Nagelhout Ch 56 Acute Pain.docx

**[Nagelhout Ch 56 Acute Pain: Physiology & Management]** **Pain** - Classification based on longevity (acute vs. chronic) &/or underlying pathophysiology (nociceptive or non-nociceptive). *Nociceptive pain* - Associated with stimulation of specific nociceptors & can be either somati...

**[Nagelhout Ch 56 Acute Pain: Physiology & Management]** **Pain** - Classification based on longevity (acute vs. chronic) &/or underlying pathophysiology (nociceptive or non-nociceptive). *Nociceptive pain* - Associated with stimulation of specific nociceptors & can be either somatic or visceral. - Somatic pain has identifiable locus 2/2 tissue damage causing release of chemicals from injured cells that mediate pain. - Well localized, sharp, & hurts at point/area of stimulus. - Visceral pain often associated with distension of organ capsule or obstruction of hollow viscus. - Diffuse, dull, cramping, squeezing or vague in nature, & can be referred to another area. - Also, often with autonomic reflexes such as NxV, & diarrhea. *Non-nociceptive pain* - Neuropathic pain caused by damage to peripheral or central neural structures resulting in abnormal processing of painful stimuli. - Burning, tingling, or shock-like. - Inflammatory pain is result of sensitization of nociceptive pathway from mx mediators released at site of tissue inflammation w/out neural injury. [Anatomy & physiology] - Somatic nociceptive pain commonly defined in 4 processes: transduction, transmission, modulation, & perception. *Transduction (peripheral sensitization) --* transformation of noxious stimuli into an AP. - Noxious stimulus detected by pain receptors, or nociceptors, which are unspecialized free nerve endings → conduct stimuli to dorsal horn of SC. - Peripheral nociceptors categorized according to morphology: - Myelinated Aδ elicit fast-sharp pain. - Nonmyelinated C fibers "aka" polymodal fibers elicit slow-dull, burning, throbbing & aching pain. - Biochemical events take place including release of chemical mediators from inflammatory response & neurotransmitters from nociceptive nerve endings: - Substance P is peptide released from peripheral afferent nociceptor C fibers & involved with slow, chronic pain. Acts via G protein-linked neurokinin-1 receptor → vasodilation, plasma protein extravasation, mast cell degranulation, & sensitization of stimulated sensory n. - Glutamate is major excitatory neurotransmitter released in CNS & from Aδ & C primary afferent fibers, & causes initial, fast, sharp pain. - Bradykinin is peptide released during inflammatory process. Acts via bradykinin receptors (B1/B2) for direct stimulating effect on peripheral nociceptors. - Histamine is amine released from mast cells, basophils, & plts via substance P. Acts on various histamine receptors → edema & vasodilation. - Serotonin (5-HT) is amine stored & released from plts after tissue injury. Acts on mx receptors & nociceptors, & can potentiate bradykinin-induced pain. - Prostaglandins (PGs) are metabolite of arachidonic acid, specifically synthesized from COX-1 & COX-2. Sensitize peripheral nociceptors → hyperalgesia. - Cytokines released in response to tissue injury by immune & nonimmune cells via inflammatory response. Can lead to ↑ PG production. - Calcitonin gene-related peptide (CGRP) is peptide found & released from peripheral afferent nociceptor C fiber. Produces local cutaneous vasodilation, plasma extravasation, & sensitizes stimulated sensory n. - Chemical mediators & neurotransmitters stimulate peripheral nociceptors → Na influx (depolarization), & subsequent K efflux (repolarization) → AP results → generates pain impulse. *Transmission (central sensitization)* -- AP conducted from periphery to CNS. - Spinothalamic (anterolateral) tract carries pain signals from trunk & lower extremities. - Primary afferent neurons Aδ & C fibers cell bodies located in dorsal root ganglia of SC → fibers enter dorsal cord & segregate & ascend/descend several spinal segments in tract of Lissauer → leave tract of Lissauer & enter gray matter of dorsal horn → synapse with 2^nd^-order neurons & terminate primarily in Rexed laminae I, II, & V → 2^nd^-order neurons cross midline of SC through anterior commissure & ascend in anterolateral pathway to thalamus → synapse with 3^rd^-order neurons in lateral thalamus & intralaminar nuclei → send projections to cerebral cortex. 