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PAIN Lynn Fitzgerald Macksey CRNA, MSN

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The emotional experience of pain is based on the individuals subjective experience. Emotional pain is associated with ACTUAL or POTENTIAL tissue damage

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Situational, behavioral, and emotional factors all play a role

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Motivations Expectations all strongly modify nociceptive input

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Does the same stimulus or damage cause the same sensation in all people? We now know the old concept of linear pain transmission implied a fixed relationship between a stimulus and perception.

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Pain is whatever the person says it is!

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4 PHYSIOLOGIC PROCESSES IN SENSORY PAIN 1.Transduction 2.Transmission 3.Interpretation/Perception 4.Modulation

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Lets review this process quickly.

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First order neuron: brings pain information to the CNS via the nociceptors to the dorsal horn of the spinal cord

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Second order neuron: synapses with the first order neurons in the dorsal horn picks up excitatory NT, crosses the midline and heads toward the spinothalamic tract (STT).

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Third order neuron: meets up at the spinothalamic pathway and carries pain neurotransmitters to midbrain, brainstem, thalamus/hypothalamus, limbic system and then to cerebral cortex.

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1. Transduction Pain begins with the stimulation of peripheral nerve fiber receptors called nociceptors. Nociception is caused by noxious thermal, mechanical, or chemical stimuli. Nociceptors carry the pain stimulus to the spine.

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Transduction peripheral nociceptors carry pain towards spinal cord.

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Nociceptors 2 main types Type-A delta nerve fibers Small, myelinated nerve fibers; carries impulse quickly. Sharp or fast pain; stabbing, shooting pain Type-C nerve fibers Unmyelinated nerve fibers; slower pathway than A fibers Dull or slow pain; throbbing, burning, and achy. Constitute nearly 90% of peripheral sensory fibers

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2. Transmission First order neuron

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First order neurons arrive in the dorsal horn the first six Rexed laminae --- and to the substantia gelatinosa

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Neurotransmitters endogenous chemicals carried from a pre- to post-synaptic receptor across the synapse.

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2 excitatory neurotransmitters (NT)

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Other excitatory NT besides glutamate and substance P Histamine Prostaglandin Bradykinin Potassium Hydrogen Serotonin Acetylcholine Norepinephrine

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Transmission After picking up the NT at the 1 st order neuron synapse, second order neurons cross the midline close to their level of origin and carry these NTs to the contralateral spinothalamic tract (STT)

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After synapsing with the 2nd order neurons of the STT Third order neurons travel to the thalamus and other key areas of the brain

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From the STT, the impulse goes to raphe nuclei, reticular system, and periaqueductal gray matter of the brain

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and from there, pain neuro- transmitter messages project out to the cerebral cortex. 3. INTERPRETATION AND PERCEPTION

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Modulation Modulation of pain occurs in.. supraspinal structures and in the spinal cord

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Modulation MEDULLA/MIDBRAIN produce ENDOGENOUS OPIOIDS and INHIBITORY NEUROTRANSMITTERS which travel down the descending pathways

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Modulation Endogenous opioids aka Endorphins, beta- endorphin, dynorphin, enkephalin, opiopeptins - are a type of inhibitory neurotransmitter Endorphins initiate a series of physiologic functions resulting in cellular hyperpolarization and inhibition of excitatory neurotransmitter release and cephalad transmission of pain impulses ENDORPHINS INHIBIT SUBSTANCE P and GLUTAMATE and other excitatory NT.

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Modulation Remember back to excitatory NT Inhibitory NT are released in the same way and block the tendency of that neuron to fire.

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Examples of inhibitory NT serotonin, norepinephrine, dopamine, glycine, enkephalin, and galanin, somatostatin, and gamma- aminobutyric acid (GABA); acetylcholine, is an inhibitory NT but it is also an excitatory NTdepending on the stimulus.

