketamine may also be appropriate. APP Order • Morphine 1-2 mg 5 minutely up to 10 mg PRN • Fentanyl 20-40 mcg 5 min. up to 200 mcg PRN Notice which pain settles with opioid. Is there a pain that appears not to be responsive? Has a non-opioid been considered? Opioid Recovery room loading • Small amounts often to gain rapid analgesia • Peak effect of morphine ~ 15 minutes 13 • • • Load then allow time for medication to peak Minimum wait of 20- 30 minutes in recovery following parenteral opioid administration Ketamine improves analgesia in patients with severe pain that is poorly responsive to opioids (level 11) ANZCA 2005 Practice points • Opioid requirement decreases with increasing age • Continuous Intravenous Infusions • Difficult to predict the infusion rate required to achieve consistent analgesia in each individual. • It takes 5 half-lives of a drug to reach a constant plasma drug concentration following changes in infusion rate • Programmed bolus doses should be used to achieve patient comfort, before rate changes. Practice Points Pain and opioids • Pain acts as a physiological antagonist to the central depressant effects of opioids • As tolerance develops to the analgesic effect, so to does a greater tolerance develop to the respiratory depressant effect. • Respiratory effects of opioids • May produce a decrease in tidal volume and respiratory rate, or changes in respiratory rhythm. • Respiratory depression more likely when: – first dose is given – pain subsides (e.g. IDC insertion) – drug dose error – the dose not reviewed in renal failure Adverse effects of opioids – CNS:sedation;euphoria ;constriction of pupils (miosis) – GIT Emesis stimulation of the chemoreceptor trigger zone in the medulla. – worst in ambulatory patients. – Constipation:delayed gastric emptying, inhibition of bowel motility. – Urinary retention: increased tone in the bladder sphincter – CVS: Hypotension- Arteriole and vein vasodilatation; – histamine release:Pruritus; histamine release which may result in local or generalised itching, not associated with a rash. – Allergy: rare, but similar to other allergic reactions. Management options for opioid induced side effects. • Decrease the dose of opioid (e.g. PCA dose). • Regular concurrent use of other analgesics and non drug therapies. • Monitoring sedation levels will help prevent clinically significant respiratory depression. • Decrease the dose of opioid if constantly drowsy thus preventing respiratory rate depression • Sedation and respiratory depression can be exaggerated by the co - administration of e.g. diazepam, temazepam, or prochlorperazine with an opioid. • . Opioid requirement decreases with increasing age Continuous Intravenous Infusions • Difficult to predict the infusion rate required to achieve consistent analgesia in each individual. • It takes 5 half-lives of a drug to reach a constant plasma drug concentration following changes in infusion rate 14 • Programmed bolus doses should be used to achieve patient comfort, before rate changes. Pain and opioids • Pain acts a a physiological antagonist to the central depressant effects of opioids • As tolerance develops to the analgesic effect, so to does a greater tolerance develop to the respiratory depressant effect. Respiratory effects of opioids • May produce a decrease in tidal volume and respiratory rate, or changes in respiratory rhythm. • Respiratory depression more likely when: – first dose is given – pain subsides (e.g. IDC insertion) – drug dose error – the dose not reviewed in renal failure. STATEMENT OF EVIDENCE • As significant background and /or intermittent hypoxaemia may occur for a number of days postoperatively, Supplemental oxygen is recommended for at least the first 48-72 hours following major surgery and in elderly or high-risk patients regardless of the analgesic method used. NHMRC Reader et al 1992a Adverse effects of opioids • Central Nervous system – sedation – euphoria – constriction of pupils (miosis) • Emesis – stimulation of the chemoreceptor trigger zone in the medulla. – worst in ambulatory patients. • Constipation – delayed gastric emptying, inhibition of bowel motility. • Urinary retention – increased tone in the bladder sphincter • Hypotension – arteriole and vein vasodilatation – histamine release • Pruritus – histamine release which may result in local or generalised itching, not associated with a rash. • Allergy – rare, but similar to other allergic reactions. Management options for opioid induced side effects. 15 • • • • • Decrease the dose of opioid (e.g. PCA dose). Regular concurrent use of other analgesics and non drug therapies. Monitoring sedation levels will help prevent clinically significant respiratory depression. Decrease the dose of opioid if constantly drowsy thus preventing respiratory rate depression Sedation and respiratory depression can be exaggerated by the co - administration of e.g. diazepam, temazepam, or prochlorperazine with an opioid. Morphine • Gold standard • Receptors: Mu +++ kappa + delta + agonist • short half life 2-3 hours. • Two main metabolites M3G and M6G, M6G is approximately twice as potent an analgesic as morphine. Bupamorphine 7 days 72 hr to peak • Partial agonist may antagonize the effects of a previously administered agonist Opioids depending on – proportion of receptors occupied – time interval between the administration of the two drugs – Buprenorphine patches are available as low-dose 7d release patches or in higher dose patches replaced every 72hr. Steady plasma concentrations occur on average 12hr after application of the transdermal patch. Dangerously high plasma concentrations can occur if patients are actively warmed whilst wearing a transdermal patch, also pressure sensitive BD label checking and signing safe guide • Example: Buprenorphine was compared with naloxone for reversal of prepoperative fentanyl (Boysen K et al 1988) • Acute Pain in Buprenorphine Maintained Patients Use some form of opioid maintenance medication prefer Tramadol Acute pain in hospitalized patient provide analgesia as indicated for the condition Caution: avoid high dose analgesic medication compounded with paracetamol in patient with Hepatitis B or C consider maintenance with methadone pre operative 7/7 weaning Norspan Methadone—long-acting pure opioid agonist. In the acute pain setting methadone should be continued at the same dose. If the patient is unable to take methadone orally, substitution with parenteral methadone or other opioids may be required in the short term Oxycodone • Synthetic opioid with better oral bioavailability than morphine and a slightly longer duration of