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



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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].
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 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.

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), & transcription-dependent 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 interesting avenue of development .( N. Vadivelu, S. Mitra, & D. Narayan, (2010)c 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 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.

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
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 of acute pain chart at each patient bed., pain is considered the 5th 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.



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.

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

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 data. (Clinical Pharmacokinetics August 1993, Volume 25, Issue 2, pp 103-114 Date: 04 Nov 2012 Clinical Pharmacokinetics of Drugs in Obesity GeorgesCheymolSummary



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