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Dorsal Horn and Lamina II dorsal horn is the principal site of pain modulation substantia gelatinosa is the major site of action of opioids. This is the point at which the peripheral nervous system synapses with the CNS and where many different neurotransmitters are effectors

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The first-order neuron travels ____ and to_____? Peripheral nociceptors to the dorsal horn of the spinal cord

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The dorsal horn of the spinal cord gray matter is made up of? a. the first six Rexed lamina b. Lissauers tract c. 1st and 2nd order neurons d. the start of the 3rd order neurons A: the first six Rexed lamina These first six lamina receive all afferent neural activity and represent the principal site of modulation of pain by ascending and descending neural pathways.

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Rexed Lamina II in the dorsal horn gray matter is also called? a. motor horn (anterior) b. spinothalamic tract c. substantia gelatinosa d. intermediolateral column c. substantia gelatinosa

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The substantia gelatinosa is believed to? a. play a role in nociceptive input b. receive stimuli from wide dynamic range (WDR) neurons c. the area of the spinal cord where the second- order neuron begins its path d. the area of the spinal cord where the first- order neuron begins its path a. play a role in nociceptive input

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The second order neuron travels ____ and to_____? After synapsing and picking up the neurotransmitters at the dorsal root ganglion, second order neurons cross the midline close to their level of origin and carry these chemicals to the contralateral spinothalamic tract (STT)

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The spinothalamic tract sends stimulus to? a. nucleus raphe magnus b. amygdala nuclei c. reticular formation d. periaqueductal gray 1. a, b, c 2. all but b 3. a and d 4. all of the above answer: 2; all but the amygdale nuclei. STT does send to the nucleus raphe magnus, reticular formation, the periaqueductal gray, as well as to the thalamus.

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The third-order neuron travels from ____ and to_____? Spinothalamic tracts to the nucleus raphe magnus, reticular formation, the periaqueductal gray, as well as to the thalamus.

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WHAT HAPPENS IN THE BODY WITH PAIN Neuroendocrine catecholamines cortisol angiotensin II ADH aldosterone adrenocorticotropic hormone growth hormone glucagon lower levels of insulin

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Pain CV Release of catecholamines from sympathetic nerves and adrenal medulla Release of aldosterone and cortisol from adrenal cortex Release of ADH from hypothalamus & activation of renin-angiotensin system Salt/water retention Tachycardia, myocardial work Hypertension

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Pain Pulmonary skeletal muscle tension decrease lung compliance splinting hypoventilation atelectasis VQ ratio abnormality hypoxemia respiratory failure increased respiratory rate

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Pain GI pain-induced hyperactivity may cause inhibition of GI postoperative ileus, nausea and vomiting GU reflex inhibition of visceral smooth muscle urine retention

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Pain Coagulation platelet adhesiveness fibrinolysis Decreased immune function

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POSTOPERATIVE STRESS SYNDROME Postoperative pain is one of the elements of the acute postoperative stress syndrome that includes increased levels of stress hormones which include: Adrenocorticotrophic hormone (ACTH) Cortisol Catecholamines Interleukins Along with: decreased insulin release and fibrinolysis

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POSTOPERATIVE STRESS SYNDROME These hormonal changes lead to increased myocardial oxygen consumption and associated risks of myocardial ischemia and infarction, hypertension, increased coagulability, decreased regional blood flow, increased risk of infection, depression, and loss of sleep.

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When we talk about pain transmission, we must also talk about the inflammatory response. Inflammatory response

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INFLAMMATION is a part of the pain response The inflammatory effects can be greater in magnitude than the initial injury.

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Mediators of inflammation Histamine- cause moderate vasodilation and considerable increase in vascular permeability, (from mast cells and connective tissue release) Serotonin (5-HT) - causes some vasodilation, and increase in vascular permeability. (from blood products). Serotonin both excitatory & inhibitory Bradykinin- causes considerable vasodilation and pain, with small increase in vascular permeability. (activation of clotting cascade) Prostaglandins- cause considerable vasodilation and chemotaxis, with small increase in vascular permeability and pain. (released from damaged membranes) Leukotrienes- cause a considerable vascular permeability and chemotaxis. (released from injured tissue/membrane)

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Inflammation: Eicosanoids prostaglandins, prostacyclins, thromboxanes and leukotrienes TThese eicosanoids are ligands that bind to the cell surface; they exert complex control mainly in inflammation, and as messengers in the central nervous system.