action than oral morphine. Receptors: Mu+++, Kappa+ and Delta+ agonist • • 20mg oral oxycodone ~ 10 mg IM morphine • Oral oxycodone will take ~ 40 minutes to act Also available in a control release tablet – 40% of drug dose is released in first hour( enteric coated (functioning gut required) Synthetic opioid with better oral bioavailability than morphine and a slightly longer duration of action than oral morphine. • 16 Codeine Receptor: Mu+++ kappa+ and delta+ agonist Well absorbed orally but a low affinity for opioid receptors. Owes its analgesic effects to conversion by CYP2D6 to morphine, a pathway that is inactive in about 10% of the population. Number Needed to Treat = 16.7 for 60mg dose and 1.9 for combination 1gm paracetamol with 60mg codeine. Synthetic Opioids Pethidine Rarely used `synthetic opioid Receptor Mu ++ kappa+ and delta + agonist. • elimination half life 2 - 6 hours. • norpethidine is its main metabolite, it has a long half life of 15 - 20 hours and will provide analgesia. • build up of norpethidine can cause irritability, tremors and convulsions. • Pethidine has been reported to more than double the risk of delirium. • Muscle fibrosis can occur when administered by IM route Intra Operative Remifentanil • Ultra short acting synthetic opioid • half-life is ~ 3 minutes. Usually delivered by infusion and rapid recovery when stopped. • Long acting analgesics may be needed before discontinuation. • Not for epidural or spinal route use as contains glycine Alfentanil • derived from fentanyl • onset of analgesia in 15-120 seconds • duration of analgesia is dose related. • when compared to fentanyl, alfentanil is 25% more potent. • elimination half life of 90 minutes is significantly shorter than other opioids. • secondary serum peak levels reported. • • Fentanyl • Receptors: Mu+++ and delta+ agonist • Onset of analgesia 30 - 120 seconds Half life 1-2 hours Peak onset 1 -5min, duration 30min, metabolite <72hrs (lipid soluable)/inert • No active metabolite - safer opioid in the presence of renal impairment. • Secondary serum peak levels reported @ 4hr (caution with continuos IV infusion ) leak taken up in fat cell with rebound release reported • Life threatening respiratory depression has been reported when transdermal or IV route fentanyl has been administered to opioid naïve patients (particularly early patch design) • spinal anaesthesia. Fentanyl 10–30µg has a rapid onset (10–20 min) and a short duration • Transdermal administration. Very lipid-soluble opioids are absorbed through skin. Fentanyl patches are available in five sizes (12–100µg/hr) and patches are replaced every 72hr of action (4–6hr) Tramadol racemic mixture • synthetic centrally acting opioid-like drug 17 • • • • • • • • Less than half of its analgesic activity is at the µ-opioid receptor. It inhibits noradrenaline and serotonin uptake at nerve terminals, thereby enhancing the inhibitory pathway. Lower tolerance & abuse potential, less respiratory depression, & constipation compared to other opioids reported. Metabolised in the liver & excreted in the kidney. Main metabolite of tramadol is Odesmethyltramadol (M1) which is more potent. Formation of M1 also depends on the presence of CYP2D6 within the cytochrome P450 system (see codeine). Parenteral load give slowly (15-30 minutes) to reduce incidence of adverse reaction Nausea and dizziness - very common > 1/10 Drug interactions with anti-convulsants, and anti-depressants .Serotonin syndrome Minimal respiratory and gastro-intestinal stasis. Drug interaction with warfarin, and not recommended if coexisting condition of epilepsy exists Equianalgesia (note equianalgesia differ from text to text slightly) Drug Oral dose (mg) Parental dose (mg) Morphine 30 10 Pethidine 300 75 Oxycodone 20 – 30 Codiene 200 - 240 • • • • • • • • • • • • • • • • • • • • • • • • • • • Systemic Medications: Opioids Opioid Receptors: ì, ê and ä 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 Tramadol: Reasemtic noradrenaline /serotonin Moderate affinity ì receptor agonist 5ht3 agonist. Acts on spinal modulating pathways Inhibition of neuronal NA and Serotonin uptake Stimulation of presynaptic serotonin release Adverse Effects: Nausea & Vomiting: Ondansetron interferes with analgesic effect Non addictive, less sedation Dose: 3 mg/kg IM/IV/PO for moderate to severe pain 18 • • • • • • • • Buprenorphine:Semisynthetic, Agonist-Antagonist Routes of administration: IV, IM, Neuraxial, SC, SL, Trasdermal Useful in morphine intolerant patient;Ceiling effect for respiratory depression, but not for analgesia. Antiflammatory action:Useful in intra-articular injections; Prolongs duration of analgesia in peripheral nerve blocks with LA Methadone:Synthetic broad spectrum opioid;Mu receptor agonist;NMDA antagonist;Inhibitor of monoamine transmitters Useful in treatment of neuropathic pain; Orally well absorbed; No dose adjustment in renal disease; Drug most commonly used for opioid rotation • • ANZCA’s Opioid Key messages 1. Dextropropoxyphene has low analgesic efficacy (U) (Level I [Cochrane Review]). 2. Tramadol is an effective treatment for neuropathic pain (U) (Level I [Cochrane Review]). 3. Gabapentin, non-steroidal NSAIDs and ketamine are opioid-sparing medications and reduce opioid-related side effects (N) (Level I). 4. In appropriate doses, droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine and granisetron are effective in the prevention of postoperative nausea and vomiting (N) (Level I [Cochrane Review]). 5. Alvimopan and methylnaltrexone are effective in reversing opioid-induced slowing of gastrointestinal transit time and constipation (N) (Level I [Cochrane Review]). 6. Droperidol, dexamethasone and ondansetron are equally effective in the prevention of postoperative nausea and vomiting (U) (Level I). 7. Paired combinations of 5HT3 antagonist, droperidol or dexamethasone provide superior prophylaxis of postoperative nausea and vomiting than either compound alone (N)(Level I). 8. Naloxone, naltrexone, nalbuphine, droperidol and 5HT3 antagonists are effective treatments for opioid-induced pruritus (N) (Level I). 9. Opioids in high doses can induce hyperalgesia (N) (Level I). 10. Tramadol has a lower risk of respiratory depression and impairs gastrointestinal motor function less than other opioids at equianalgesic doses (U) (Level II). 11. Pethidine is not superior to morphine in treatment of pain of renal or biliary colic (U) (Level II). 12. Morphine-6-glucuronide is an effective analgesic (N) (Level II). 13. In the management of acute pain, one opioid is not superior over others but some opioids are better in some patients (U) (Level II). 