2 types of 2^nd^-order neurons: - Nociceptive neurons receive input from Aδ & C fibers. - Wide-dynamic-range (WDR) neurons receive input from Aδ, C, & Aβ fibers. *Perception* - Occurs once signal is recognized by various areas of brain, including amygdala, somatosensory areas of cortex, hypothalamus, & anterior cingulate cortex. *Modulation --* involves altering neural afferent activity along pain pathway. - Can suppress or enhance pain. - Suppression occurs through local inhibitory interneurons & descending efferent pathways. - Descending axons from cerebral cortex, hypothalamus, thalamus, periaqueductal gray area (PAG), nucleus raphe magnus, & locus coeruleus via dorsolateral funiculus (DLF) synapse with & suppress pain transmission to brainstem & SC dorsal horn → APs arrive at substantia gelatinosa & activate enkephalin-releasing neurons → enkephalin binds to opiate receptors on presynaptic 1^st^-order or postsynaptic 2^nd^-order afferent fibers → ↓ substance P release suppresses ascending pain transmission. **Physiologic consequences** - Acute pain is responsive to pharmacotherapy & tx of precipitating cause. - Poorly controlled acute pain may lead to chronic pain states. - Neuroendocrine responses triggered primarily by SNS in response to surgical stress & pain. - ↑ catecholamine release from SNS & adrenal glands, ↑ cortisol → ↑ HR, ↑ vascular resistance (peripheral, systemic, & coronary), ↑ myocardial contractility, & ↑ BP → ↑ myocardial demand & myocardial O~2~ consumption. - Overall, incidence of ↑ myocardial O~2~ demand & ↓ myocardial O~2~ supply can have deleterious effects in those with coexisting cardiovascular dz. - Significant effects on respiratory system & most pronounced in those having sx/trauma in upper abdominal area & thorax. - ↓ VC, ↓ IC, & ↓ FRC → ↓V~T~ & physical ability to clear airway 2/2 limited thoracic & abdominal movement. - Splinting & reluctance to breathe deeply or cough → atelectasis & PNA. - Pulmonary alterations aggravated in those with preexisting pulmonary dysfunctions or ↓ FRC. - Risk for DVT & subsequent PE 2/2 decrease/delay in mobilization. [Acute pain assessment] - Predictors of acute postop pain after elective sx: presence of preop pain, fear regarding sx outcome, pts who catastrophize pain, & expected postop pain. - The most reliable pain assessment tool is via self-report because pain is subjective. [Preventive analgesia] - Asserted that by administering analgesics prior to noxious stimulation a ↓ pain response would result based on the premise that peripheral & central sensitization results from noxious stimulation. - Preemptive analgesia refers to administration of analgesics preop. - Preventive analgesia refers to administration of analgesics throughout periop course. **Pharmacology** [NSAIDs] - Best known for their use for mild-moderate postop pain & pain r/t inflammatory conditions. - NSAIDs + opioids → synergistic effect. - Has anti-inflammatory, antipyretic, & analgesic properties. - Inhibit COX → prevent conversion of arachidonic acid to PGs. - PGs (primarily PGE~1~ & PGE~2~) responsible for sensitizing & amplifying peripheral nociceptors to inflammatory mediators (substance P, bradykinin, & 5-HT) released with tissue trauma → hyperalgesia. - Mediate pain by enhancing release of substance P & glutamate in 1^st^-order neurons, ↑ nociceptive transmission at 2^nd^-order neurons, & inhibit release of descending inhibitory neurotransmitters. - Caution with Samter's triad: asthma, nasal polyps, & ASA sensitivity. *Ketorolac* - Nonselective COX inhibitor. - Analgesic potency of ketorolac 30 mg IM equivalent to morphine \~12 mg IM. - Should not be given beyond 5 days due to potential AE by COX-1 inhibition. - Contraindications: coagulopathies, renal failure, active PUD, GI bleeding, hx of asthma, NSAID hypersensitivity, & sx that involves high risk for postop bleeding. - Controversy regarding bone healing & NSAID administration. - Inhibition of COX-1, COX-2, & PG synthesis interrupts normal PG effect on osteoblast & osteoclast functioning that promotes bone healing. - No current recs regarding NSAID administration & orthopedic procedures. *Acetaminophen (Ofirmev)* - Suitable for acute, mild-moderate postop pain & fever. - Has minimal anti-inflammatory effects with mainly analgesic & antipyretic properties. - Not true NSAID, ↓ PG synthesis by uncertain mechanism. - Primarily hepatic metabolism. - Contraindication: hepatic impairment, acute liver dz, alcoholism, malnutrition, severe hypovolemia, severe renal impairment. - Common SE: NxV, headache, & insomnia. - Dosing for adults \>50 kg: 1000 mg q6h or 650 mg q4h, infused over 15 mins, max 4000 mg/day. - Dosing for children \>2 yrs & \3 months or beyond normal course of healing. - Often associated with insomnia, lost workdays, impaired mobility, & emotional distress. *Chronic pain analgesics & adjuncts* Anticonvulsants - Commonly used for neuropathic pain syndromes when tx is refractory