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Cyclooxygenase Pathway Naturally occurring mediators of inflammation AND PAIN!

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Arachidonic acid is converted by cyclooxygenase compounds to synthesize specific eicosanoids - - - prostaglandins, prostacyclins, & thromboxane

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Cyclooxygenase Pathway Two main forms of cyclooxygenase (though a 3rd has been identified): COX-1 and COX-2 Cox-1 and 2 are the targets of non- steroidal anti-inflammatory drugs (NSAIDs) and non-opioid analgesics

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COX-1 COX-1 is a constituative (produced all the time) enzyme in the gastric mucosa, renal parenchyma and platelets. Protects the inner lining of the stomach and the gastric mucosa. Causes platelet aggregation Mediates renin release and maintenance of renal blood flow

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The inhibition of COX I is undesirable.

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Inhibition of COX I Why is inhibiting COX 1 undesirable? When the COX-1 enzyme is blocked, inflammation is reduced, but *the protection of the lining of the stomach also is lost. Can cause ulceration and bleeding from the stomach and the intestines. *platelet function inhibitedbleeding *hypertension, salt and water retention, hyperkalemia can occur

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COX-2 COX-2 is present constitutively in small amounts, but is highly inducible (must be turned on) at sites of inflammation. Expression varies markedly depending on stimulus.

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Because COX II is only present at inflammation then. The inhibition of COX II is desirable.

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Inhibition of COX II COX II enzyme is located in areas involved in inflammationa COX II blocker inhibits generation of prostaglandins thereby inhibiting inflammation, pain, and fever.. CCOX II is not located in the stomach. and there are fewer GI complications.

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Understanding pain and how drugs work Receptor-Ligand Interaction Drugs affect receptor sites in two ways -

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Affinity the ability of a drug to bind to a receptor

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Efficacy .the capacity of a drug to produce an effect.

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Agonist An agonist will produce the maximum possible effect of binding with the receptor. Strong agonists (eg. morphine, methadone) - act as complete agonists at receptors; Mild-moderate agonists (eg. codeine; propoxyphene [Darvon]; tramadol [Ultram]) - has less intrinsic efficacy

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Partial agonist AKA mixed agonist-antagonist Effect is based on their concentration and on the presence of a full agonist. If administered alone, it will act as a partial agonist. If administered with a small dose of a full agonist, the two will be additive up to the maximum of the partial agonist If administered with a large dose of a full agonist, the partial agonist will act as an antagonist to the agonist.

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Antagonist produces no direct effect when binding with the receptor; blocks or dampens agonist responses. Examples: eg. naloxone [Narcan], naltrexone [ReVia] act as "pure" competitive antagonists at opiate receptors. occupy opiate receptors without producing a pharmacological effect; will precipitate rapid withdrawal symptoms in addicts.

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Antagonist Antagonists have affinity for a receptor But no efficacy!!

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Mixed agonist-antagonist DRUG UseReceptorsNotes Nalbuphine (Nubain) Used to antagonize respiratory depressant effects of full agonists while maintaining analgesia. Also used to treat pruritus due to neuraxial opioids. Partial Mu, and Kappa agonist; provides analgesia, sedation. Can precipitate withdrawal symptoms in opioid tolerant patients. OR dose 3mg/kg followed by 0.25mg boluses; for pruritus dose 5-10 mg every 3 hours Butorphanol (Stadol) Used to antagonize respiratory depressant effects of full agonists while maintaining analgesia. Effective in treating postoperative shivering. Partial Mu, and Kappa agonist; has increased sedative properties due to kappa Post-op dose 3mg Buprenorphine (Buprenex) Used to antagonize respiratory depressant effects of full agonists while maintaining analgesia. Mu agonist, Kappa antagonist. In small to medium doses, is more potent than Morphine. Overdose cannot be treated with naloxone.

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How Do Pain Treatments Work What do we use???