14. The incidence of clinically meaningful adverse effects of opioids is dose-related (U) (Level II). 15. High doses of methadone can lead to prolonged QT interval (N) (Level II). 16. Haloperidol is effective in the prevention of postoperative nausea and vomiting (N) (Level II). 17. Opioid antagonists are effective treatments for opioid-induced urinary retention (N) (Level II).PTER 4 18. In clinically relevant doses, there is a ceiling effect for respiratory depression with buprenorphine but not for analgesia (N) (Level III-2). 19. Assessment of sedation is a more reliable way of detecting early opioid-induced respiratory depression than a decreased respiratory rate (S) (Level III-3). 19 20. The evidence for risk of cardiac arrhythmias following low-dose droperidol is poor (N) (Level III-3). 21. In adults, patient age rather than weight is a better predictor of opioid requirements, although there is a large interpatient variation (U) (Level IV). 22. Impaired renal function and the oral route of administration result in higher levels of the morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide with increased risk of sedation and respiratory depression (S) (Level IV). The following tick box þ represents conclusions based on clinical experience and expert opinion. ;; The use of pethidine (U) and dextropropoxyphene (N) should be discouraged in favour of other opioids. Paracetamol • Used as a component of multimodal therapy. • Importance of around the clock regular dosing. • Intravenous route option (give over 15 minutes 6/24hr) • Commence ASAP • 4g daily in adult (warfarin interaction at 3 g per week ↑ INR potential) • ANZCA’s Paracetamol Key Message Paracetamol (acetaminophen) is the only remaining para-aminophenol used in clinical practice and is an effective analgesic (see below) and antipyretic. It is absorbed rapidly and well from the small intestine after oral administration with a bioavailability of between 63% and 89% (Oscier & Milner, 2009). It can also be given rectally and intravenously (see below and Section 6). The mechanism of action of paracetamol remains unclear. In contrast with opioids, paracetamol has no known endogenous binding sites, and unlike NSAIDs, apparently does not inhibit peripheral cyclo-oxygenase activity. There is increasing evidence of a central antinociceptive effect. Although the mechanism of analgesic efficacy of paracetamol remains elusive, it may involve direct and indirect inhibition of central cyclo-oxygenases, but the activation of the endocannabinoid system and spinal serotonergic pathways also appear to be essential (Bertolini et al, 2006; Botting, 2006; Pickering et al, 2006; Mallet et al, 2008; Pickering et al, 2008). Paracetamol has also been shown to prevent prostaglandin production at the cellular transcriptional level, independent of cyclo-oxygenase activity (Mancini et al, 2003). As one of the mechanisms of action of paracetamol appears to be linked to the serotonergic system, it is possible that other drugs with serotonergic effects could affect pain relief. In volunteers, coadministration of tropisetron or granisetron blocked the analgesic effects of paracetamol (Pickering et al, 2006 Level II; Pickering et al, 2008 Level II). The significance of this in the clinical setting has not yet been elucidated. NSAIDs The term NSAIDs is used to refer to both nsNSAIDs and coxibs (COX-2 selective inhibitors). NSAIDs have a spectrum of analgesic, anti-inflammatory and antipyretic effects and are effective analgesics in a variety of acute pain states. Many effects of NSAIDs can be explained by inhibition of prostaglandin synthesis in peripheral tissues, nerves, and the CNS (Botting, 2006). However, NSAIDs and aspirin may have other mechanisms of action independent of any effect on prostaglandins, including effects on basic cellular and neuronal processes. Prostaglandins are produced by the enzyme prostaglandin endoperoxide (PGH) synthase, which has both cyclo-oxygenase and hydroperoxidase sites. Two subtypes of cyclo-oxygenase enzyme have been identified – the ‘constitutive’ COX-1, the ‘inducible’ COX-2: a COX-3 is also being investigated (Simmons et al, 2004; Gajraj & Joshi, 2005; Botting, 2006; Kam & So, 2009). 20 Prostaglandins have many physiological functions including gastric mucosal protection, renal tubular function and intrarenal vasodilation, bronchodilatation, production of endothelial prostacyclin that leads to vasodilation and prevents platelet adhesion, and platelet thromboxane that results in platelet aggregation and vessel spasm. Such physiological roles are mainly regulated by COX-1 and are the basis for many of the adverse effects associated with ns NSAID use. Tissue damage induces COX-2 production leading to synthesis of prostaglandins that result in pain and inflammation, and COX-2 induction within the spinal cord may play a role in central sensitisation. COX-2 may also be ‘constitutive’ in some tissues, including the kidney, cardiovascular system and brain (Kam & So, 2009). NsNSAIDs are ‘nonselective’ cyclo-oxygenase inhibitors that inhibit both COX-1 and COX-2. Aspirin acetylates and inhibits cyclo-oxygenase irreversibly but nsNSAIDs are reversible inhibitors of the enzymes. The coxibs have been developed to inhibit selectively the inducible form (Simmons et al, 2004; Gajraj & Joshi, 2005; Botting, 2006). NSAIDs Mechanism of Action:Inhibition of Cyclo-oxygenase enzymes (type 1 & 2);Reduce concentrations of PGE2 : Sensitise peripheral nociceptors to histamine and bradykinin;Centally Increase Substance P and Glutamate Increase sensitivity of second order neurons Decrease NTs from descending pathway Benefits:Opioid Sparing; Reduced incidence of opioid side effects: Anti-inflammatory effects Adverse Effects: Platelet Dysfunction; Gastrointestinal Ulceration; Nephrotoxicity; Impaired bone healing; Hypersensitivity Non Steroidal anti-inflammatory drugs.