to traditional analgesics. - Inhibit neuronal excitation & stabilize nerve membranes in effort to ↓ repetitive neural ectopic firing, which is common in neuropathic pain. - Gabapentin & pregabalin are structural analogs of GABA, which lack affinity for GABA receptors. - MOA believed that they block α~2~δ subunit of presynaptic voltage-gated Ca channels in CNS → prevent excitatory neurotransmitter release. - Exhibit anticonvulsant, anxiolytic, & anti-hyperalgesic effects. - Pregabalin requires less dosing with fewer SEs. - Renal excretion of unchanged form → compromised renal function requires dose modifications. - SE dose dependent & include dizziness, somnolence, peripheral edema, & weight gain. - Pts scheduled for sx, routinely taking anticonvulsants as part of chronic pain syndrome tx regimen should continue taking it to optimize their pain management. [ ] Antidepressants - Effective in tx of neuropathic pain syndromes. - Analgesic dose lower than antidepressive dose & analgesic effects may not occur until 4-10 days after initiating tx. - In presence of central sensitization, descending inhibitory pathway, which uses inhibitory neurotransmitters is altered → antidepressants may block reuptake of serotonin & NE in CNS → ↑ their availability. - May also act at other sites: block Na & Ca channels, ↓ PGE~2~ & TNF-α, block NMDA receptors, & enhance opioid receptors. - Metabolism of all antidepressants is primarily hepatic. - TCAs (amitriptyline, nortriptyline) tend to have more SEs because they antagonize other receptors, including muscarinic (dry mouth, blurred vision, urinary retention), histaminergic (sedation, appetite stimulation with subsequent weight gain), & adrenergic (orthostatic hypotension, prolonged QTi). - Contraindication: hx of recent MI, prolonged QTi, cardiac dysrhythmias, unstable CHF. - SNRIs (duloxetine, venlafaxine) lack affinity for cholinergic, histaminergic & adrenergic receptors. - SE: nausea, dry mouth, somnolence, headaches, & sexual dysfunction. - SSRIs primarily used for tx of depression, & their analgesic effects are relatively weak. - Serotonin syndrome -- acute toxicity of serotonin manifesting as anxiety, agitation, delirium, seizures, hyperthermia, diaphoresis, ↑ HR, HTN or hypotension, hyperreflexia, myoclonus, & muscle rigidity. Corticosteroids - Used as adjuncts for mx types of acute onset & chronic pain syndromes. - Effects include autoimmune, anti-inflammatory, antiedema, & antiallergic. - Inhibit PLA~2~ on cell membranes → prevent release of AA → ↓ inflammatory cytokines & PGs. - Injected epidurally, block C fiber transmission → nociceptive properties. - Suppress ectopic firing of nociceptors in presence of nerve injury → direct membrane-stabilizing effect. - SEs reflective of supraphysiologic doses exceeding rate of endogenous steroid production, which is \~20 mg/day of hydrocortisone or equivalent for \>3 wks. - Effects dependent upon degree of hypothalamic-pituitary-adrenal (HPA) axis suppression. - In event of major sx after recent administration of epidural steroid, prudent to give dose of exogenous steroid. Methadone - Synthetic opioid & structurally, racemic mixture of 2 enantiomers, D-isomer (S-methadone) & L-isomer (R-methadone). - D-isomer anatomizes NMDA receptor & inhibits serotonin & NE uptake → tx of neuropathic pain, prevention of opioid tolerance & hyperalgesia. - L-isomer binds to opioid receptors → analgesia. - Highly lipophilic, long ½-life of 15-60 hrs, lacks active metabolites → useful for chronic nonmalignant pain management. - Metabolism primarily via CYP450, specifically CYP3A4 & CYP2B6, & metabolites renally excreted. - SEs similar to other opioids, including respiratory depression & excessive sedation. - Respiratory depression peak effects occur later than analgesic peak effects. - QTi prolongation \>500 ms → risk for lethal ventricular tachyarrhythmias & torsade de pointes. - If chosen as analgesic for periop pain management, ECG required preop with identifying those at risk for QTi prolongation. - Risk factors: concomitant use of antiarrhythmics, some TCAs & CCBs, ↓ K, & hx of prolonged QTi. Buprenorphine - Used to tx moderate-severe acute pain as well as chronic pain. - Primarily used as alt. to methadone maintenance therapy for tx of opioid use disorder or MAT programs. - It is a semisynthetic opioid derivative that acts as a partial agonist at mu receptor & full antagonist at kappa receptor. - Extremely high affinity → prolonged DOA & resistance to naloxone antagonism → prevents binding of mu receptor by concurrently administered full opioid agonists. - Metabolized via CYP450(3A4) through *N*-dealkylation to active