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Pre-emptive analgesia It is thought that preventing pain prevents the excitability of the sympathetic nervous system (flight or flight) that we now know leads to subsequent functional changes to the nerves. this all leads to a reduced analgesic need. What we can usenon-opioid analgesics, COX-2 inhibitors, nerve blocks, etc.

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Pain intensity & management Pain IntensityPain managementSurgery examples Mild COX-2 inhibitors (pre and postop) Local anesthesia infiltration Single injection blocks Oxycodone, hydrocondone PRN Carpal tunnel release Hardware removal Moderate to severe COX-2 inhibitors (pre and postop) Intraarticular local anesthetic infiltration Continuous nerve blocks PCA opioids x 24 hours Oxycodone PRN and prior to physical therapy Total joint replacement long-bone fracture ORIF ACL repair

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Pain intensity & management Pain IntensityPain management Surgery examples Severe PREOP COX-2 inhibitors (pre and postop) Preoperative clonidine Intra-articular local anesthetic infiltration Continuous nerve blocks POSTOP PCA opioids x 24 hours Oxycodone PRN and prior to physical tx Thoracic, open heart surgery, open abdominal surgery

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Pain IntensityPain management Severe Decrease the original opioid dose and introduce an additional opioid at low dose. IV Acetaminophen (Tylenol) NMDA antagonists: subanesthetic doses of ketamine nitrous oxide methadone tramadol Muscle relaxants Benzodiazepines

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Coxibs=cyclooxygenase inhibitors. NE=norepinephrine. NSAIDs=non-steroidal anti-inflammatory drugs. Peripheral nociceptors Descending modulation Ascending input via spinothalamic tract Peripheral nerve Dorsal horn Opioids 1 Alpha-2 agonists 1 Acetaminophen 1 Anti-inflammatory agents 1 Ketamine 2 Opioids 1 Alpha-2 agonists 1 Acetaminophen 1 Anti-inflammatory agents 1 Ketamine 2 Local anesthetics (peripheral nerve block) 1 Local anesthetics (peripheral nerve block) 1 Pain Local anesthetics (epidural) 1 Opioids 1,3 Alpha-2 agonists 3 NMDA antagonists 3 Local anesthetics (epidural) 1 Opioids 1,3 Alpha-2 agonists 3 NMDA antagonists 3 Local anesthetics (field block) 1 NSAIDs, coxibs 1 Local anesthetics (field block) 1 NSAIDs, coxibs 1 Simultaneous use of a combination of 2 analgesics that act at different sites within the central and peripheral nervous systems can be used in an effort to: Reduce pain Minimize opioid use and related side effects Simultaneous use of a combination of 2 analgesics that act at different sites within the central and peripheral nervous systems can be used in an effort to: Reduce pain Minimize opioid use and related side effects A Multimodal Approach

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Local Anesthetics relieve pain by blocking the sodium channels from within the nerves, this blocks the transmission of nociceptive impulses from reaching the dorsal horn of the spinothalamic tract. LA can be given peripherally and by neuraxial anesthesia (epidural and spinal).

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COX 1 Inhibitors Diclofenac (Voltaren, Cataflam) Diflunisal (Dolobid) Etodolac (Lodine) Flurbiprofen (Ansaid) Naproxen (Anaprox, Naprosyn) Ibuprofen (Motrin and others) Indomethacin (Indocin) Ketorolac (Toradol) Meclofenamate (Meclomen) Mefenamic acid (Ponstel) Meloxicam (Mobic)

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COX-2 Inhibitors Celecoxib (Celebrex) Valdecoxib (Bextra) and Rofecoxib (Vioxx)- taken off market

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NSAIDs All NSAIDS have same mechanism of action in common: the principal effect is inhibition of cyclooxygenase resulting in the inhibition of prostaglandin synthesis. Certain effects may also be related to altered synthesis of the four families of eicosanoids.