(NSAID’s) • All have three properties in common – analgesic – anti-pyretic – anti inflammatory • Primary action is the inhibition of the production of cyclo-oxygenase (COX) and thus the inhibition of the production of prostaglandins, prostacyclin and thromboxane • Prostaglandin function – released in response to cell damage – sensitise and activate nociceptors to bradykinin – some are hyperalgesic PGI2 and PGE2 – PGE2 inhibits acid secretion and increases mucous secretion in the stomach. – Exert a pyretic effect through the hypothalamus – vasodilatation and diuresis within the kidney – responsible for many endocrine functions Generic name – Ibuprofen (400mg) – Diclofenac (50mg) – Naproxen – Indomethacin – Ketoralac 10mg – Piroxicam (Feldene) NNT 2.7 2.3 Elimination 1/2 life Hrs 2 1 15 6 6 53 21 Non Steroidal Anti -Inflammatory Drugs • Used with caution in the elderly. • The route of administration does not influence the potential for serious side effects. • Safer to use the NSAIDs with lowest observed risk e.g Ibuprofen, Diclofenac. Contraindications must be respected. • Prior gastric ulceration • Concurrent use of oral anticoagulants. • Interaction with Ace inhibitors and B blockers. • Concurrent use of gentamicin. NSAID’s • Effective for mild to moderate pain • Reduces opioid requirement • Drug of choice after day case surgery. • Selective COX 2 inhibitors e.g meloxicam (elim. 1/2 life 20 hrs), IV paracoxib (single dose given in theatre) replaces celebrax, (elim. ½ life 10 – 20 min – is a prodrug (no effects on body needs to be metabolized to have effect) – converted to valdecoxib (1/2 life 6 – 8hrs). Cox 2 inhibitors have less GIT side effects, does not affect platelet aggregation and thromboxane production. Non Steroidal anti-inflammatory drugs( NSAID’s) • Most exhibit a spectrum of action including: • analgesic • anti-pyretic • anti-inflammatory • anti-platelet • Primary action is the inhibition of the production of cyclo-oxygenase (COX) and thus the inhibition of the production of prostaglandins, prostacyclin and thromboxane • Alone are effective for mild to moderate pain and are seen as a component of multimodal therapy for severe pain. • May reduce opioid requirements by up to 30% • ? Drug of choice after day case surgery. • The route of administration does not influence the potential for serious side effects • Selective COX 2 inhibitors e.g celecoxib – has little or no effect on COX 1 at therapeutic doses. • • Potential side effects – renal dysfunction – gastric irritation – reversible platelet dysfunction. – trigger asthma Safer to use the NSAID’s with shorter half life e.g. Diclofenac, Ibuprofen, or COX 2. IV - Parecoxib sodium (dynastat) Cox 2 (only given in theatre) 22 • Contraindications must be respected. Paracetamol &NSAIDs Key messages 1. Paracetamol is an effective analgesic for acute pain; the incidence of adverse effects comparable to placebo (S) (Level I [Cochrane Review]). 2. Non-selective NSAIDs are effective in the treatment of acute postoperative and low back pain, renal colic and primary dysmenorrhoea (N) (Level I [Cochrane Review]). 3. Coxibs are effective in the treatment of acute postoperative pain (N) (Level I [Cochrane Review]). 4. With careful patient selection and monitoring, the incidence of nsNSAID-induced perioperative renal impairment is low (U) (Level I [Cochrane Review]). 5 Non-selective NSAIDs do not increase the risk of reoperation for bleeding after tonsillectomy in paediatric patients (Q) (Level I [Cochrane Review]). 6. Coxibs do not appear to produce bronchospasm in individuals known to have aspirinexacerbated respiratory disease (U) (Level I). 7. In general, aspirin increases bleeding after tonsillectomy (N) (Level I). 8. Non-selective NSAIDs given in addition to paracetamol improve analgesia compared with paracetamol alone (U) (Level I). 9. Paracetamol given in addition to PCA opioids reduces opioid consumption but does not result in a decrease in opioid-related side effects (N) (Level I). 10. Non-selective NSAIDs given in addition to PCA opioids reduce opioid consumption and the incidence of nausea, vomiting and sedation (N) (Level I). 11. Non-selective NSAIDs and coxibs are effective analgesics of similar efficacy for acute pain (U) (Level I).PTER 4 12. Preoperative coxibs reduce postoperative pain and opioid consumption, and increase patient satisfaction (N) (Level I). 13. Coxibs given in addition to PCA opioids reduce opioid consumption but do not result in a decrease in opioid-related side effects (N) (Level I). 14. Coxibs and non-selective NSAIDs have similar adverse effects on renal function (U) (Level I). 15. Non-selective NSAIDs do not significantly increase blood loss after tonsillectomy but do increase the need for reoperation due to bleeding (N) (Level I). 16. Parecoxib and/or valdecoxib compared with placebo do not increase the risk of cardiovascular adverse events after non-cardiac surgery (N) (Level I). 17. Coxibs and non-selective NSAIDs are associated with similar rates of adverse cardiovascular effects, in particular myocardial infarction; naproxen may be associated with a lower risk than other non-selective NSAIDs and celecoxib may be associated with a lower risk than other coxibs and non-selective NSAIDs overall (N) (Level I). 18. Perioperative non-selective NSAIDs increase the risk of severe bleeding after a variety of other operations compared with placebo (N) (Level II). 19. Coxibs do not impair platelet function; this leads to reduced perioperative blood loss in comparison with non-selective NSAIDs (S) (Level II). 20. Short-term use of coxibs results in gastric ulceration rates similar to placebo (U) (Level II). 23 21. Use of parecoxib followed by valdecoxib after coronary artery bypass surgery increases the incidence of cardiovascular events and is therefore contraindicated (S) (Level II). The following tick boxes þ represent conclusions based on clinical experience and expert opinion. ;; Adverse effects of NSAIDs are significant and may limit their use (U). ;; The risk of adverse renal effects of non-selective NSAIDs and coxibs is increased in the presence of factors such as pre-existing renal impairment, hypovolaemia, hypotension, use of other nephrotoxic agents and ACE inhibitors (U). Inhalational agents Key messages 1. Nitrous oxide has some analgesic efficacy and is safe during labour (U) (Level I). 2. Nitrous oxide is an effective analgesic agent in a variety of other acute pain situations (U) (Level II). 