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Anaesthesiology
Acute Pain Management
Built from Barash Clinical Anesthesia, 9th Edition
What’s inside
20 sections · 199 slides
Overview
- Scope and impact of acute pain management
- Guidelines and the three classes of acute pain
Defining Acute Pain
- Pain is 'an unpleasant sensory and emotional experience' linked to real or possible tissue damage. The definition covers both the feeling and the emotion, not just the nerve signal. Badly managed pain after surgery changes both the peripheral and central nervous systems. This change is called neuronal plasticity: the wiring adapts, like a path worn into grass. Inguinal herniorrhaphy (groin hernia repair) and abdominal hysterectomy are others. Saphenous vein stripping and open cholecystectomy (gallbladder removal) also feature.
- Three classes of acute pain
Anatomy of Acute Pain
- Nociception means detecting tissue-damaging stimuli, the raw signal before it feels like pain. The pathway is afferent (inward-going), has three neurons in series, and two ascending routes. The two routes are the anterolateral tract and the dorsal column medial lemniscal pathway. Nociceptors are free nerve endings, meaning bare fibre tips with no special capsule. Their cell bodies live in the dorsal root ganglia, small swellings beside the spinal cord. First-order neurons come in two flavours: A delta fibres and polymodal C fibres.
- First-order neurons run from the periphery to the spinal cord. Second-order neurons cross and climb the cord to the thalamus. Third-order neurons carry the signal from thalamus to somatosensory cortex. Notice the relay stations: each is a place a drug or block can act.
- First pain and second pain
- Primary afferent nerves
- A beta fibres are the thickest (12 to 20 microns) and fastest, over 40 metres per second. They serve low-threshold mechanoreceptors, endings that fire to light touch and vibration. A delta fibres are thinner (1 to 4 microns) and mid-speed, 10 to 40 metres per second. C fibres are unmyelinated, under 1.5 microns, and slowest at under 2 metres per second. The main landing zones are laminae I, II and V (Rexed's numbered layers of the horn). There they release excitatory amino acids and neuropeptides onto the next neuron.
- The dorsal root entry zone is where sensory fibres enter the cord. A delta and C fibres end superficially in laminae I and II. Thick A beta fibres dive deeper, then loop up to lamina III. The inset on the left shows the real histology of the dorsal quadrant.
- Nociceptive-specific neurons sit mainly in lamina I and fire only to noxious input. They handle the sensory-discriminative part: what kind of pain and exactly where. Wide dynamic-range (WDR) neurons sit mainly in laminae IV, V and VI. They use the dorsal column medial lemniscus and the anterior lateral spinothalamic tract. They synapse on third-order neurons in the thalamus, the brain's sensory switchboard. Only there is the incoming signal actually experienced as pain.
- Efferent pathways regulating nociception
- Efferent means outward-going: signals sent down from the brain to the cord. They start in the motor cortex, hypothalamus, periaqueductal grey and nucleus raphe magnus. They release noradrenaline, serotonin and endorphins into the dorsal horn. The effect is to turn down incoming pain traffic, like a volume knob on the cord. Many analgesic drugs work by boosting this built-in braking system. Tissue injury drives neuroplastic changes throughout the nervous system.
Pain Processing
- Hyperalgesia and allodynia
- Pain sensitization
- The four elements of pain processing
- Transduction is where a noxious heat, chemical or pressure stimulus becomes an action potential. Transmission is that signal travelling on through first-, second- and third-order neurons. Their cell bodies sit in the dorsal root ganglion, dorsal horn and thalamus in that order. Blocking transduction or transmission is what local anaesthetics and nerve blocks do. Modulation can go either way: inhibition (turning it down) or augmentation (turning it up). It also comes from descending pathways dropping noradrenaline, serotonin and endorphins.
- Central sensitization is a consequence of neuronal plasticity in the cord. It happens when C fibres repeatedly stimulate wide dynamic-range neurons in the dorsal horn. Each repeat adds to the last, like a drumbeat that gets louder without hitting harder. Perception is the final step: painful input integrated in somatosensory and limbic cortices. The limbic part explains why pain carries fear and distress, not just location. That is the core reason for combining drugs with different sites of action.
- The figure maps drugs onto the four steps of the pathway. Look for where NSAIDs act (transduction) versus opioids (modulation and perception). Serotonin (5HT) and noradrenaline (NE) mark the descending modulating pathways. NMDA receptors and nitric oxide appear at the spinal modulation step.