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NONOPIOID ANALGESICS Also considered COX inhibitors Irreversibly inhibit thromboxane A2 (platelet aggregate stimulator and vasoconstrictor) Examples include: Aspirin (acetylsalicylic acid) also considered an NSAID Tylenol (acetaminophen) (nonacetylated salicylate)

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Where COX inhibitors work Block the cyclooxygenase pathway but arachidonic acid already formed

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Steroids Inhibits inflammatory response. Steroidal anti- inflammatory effects are more profound than COX inhibitors. Corticosteroids - block Phospholipase A2

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Opiates Opiates are drugs built on same structures as MSO4. The synthetic opioids are not structurally related to Morphine. i.e.: Fentanyl, Meperidine

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How do opioids work Opioids relieve pain by attaching to opioid receptors dispersed throughout the CNS and other tissues. Receptor stimulation inhibits the presynaptic release and postsynaptic response to nociceptive NT's such as acetylcholine and substance P.

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Dorsal Horn and Lamina II The dorsal horn is the principal site of pain modulation for both ascending and descending pathways. Opioid analgesics-3 major effects Inhibit release of pain neurotransmitters Hyperpolarize postsynaptic neuron making it less likely to fire an action potential Exerting an anti-hyperalgesia effect on the afferent neuron the substantia gelatinosa, is believed to play a major role in modulating nociceptive input and is the major site of action of opioids.

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Opioid receptors ReceptorAgonistWorks byMajor action Side effectsNotesAntagonist Mu-1 Morphine synthetic opioids (Fentanyl, etc.), phenylpiperidin, endorphine Opioid couples to K+. Conductance Receptor activation, inhibits NT release & Hyper polarizes Cell membrane Analgesia (supraspinal : Brain- in limbic system, hypothalams, and thalamus); Euphoria, well-being Sedation, Respiratory depression, miosis, bradycardia, pruritis, Urinary retention, NAUSEA AND VOMITING, constipation, bradycardia, Diuretic (suppresses ADH) Low-abuse potential Naloxone Nalbuphine Buprenorphine

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Mu-2 Morphine synthetic opioids (Fentanyl, etc.), phenylpiperidine, endorphins Analgesia (spinal); Euphoria, Respiratory depression Depression of ventilation, Marked constipation, Diuretic (suppresses ADH), miosis High risk of Physical dependence Naloxone

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Kappa Dynorphin Nalbuphine Butorphanol Pentazocine Inhibits Ca++ effect Analgesia (spinal & supraspinal; Dysphoria sedation, miosis, Diuretic (suppresses ADH), miosis Low-abuse potential Naloxone

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Delta Enkephalins Butorphanol Pentazocine Analgesia (spinal & supraspinal), Antidepressant effects Depression of ventilation, some constipation, Urinary retention Physical dependence Naloxone

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Sigma Pentazocine Action unknown Dysphoria, delirium, mydriansis, hallucinations, tachycardia, hypertension Little is know about These receptors, not an Opioid receptor. Effects of sigma Receptor stimulation include: hypertonia (increased muscle tension) tachycardia tachypnea mydriasis (pupil dilation) Euphoria or dysphoria anti-depressant effect

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Epsilon Endorphin Decrease Stress response do not appear to be related to analgesia; exact role unknown

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Pharmacologic adjuvants Antiepileptics: Gabapentin, Valproate, and Phenytoin Antidepressants: Amitriptyline, Desipramine, and Nortriptyline Alpha-2 adrenergic Agonists: Tizanidine and Clonidine Benzodiazepines: Diazepam, lorazepam, and clonazepam Corticosteroids: Prednisone and Dexamethasone

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Pharmacologic adjuvants NMDA receptor: Dextromethorphan and Ketamine Miscellaneous: Baclofen and Calcitonin Muscle relaxants: Cyclobenzaprine, carisoprodol, and methocarbamol

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Consequences of inadequate pain relief The issue of postoperative pain is the most distressing factor for most patients going for surgery.

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Patients have the right to adequate analgesia.

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References Millers Anesthesia Barash Clinical Anesthesia Stoeltings Anesthesia and Co-Existing Disease Morgan, Mikhail, & Murray Clinical Anesthesiology Evers & Maze Anesthetic Pharmacology

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The End