3. Methoxyflurane, in low concentrations, may be an effective analgesia in the hospital and prehospital setting (N) (Level IV).APTER 4 The following tick boxes þ represent conclusions based on clinical experience and expert opinion. ;; Neuropathy and bone marrow suppression are rare but potentially serious complications of nitrous oxide use, particularly in at-risk patients (U). ;; The information about the complications of nitrous oxide is from case reports only. There are no controlled studies that evaluate the safety of repeated intermittent exposure to nitrous oxide in humans and no data to guide the appropriate maximum duration or number of times a patient can safely be exposed to nitrous oxide. The suggestions for the use of nitrous oxide are extrapolations only from the information above. Consideration should be given to duration of exposure and supplementation with vitamin B12, methionine, and folic or folinic acid (U). ;; If nitrous oxide is used with other sedative or analgesic agents, appropriate clinical monitoring should be used (U). NMDA-receptor antagonists NMDA receptor/ion channel complexes are sited peripherally and centrally within the nervous system (De Kock & Lavand’homme, 2007). Activation of NMDA receptors via glutamate release from excitatory synapses augments the propagation of nociceptive information and is linked to learning and memory, neural development and neuroplasticity, as well as acute and chronic pain states and opioid-induced tolerance. At the spinal level, NMDA receptor activation results in the development of central sensitisation manifested clinically as hyperalgesia and allodynia (De Kock & Lavand’homme, 2007; Hocking et al, 2007). The NMDA-receptor antagonists ketamine, dextromethorphan, amantadine, memantine and magnesium have been investigated for the management of acute pain. NMDA antagonist Ketamine • Used as an analgesic in sub-anaesthetic doses • Ketamine bolus loading in PAR • May be administered as intravenous infusion - refer to protocol in Pain service folder • NMDA receptor antagonist • Useful in neuropathic and inflammatory induced pain, patient’s with opioid tolerance. • Opioid sparing Ketalar/Ketamine 24 Generic Ingredients: ketamine hydrochloride Company Hospira Australia Pty Ltd Pregnancy Category B3* Permitted in sport Use: Nonbarbiturate IV and IM anaesthetic esp for short procedures; induction prior to other general anaesthetics; supplement to low potency agents Contra: Hazardous raised BP conditions eg severe CV disease, heart failure, severe or poorly controlled hypertension, recent MI, stroke history, cerebral trauma, intracerebral mass/ haemorrhage Prec: Acute, chronic alcoholism; incr CSF pressure, IOP; psychiatric illness, neurosis; acute intermittent porphyria; seizures; intracranial mass, lesions, head/ globe injury, hydrocephalus; pulmonary, URTI; hyperthyroidism; hypovolaemia; dehydration; mild-mod hypertension; tachyarrhythmias; abuse potential; sole use in pharynx, larynx, bronchial tree, visceral pain pathway procedures; renal, hepatic impairment; cirrhosis; rapid IV admin (< 60 sec); cardiac disease (monitor); pregnancy; lactation (should not use); others, see full PI Adverse: Arrhythmia; incr/ decr BP, pulse; respiratory depression, apnoea, laryngospasm; diplopia; nystagmus; emergence reaction (hallucination, illusion, delirium, confusion, excitement, irrational behaviour); anaphylaxis; incr muscle tone; GI effects incl hypersalivation; inj site reaction Interact: Halogenated hydrocarbon anaesthetics, barbiturates, narcotics; benzodiazepines; ergometrine; theophylline; atracurium; tubocurarine; CNS depressants incl skeletal muscle relaxants; thiopental; thyroid hormones; antihypertensives Ketalar Solution for injection (S8) Ketamine (HCl); benzethonium Cl; single use vial Dose Individualise dose; for IMI or slow (60 sec) IVI. Induction. IVI: range 1-4.5 mg/kg; 2 mg/kg usually produces anaesthesia within 30 sec, lasting 5-10 min. IMI: range 6.5-13 mg/kg; 10 mg/kg usually produces anaesthesia within 3-4 min, lasting 12-25 min; see full PI. Maintenance. May admin additional incremental IV, IM doses (1/2 to full induction dose). Hepatic impairment, cirrhosis: consider dose reduction Pack 200 mg/2 mL [5] Reference MIM’s online 2011 NMDA Antagonists Ketamine:NMDA receptor antagonism theoretically reduces central sensitisation, hyperalgesia and opioid tolreance Currently role in postoperative pain relief is complex; Insignificant difference in pain ; Clinically insignificant opioid sparing Psychomimetic side effects – hallucination, nighmares NMDA antagonist • Ketamine • Mechanism of action – selective blocking agent of the excitatory receptor NMDA. – ? other mechanisms of action • Used in neuropathic pain states at low doses. Ketamine is a water- and lipid-soluble drug that rapidly penetrates into the CNS. Like the barbiturates, ketamine accumulates rapidly and then undergoes redistribution with subsequent degradation in the liver 25 ketamine acts by interrupting association pathways between the thalamocortical and the limbic systems NMDA receptor antagonists:Ketamine doses (0.15–1 mg/kg), exerts a specific NMDA blockade & hence, modulates central sensitization .(2) Acute neuropathic pain after surgery Parenteral ketamine (NMDA receptor antagonist, 5mg/hr) & Lignocaine (neuronal membrane stabilisation, 5mg/kg over 30–40min followed by 0.5–1.5mg/kg/hr) can be given in the acute phase to alter both peripheral and central neuronal plasticity. Treatment may take up to a week or more. This should be supervised by a suitably qualified pain specialist NMDA-receptor antagonists ANZCA’s Key messages 1. Perioperative low-dose ketamine used in conjunction with patient-controlled analgesia morphine is opioid-sparing and reduces the incidence of nausea and vomiting (N) (Level I [Cochrane Review]). 2. In general, a perioperative low-dose ketamine infusion is opioid-sparing, but does not produce a clinically significant reduction in pain scores or opioid-related adverse effects (S) (Level I). 3. Ketamine is a safe and effective analgesic for painful procedures in children (N) (Level I). 4. Ketamine and dextromethorphan have preventive (U) but not pre-emptive analgesic effects (N) (Level I). 5. Magnesium does not reduce postoperative pain scores or opioid consumption and has no preventive analgesic effect (N) (Level I). 6. Ketamine may improve analgesia in patients with severe acute pain that is poorly responsive to opioids, although evidence is conflicting (W) (Level II). 7. Ketamine reduces postoperative pain in opioid-tolerant patients (N) (Level II). The following tick box þ represents conclusions based on clinical experience and expert opinion. ;; The primary role of low dose ketamine is as an ‘antihyperalgesic’, ‘antiallodynic’, ‘tolerance-protective’ and preventive analgesic, rather than as an analgesic per se (N). Antidepressant Tricyclic anti-depressants Drug Name: Amitryptiline Mechanism of action: Increase available serotonin and noradrenaline by blocking reuptake. • Increase endorphin levels • The analgesic effect appears quicker that their antidepressant effect. (3-4 days versus 3 weeks). • The dose required for an analgesic effect is lower that that required for their antidepressant effect. • They have a muscle relaxant effect in diffuse musculoskeletal pain. • They may enhance the analgesia produced by opioids. • They are often used for neuropathic burning pain. • Side effects • sedation and anticholinergic effects including dry mouth, constipation and urinary retention. • Cardiac arrhythmias, glaucoma, weight gain and loss of libido • start at a low dose so that patients can become accustomed to using them • sometimes their side effects are beneficial e.g improvement in sleep due to sedation. Antidepressant drugs ANZC’s Key messages 26 1. In neuropathic pain, tricyclic antidepressants are more effective than selective serotonergic re-uptake inhibitors (S) (Level I [Cochrane Review]). 