metabolite, norbuprenorphine. - Caution with hx of prolonged QT &/or taking antiarrhythmics → concurrent use could result in prolonged QTi. - Prolonged use of buprenorphine &/or methadone → risks of dependence, tolerance, addiction, & rarely misuse. - Physiologic dependence defined by manifestation of withdrawal syndrome after abrupt d/c of opioid or after giving opioid antagonist or mixed agonist-antagonist. - Withdrawal symptoms include ANS responses such as ↑ irritability, restlessness, tremors, chills, muscles cramps, sweating, mydriasis, abdominal pain, diarrhea, & ↑ HR. - Prevention: taper opioid upon discontinuation, & daily scheduled opioids should be continued periop. - Psychological dependence is subjective sense of need for a specific psychoactive substance, either for its (+) effects or to avoid (-) effects associated with its abstinence. - Addiction is primary, chronic disease of brain reward, motivation, memory, & related. - Pseudo-addiction's origin of behavior is inadequate analgesia → pts no longer show drug-seeking behavior when they receive adequate analgesia. - Tolerance refers to change in drug-response relationship induced by repeated exposure to drug & manifested as need for ↑ dose to maintain analgesic effect → normal physiologic response. - If it occurs, opioid rotation suggested → involves switching from 1 opioid to another in effort to improve analgesia & ↓ SEs. - Opioid-induced hyperalgesia (OIH) occurs with chronic opioid therapy, which attributes worsening pain to high, escalating doses of opioids. - SxSs include complaints of pain in locations different from original pain area, whole-body hyperesthesia, allodynia, agitation, multifocal myoclonus jerks, & seizures. - Often improved by ↓ or d/c opioids. - Tx strategies: weaning from high-dose opioids & starting nonopioid analgesics. [Opioid tolerance] - Pts taking chronic opioid therapy (COT) at risk for higher than normal levels of postop pain, slower pain resolution, longer hospital stay, & ↑ likelihood of readmission. *Periop management* Preop - COT should be continued periop → provides uninterrupted dosing for baseline opioid requirement & avoid withdrawal. - If not taken daily scheduled opioid → equivalent dose of opioid should be given preop. - Giving benzodiazepine, along with initiating multimodal analgesia with adjuvants, is optimal & should be started within 1-2 hrs prior to sx. - Realistic expectations regarding pain control should be discussed & also options for RA/analgesia techniques. Intraop - Opioids may need to be ↑ 30-100% compared with opioid-naïve pts because of receptor downregulation &/or tolerance. - Titration to HR & BP response, + pupil size, may be useful for estimating adequate analgesia with GA. - Respiratory rate & depth may also be monitored in spontaneously breathing, awake, or anesthetized pt. - Recs that RA with LA & opioids be part of anesthetic plan whenever possible. Postop - If not able to do RA/CPNB → consider IV PCA. [Elderly] - Aging adult has alterations in pain processing & perception. - Peripherally ↓ nociceptive processing via C & Aδ fibers → ↓ ability to sense & respond to initial fast-sharp pain. - ↓ concentrations of substance P & calcitonin gene-related peptide → loss of integrity or cellular elements of nociceptive pathway. - ↓ neurotransmitters in CNS → inadequate pain signal transmission &/or neuromodulation. - Dysfunction of descending inhibitory pathway. - ↑ pain threshold, ↓ pain tolerance → altered pain perception. - ↑ risk of AEs & drug toxicity 2/2 polypharmacy, altered drug metabolism, presence of comorbidities & end-organ function, ↑ sensitivity to meds, frailty & malnutrition. - Opioid analgesics are 1^st^-line tx for major sx → give lowest dose & titrate more PRN. [Pediatric] - Nociceptive pathways are well developed in premature & full-term infants, but maturation of descending pathway precedes ascending neural pathway → pain perception & stress response may be more exaggerated. - Repeated exposure to untreated painful stimuli early in life can result in central sensitization, ↑ stress-related markers, & ↑ free radicals after simple procedures → short & long-term consequences on future pain perception & behavioral & neurologic outcome. - Nonpharmacologic approaches to acute pain management include swaddling, facilitated tucking, kangaroo care or maternal skin-to-skin contact, massage therapy, acupuncture, & nonnutritive sucking. - Beneficial for minor pain & as adjuncts to pharmacologic therapy in moderate-severe pain. - Similar to adults, opioid analgesics are 1^st^-line tx for moderate-severe postop pain. - Most commonly used opioids for PCA are morphine, hydromorphone, & fentanyl.