Chemical Mediators of Transduction and Transmission
- Surgical tissue damage activates small nociceptive nerve endings and local inflammatory cells. Nerve endings release substance P and glutamate backwards into the tissue (antidromic release). The chemical mixture directly triggers transduction by stimulating nociceptors. It also makes nociceptors more excitable, so they fire to weaker stimuli. That second effect is peripheral sensitization of C fibres and high-threshold mechanoreceptors. The clinical result is primary hyperalgesia: extra pain at the site of injury itself.
- Algogenic substances
- Algogenic substances (continued)
- Prostaglandins and leukotrienes sensitise them rather than firing them. Histamine causes vasodilation, swelling and itch, and boosts the bradykinin response. Excess hydrogen ions from injury and ischaemia raise pain and hyperalgesia. Nerve growth factor makes mast cells release histamine and causes heat hyperalgesia. Postoperative pain and the surgical stress response overlap but are not the same. Surgical stress releases cytokines: interleukin-1, interleukin-6 and tumour necrosis factor alpha.
- The figure shows the ending sitting among the inflammatory mediators. Notice how many different cell types feed chemicals onto one nerve terminal. That is why a single-drug approach rarely blocks peripheral pain completely.
- Excitatory amino acids glutamate and aspartate drive spinal pain transmission. Excitatory neuropeptides substance P and neurokinin A add to that drive. Inhibitory amino acids glycine and GABA oppose it; pain reflects the balance. Receptors involved are NMDA, AMPA, kainate and the metabotropic receptor. Repetitive C-fibre firing onto WDR neurons at 0.5 to 1 Hz triggers wind-up. The clinical result is secondary hyperalgesia: increased pain outside the injured area.
- C fibres release substance P, CGRP and glutamate onto second-order neurons. Fast direct excitation runs through non-NMDA receptors, not NMDA ones. Interneurons then drive NMDA-mediated excitation, raising intracellular calcium. Prostaglandins and nitric oxide diffuse back and boost transmitter release. Astrocytes and microglia add more prostaglandins after nerve injury.
- Primary hyperalgesia comes from toxic substances released at the injury site. Those substances spread outward, producing secondary hyperalgesia in nearby tissue. As C fibres fire faster, their transmitters summate on second-order neurons. That prolonged depolarisation is wind-up. Binding to postsynaptic receptors then produces activity-dependent spinal plasticity.
- Ordinary nociceptive traffic runs through AMPA, NK1 and CGRP synapses to the thalamus. Glutamatergic NMDA synapses barely contribute to that primary transmission. NMDA receptors matter for spinal sensitization instead. So blocking NMDA completely still lets pain signals reach the thalamus. NMDA antagonists are therefore antihyperalgesic rather than plain analgesic.
The Surgical Stress Response
- The neuroendocrine response to surgery
- Consequences of poorly managed acute pain
- Cardiovascular: fast heart rate, high blood pressure and a harder-working heart. Pulmonary: splinting (muscle spasm), smaller vital capacity, atelectasis, hypoxia, infection risk. Gut and kidney: ileus (bowel stops moving), oliguria and urinary retention. Blood and immunity: more clots, impaired immune function. Muscle and mind: weakness, poor mobility, anxiety, fear and dissatisfaction.
Preventive Analgesia
- Preventive analgesia is any antinociceptive regimen given at any time in the perioperative period. Its purpose is to blunt pain-induced sensitisation of the nervous system. The timing is deliberately open: before, during or after surgery all count. The older term preemptive analgesia meant giving the drug before the skin incision. The claim was that the same regimen works better before surgery than after. Preventive analgesia replaces it and is judged by effect, not by clock time.
- That activation drives wind-up, facilitation and central sensitization. It also expands receptive fields, so a wider skin area becomes painful. And it produces long-term potentiation, a lasting strengthening of the pain synapse. Together these changes are the route from acute pain into a chronic pain state. Patients with pre-existing chronic pain may respond poorly to these techniques. That is one reason chronic pain patients need a different, broader plan.
- Three principles of successful preventive analgesia
Strategies for Acute Pain Management
- Two kinds of postoperative pain
- Neuropathic pain follows accidental nerve injury: cutting, traction, compression or entrapment. Features include continuous burning, shooting attacks, or electric-shock pain. It comes with allodynia, hyperalgesia and dysaesthesia (unpleasant abnormal sensation). Onset may be delayed and it may not follow a dermatome (a nerve's skin territory). Spotting it matters because these patients are at higher risk of chronic pain. Gallbladder surgery and thoracic surgery both feature on the list.