2. Duloxetine is effective in painful diabetic neuropathy and fibromyalgia (N) (Level I [Cochrane Review]). 3. There is no good evidence that antidepressants are effective in the treatment of chronic low back pain (R) (Level I [Cochrane Review]). 4. Tricyclic antidepressants are effective in the treatment of chronic headaches (U) and fibromyalgia (N) (Level I). 5. Antidepressants reduce the incidence of chronic neuropathic pain after herpes zoster (U) (Level II). Note: withdrawal of previous key message: Antidepressants reduce the incidence of chronic neuropathic pain after breast surgery This has been deleted as the information and evidence supporting it has been withdrawn.HAPTER 4 The following tick boxes represent conclusions based on clinical experience and expert opinion. ;; Based on the experience in chronic neuropathic pain states, it would seem reasonable to use tricyclic antidepressants and selective serotonin re-uptake inhibitors in the management of acute neuropathic pain (S). ;; To minimise adverse effects, particularly in elderly people, it is advisable to initiate treatment with low doses (U). Anticonvulsant drugs Anti-convulsants • Drug Names:Carbamazepine /Sodium Valproate Gabapentin • Mechanism of action • stabilise nerve cell membranes by blockade of voltage sensitive sodium channels • Increase brain serotonin, and GABA • reduce evoked and spontaneous activity of spinal neurons with and without peripheral nerve injury • ? modulates voltage dependant calcium channels. • Used in neuropathic pain to combat pain described as shooting / knife like. • Side effects • dizziness, sedation, gait disturbance, GIT upset, liver dysfunction, thrombocytopenia and bone marrow depression. Gabapentin does not have the above severe adverse side effects Anti-convulsants • Carbamazepine /Sodium Valproate • Gabapentin • Mechanism of action – stabilise nerve cell membranes by blockade of voltage sensitive sodium channels – Increase brain serotonin, and GABA – reduce evoked and spontaneous activity of spinal neurons with and without peripheral nerve • injury – ? modulates voltage dependant calcium channels. Used in neuropathic pain to combat pain described as shooting / knife like. 27 • Side effects – dizziness, sedation, gait disturbance, GIT upset, liver dysfunction, thrombocytopenia and bone marrow depression. – Gabapentin does not have the above severe adverse side effects. Anticonvulsant drugs Key messages 1. Gabapentin is effective in the treatment of chronic neuropathic pain (Q); lamotrigine is most likely ineffective (N) (Level I [Cochrane Review]). 2. Carbamazepine is effective in the treatment of trigeminal neuralgia (N) (Level I [Cochrane Review]). 3. Pregabalin is effective in the treatment of chronic neuropathic pain related to diabetic neuropathy (N) (Level I). 4. Perioperative gabapentinoids (gabapentin/ pregabalin) reduce postoperative pain and opioid requirements (U) and reduce the incidence of vomiting, pruritus and urinary retention, but increase the risk of sedation (N) (Level I). The following tick box þ represents conclusions based on clinical experience and expert opinion. ;; Based on the experience in chronic neuropathic pain states, it would seem reasonable to use anticonvulsants in the management of acute neuropathic pain (U). Anti-arrhythmic agents; Membrane stabilisers • Intravenous lignocaine (Beirs Block) • Oral mexiletine (not used in Theatre) • Sodium channel blockers which act to suppress abnormal activity in damaged neurones, without blocking normal nerve conduction. Membrane stabilisers ANZCA’s Key messages 1. Both lignocaine (lidocaine) and mexiletine are effective in the treatment of chronic neuropathic pain (S); there is no difference in efficacy or adverse effects compared with carbamazepine, amantadine, or morphine (N) (Level I [Cochrane Review]). 2. Perioperative intravenous lignocaine reduces pain and opioid requirements following abdominal surgery (S) as well as nausea, vomiting, duration of ileus and length of hospital stay (N) (Level I). The following tick boxes represent conclusions based on clinical experience and expert opinion. ;; Based on the experience in chronic neuropathic pain states, it would seem reasonable to use membrane stabilisers in the management of acute neuropathic pain (U). ;; Lignocaine (intravenous or subcutaneous) may be a useful agent to treat acute neuropathic pain (U). 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, 28 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 a2receptors 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 29 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] 30 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 31 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 32 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 46 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 33 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. 34 + 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 Tramadol: Moderate affinity ì receptor agonist. Acts on spinal modulating pathways Inhibition of neuronal NA and Serotonin uptake Stimulation of presynaptic serotonin release Adverse Effects: Nausea & Vomiting Ondansetron interferes with analgesic effect Non addictive, less sedation Dose: 3 mg/kg IM/IV/PO for moderate to severe pain Buprenorphine: Semisynthetic, Agonist-Antagonist Routes of administration: IV, IM, Neuraxial, SC, SL, Trasdermal Useful in morphine intolerant patient Ceiling effect for respiratory depression, but not for analgesia. Antiflammatory action Useful in intra-articular injections Prolongs duration of analgesia in peripheral nerve blocks with LA Methadone: Synthetic broad spectrum opioid Mu receptor agonist NMDA antagonist Inhibitor of monoamine transmitters Useful in treatment of neuropathic pain Orally well absorbed No dose adjustment in renal disease Drug most commonly used for opioid rotation 35 NSAIDs Mechanism of Action Inhibition of Cyclo-oxygenase enzymes (type 1 & 2) Reduce concentrations of PGE2 : Sensitise peripheral nociceptors to histamine and bradykinin Centally Increase Substance P and Glutamate Increase sensitivity of second order neurons Decrease NTs from descending pathway Benefits: • Opioid Sparing • Reduced incidence of opioid side effects • Anti-inflammatory effects Adverse Effects: • Platelet Dysfunction • Gastrointestinal Ulceration • Nephrotoxicity • Impaired bone healing • Hypersensitivity α2 Adrenergic Agonists Primarily preoperative and intraoperative use Clonidine: • α2 agonist, α2: α1 biding 220:1 • PO, IV, TD, Neuraxial routs • Reduced postoperative opioid requirement • SE: Sedation, Bradycardia, hypotension Dexmedetomedine: • Superselective α2 agonist: α2:α1 binding 1620:1 • Supraspinal, Spinal & Peripheral action • No respiratory depression NMDA Antagonists Ketamine: NMDA receptor antagonism theoretically reduces central sensitisation, hyperalgesia and opioid tolreance Currently role in postoperative pain relief is uncertain Insignificant difference in pain Clinically insignificant opioid sparing Psychomimetic side effects – hallucination, nighmares Neuraxial Analgesia: Epidural Analgesia Superior to systemic opioids Efficacy determined by Catheter-incision site congruency Choice of analgesic drugs LA+Opioid 36 Rates of infusion Duration of epidural analgesia At least 2-4 days Type of pain assessment Dynamic Vs Rest Recommended catheter insertion sites Location of incision Examples of surgical procedure Congruent epidural placement Thoracic Lung reduction, Radical mastectomy Toracotomy, thymectomy T4-T8 Upper Abdominal Cholycystectomy, esophagectomy, gastrectomy, hepatic resection, whipple’s T6-8 Middle Abdominal Cystoprostatectomy, nephrectomy T7-T10 Lower Abdominal AAA repair, Colectomy, TAH, Radical prostatectomy T8-T11 Lower Extremity Femoral-Popliteal bypass, THR, TKR L1-L4 Local Anaesthetics comparison Opioids: Local Anaesthetics Act on spinal nerve roots,dorsal root ganglion or spinalcord itself. High incidence of motor block Hypotension Sign Significant failure rate due to regression and inadequate analgesia Opioids: Site of action:Lipophilic: systemicHydrophilic: spinal Cathetre-Site congruencynot essential No motor blockade No hypotension Analgesia superior to systemic opioids Differences between lipophilic and hydrophilic opioids Property Lipophilic Opioids Hydrophilic Opioids Common Drugs Fentayl, Sufentanyl Morphine, Hydromorphone Onset of analgesia Rapid (5-10 min) Delayed (30-60min) Duration of analgesia Shorter (2-4 Hrs) Longer (6-24 hrs) CSF Spread Minimal Extensive 37 Site of action Spinal ± Systemic Spinal Side Effects Lower nausea and vomiting, pruritus Early respiratory depression Nausea & vomiting, pruritus Early (<6 Hr) and Delayed (> 6 Hr) respiratory depression Local Anaesthetic-Opioid Combinations Additive Effect Superior analgesia, including dynamic pain relief Limits regression of sensory blockade Decreased LA dose requirement Analgesia superior to IV PCA with opioids Adjuvants: Clonidine: 5-20 μg/Hr Dose dependent hypotension, bradycardia Epinephrine conc. Of 2.5 μg/ml Ketamine Theoretically useful in attenuating central sensitisation Hypotension 0.7 – 3 % with epidural LAs Epidural Analgesia: Adverse Effects Motor Block 2 – 3 % with epidural LAs More with cathetre-incision incongruence Resolves within 2 hours of stopping infusion If persistant, think of Spinal hematoma/abscess, cathetre migration Nausea & vomiting 20 – 50 % with single dose neuraxial opioid 45 – 80 % with continuous opioid infusion Dose depdndent. Due to cephalad migration Less with fentanyl than morphine Treated with Naloxone, Ondansetrone, Droperidol, Metoclopramide, Dexamethasone Pruritus 60% with Opioids; 15-18 % with LAs Due to cephalad migration and activation of trigeminal nucleus. ?? Itch centre Treated with Naloxone, Droperidol Respiratory Depression Incidence 0.1 – 0.9 % with opioids Equivalent to systemic administration of opioid Early < 6 hr, Delayed > 6 hr Delayed depression with Morphine. Due to cephalad spread Risk Factors: Increasing dose, increasing age, concomitant sedatives, prolonged and extensive surgery, thoracic surgery Treatment: Naloxone 0.5 – 5 μg/kg/hr Urinary Retention Higher than with systemic opioids 10 – 30% with epidural Las Higher with higher infusion rates of LA Benefits: (LA based epidurals) Better attenuation of stress response to surgery Earlier return of GI function without contributing to bowel dehiscence Decreased postoperative pulmonary complications 38 Decreased incidence of postop MI with thoracic epidural Better postop analgesia Risks: Higher incidence of spinal hematoma with LMWHs Infections: Meningitis, Spinal Abscess (1/10000 with catheter < 4 days) Superficial cellulitis: 4-14 % Catheter migration: Intrathecal, Intravascular, subcutaneous Drug Dosing Comments Clonidine 15-45 μg Improves quality of blockade Epinephrine 0.1-0.6 mg Prolongs motor block & urinary retention Neostigmine 6.5 – 50 μg Motor blockade Nausea & vomiting Opioid Dose Fentanyl 5-25 μg Sufentanyl 2-10 μg Morphine 0.1-0.3 mg Diamorphine 1-2 mg Pethidine 10-30 mg 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 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 39 block Prolonged duration Single injection and continuous catheter techniques 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 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, medi 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 40 Complications: Intravascular injection 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 Slide (28) 32 So what does pain management look like at BHS The follow • • • Are statistics from our APS & Operational statistics Our PACU APP And a discussion of the drugs, & how they’re used currently @ BHS & those around the corner Slide (29) 33 BHS Statistics Slide (30) 34 Some Innovation in care Different ways of administering L.A. Adjunctive therapies Old drugs used differently – Gabapentin : Used pre operatively: Opioid sparing effect during the first 24 hours after a single 300 to 1,200 mg dose of gabapentin, administered one to two hours preoperatively, ranged from 20 percent to 62 percent (2) New: Adjunctives ie Capsaicin cream (used for centuries in the east) Narcotics Different routes Topical Old :Narcotic’s Buprenophine patch (<3D:7D/S/C Fat to metablosie Heat 25 - 50% increase/pressure increase, 3 week site rotation APP doing New Targin: Oxycodone/Narloxone (10/5mg) oral Tapentadol: Oxycodone/Noradrenaline oral Slide (31) 35 APP BHS Slide (32) 36 Some Adjunctives Pharmogolygt Anticonvulsants: Gabapentin • Ideally if anticonvulsants are considered they are best admninstered preoperatively (6) 41 • Gabapentin binds to the alpha-2 delta sub-unit of the presynaptic voltage gated-calcium channels responsible for the inhibition of the calcium influx.(2)prevents release of excitatory neurotransmitters in Pain Pathway Pregablin is similar to gabapentin but has a superior pharmacokinetic profile its many potential actions such as reducing opioid requirements, prevention & reduction of opioid tolerance, improvement of the quality of opioid analgesia, decreased respiratory depression, relief of anxiety, and gastric sparing make it an attractive drug to consider for control of pain in the post operative period – Slide (33) 37 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] (millers) Slide (34) 38 NSAID’s Cox 2 : Recent research indicates that, in addition to peripheral blockade of prostaglandin synthesis, central inhibition of cyclooxygenase-2 may play an important role in modulating nociception. Although nonspecific NSAIDs provide analgesic efficacy similar to coxibs, their use has been limited in the perioperative setting because of platelet dysfunction and gastrointestinal toxicity. Coxibs may be a safer alternative in that setting. Both coxibs and traditional NSAIDs may contribute to a dose-dependent increase in cardiovascular toxicity and impaired osteogenesis benefits of coxibs include improved quality of analgesia; reduced incidence of GI side effects & no platelet inhibition (note Cox 1 & 2: Ketorolac ) Paracetamol Is antipyretic & analgesic but has little, if any, anti-inflammatory action. Its analgesic action is believed to be inhibit COX-3. At the spinal cord level, it also antagonize neurotransmission by NMDA, substance P, and nitric oxide pathways IV 100 ml: 10 mg/ml @ 15/60min; Onset of action <5 -10/60, peak at 1- 2hrs (6hrly order) 42 Slide (35) 39 Central alpha2 agonist Clonidine: Its sedative, pro-anesthetic, and pro-analgesic effects ability to blunt the central sympathetic response by as yet unknown mechanism(s). It also minimizes opioid-induced muscle rigidity, lessens postoperative shivering, causes minimal respiratory depression, and has hemodynamic stabilizing effects(2) Slide (36) 40 L.A. Some innovations in care Different ways of administering: Intavenous LA: acts a membrane stabilizer (reversibly block the Na channels of the lipid membranes & prevent sudden influx of sodium ions into the axon, blocking depolarization & the action potential. (2009 Mosby: Marx: Rosen’s emergency medicine) Increase Regional LA use: continuous or intermittent bolusing (new research suggest higher efficacy than continuous infusion Epidural PCA & TAP; femoral; wound; elastomeric pump e.t.c PAIN BUSTER device elastomeric pump. An elastomeric pump is a device that has a distensible bulb inside a protective bulb with a built-in filling port, delivery tube, and bacterial filter LA and anti inflammatory medication use Acupuncture (2) perioperative acupuncture might be a useful adjunct for acute postoperative pain management. However, there are issues with applicability and generalizability of the procedure Different ways of administering R&D LA: basically two overarching approaches for prolongation of local anesthetic action. One is the use of novel delivery techniques for existing drugs. In an endeavor to “make old drugs new” [51], liposome or polymer encapsulation of local anesthetics are being formulated. The second approach is the development of novel, extremely long-acting local anesthetics; road toward achieving this goal may be long and winding, due to problems of these drug delivery systems, such as shelf life,aggregation, leakage, and toxicity (2) Slide (37) 41 New Narcotics preparations Targin: Oxycodone/Narloxone (10/5mg) Tapentadol: Narcotic (oxycondone/ tramadol):centrally acting analgesic; an agonist at μ-opioid receptor & a norepinephrine reuptake inhibitor 18-fold affinity- μ opioid receptor compared to morphine; 2 -3 less potent than morphine improved G/I tolerability compared to classical opioids. Dose unchanged in renal impairment. No Hepatoxicity IR oral: 50, 75 & 100 mg 4-6/24 <daily dose 600-700 mg Contraindicated: severe bronchial asthma, paralytic ileus,pt’s on (MAOI): SSRI’s, selective norepinephrine reuptake inhibitor SNRI, tryptans or, tricyclic antidepressants Side effect: Serotonin syndrome include:mental status changes such as hallucinations, coma, autonomic instability such as tachycardia, hyperthermia, and neuromuscular abnormalities such as hyperreflexia and incoordination. .Slide (38) 42 Narcotics used topically • Different routes Topical – Old :Narcotic’s Buprenorphine /fentanyl patch 43 Slide (39) 43 New Adjunctive drugs Capsaicin (8-methyl-N-vanillyl-6-nonenamide) acts as a TRPV-1 agonist TRPV1 receptor markedly reduced in inflammatory conditions & is present on unmyelinated C fiber endings in the periphery. Activation of the TRPV receptors releases high intensity impulses & releases substance P, which results in the initial phase of burning. Continued release of substance P in the presence of capsaicin leads to the depletion of capsaicin and a subsequent decrease in C fiber activation. Slide (40) 44 Latest research Adjunctive not seen in action Neostigmine (2,4), & recently, adenosine Neostigmine, a cholinesterase inhibitor, has been reported to possess analgesic properties when doses of 10–200 g were administered in the subarachnoid (not seen used) or epidural spaces epidurally administered neostigmine(1 g/kg) produced more than 5 h of pain relief after knee surgery (249). Neostigmine (10 g/kg) also enhanced epidural local analgesia (4) Drugs on the horizon:Prialt,(ziconotide) IT only non opioid (used Uk & USA), IT only non opioid (used Uk & USA), Prialt,(ziconotide) (used in UK/ USA 2007), Rx pain associated with cancer, AIDS and neuropathies. Based on a compound found in the poison of the South Pacific cone snail, it controls pain in a new way -- by blocking the calcium channels in nerve cells that transmit pain signals -- & may have broad implications for the future of pain management. Benefits; Non narcotic +/- 1000 stronger than morphine, non addictive Side Effects: ONLY Intrathecal high risk of side effecting, hallucinations and even psychosis in vulnerable people. Slide (41 45 Advances In Organisational Aspects Of Post operative Pain Control – – – – – Surgery Type i.e.Laparoscopic surgery, anterior hip replacement Pre/interoperatively maximized use of L.A. & NMDA receptor antagonists agents CBT pre hospitalization education Early rehabilitation Use of alternative therapies i.e. Acupuncture, meditation, mindfulness concepts(although presently not strongly supported – research occurring in this area) Slide (42) 46 Just to mention any thing not already mentioned in summary 44 45