- Matching drug class to pain type
- Multimodal therapy options by operation
- Guidelines for preoperative analgesia
- Paracetamol: 975 mg intravenously in an adult; avoid in acute decompensated liver failure. Celecoxib: 400 mg by mouth under 65 years, 200 mg over 65; avoid in existing renal failure. Gabapentin: 300 mg by mouth under 65, 100 to 300 mg over 65. Lidocaine, ketamine, magnesium, dexmedetomidine, esmolol, dexamethasone and methadone appear. Lidocaine dosing uses ideal body weight and must not be mixed with local anaesthetic blocks. Ketamine and magnesium both act at the NMDA receptor and both suit the opioid-tolerant patient.
- Guidelines for intraoperative multimodal analgesia - Dosing (Intravenous)
- Guidelines for intraoperative multimodal analgesia - Benefits
- Guidelines for intraoperative multimodal analgesia - Comments
- Guidelines for postoperative inpatient analgesia
- Guidelines for postoperative inpatient analgesia (continued)
- Guidelines for postoperative inpatient analgesia (continued)
- Guidelines for postoperative inpatient analgesia (continued)
- The table is grouped by class: paracetamol, anti-inflammatories, gabapentinoids, opioids, ketamine. Paracetamol 650 mg every 4 hours while awake, or 975 mg every 6 hours. Ketorolac 15 mg intravenously every 6 hours for 24 hours, never beyond 5 days. Oxycodone 5 mg by mouth every 4 hours as needed in the opioid-naive patient. Gabapentinoids plus opioids can cause too much sedation, so combine them carefully. A patient may report a low score of 1 out of 10 yet lie completely still in bed.
Assessment of Acute Pain
- The linear scale runs from no pain to worst imaginable pain. The faces tool lets children and non-verbal patients point instead of speak. Both are unidimensional: they capture intensity only. Use them to track change in one patient, not to compare two patients.
- These include the numerical scale, the visual analog scale and the faces rating scale. Scores vary widely between people and within the same person at different times. The McGill Pain Questionnaire and Brief Pain Inventory give a broader picture. They ask about quality, interference and mood, not just intensity. They are more cumbersome to administer at the bedside. In the end they share the same limitation as every attempt to measure pain.
- The Breakthrough Pain Questionnaire was introduced by Portenoy and Hagen for cancer patients. There it gives a picture of both the breakthrough and the background pain state. The best way to start assessing pain is to ask about it and listen to the answer. Reducing the experience to fine details can stop you asking the right question. Golden diagnostic clues that would lead to an effective treatment get missed. Assessment must be repeated: reassess to see if goals are met or harm has occurred.
- Bonica on the nature of pain
- Features of pain commonly addressed during assessment
- Features of pain commonly addressed during assessment (continued)
- Cover onset, timing, site, radiation, quality and severity of the pain. Ask about response to analgesics, including the patient's own attitudes to opioids. Record interference with daily living and the oral morphine equivalent already taken. A thorough physical examination is essential, with close attention to the neurological exam. Neurological findings may reveal nerve injury and so a neuropathic rather than nociceptive state. Provocative testing (range of motion, walking, coughing) can reproduce the pain.
Opioid Analgesics
- Beliefs about opioid prescribing have shifted dramatically for both short and long term use. An emerging field of opioid-free anaesthesia puts non-opioids and regional blocks first. Morphine is still the gold standard reference drug for potency comparisons. It converts any opioid into the equivalent milligrams of oral morphine. It is like converting different currencies into one before adding them up. OME underpins the definitions of opioid exposure and tolerance used later.
- The main opioid receptors are mu, delta, kappa and opioid receptor-like 1 (ORL1). G proteins are guanosine triphosphate regulatory proteins inside the cell membrane. Signalling goes through a second messenger such as cyclic AMP, or through an ion channel. The pharmacologic differences between opioids come from how they engage these receptors. Mu receptors also sit in periaqueductal grey, nucleus raphe magnus and rostral ventral medulla. Peripheral opioid receptors that mediate analgesia sit on primary afferent neurons.
- Spinal mechanisms of opioid analgesia
- Opioid analgesic pharmacokinetics
- Opioid equianalgesic dosing
- Opioid equianalgesic dosing (continued)
- The reference point is 10 mg of intravenous morphine, equal to 30 mg by mouth. Hydromorphone 1.5 to 2 mg intravenously, or 6 to 8 mg orally, matches that. Fentanyl 100 micrograms intravenously is the equivalent parenteral dose. Meperidine 100 mg intravenously or 300 mg orally is listed. Surgical and patient factors: first 24 hours after surgery, orthopaedic or transplant surgery. Also age over 60, female sex, ASA class 3 and 4, opioid dependence, genetic polymorphism.
- Delirium, hallucinations, myoclonus (muscle jerks), falls and dizziness also occur. In 402 orthopaedic surgery patients, constipation, vomiting and confusion lengthened hospital stay. Of all the side effects, opioid-induced constipation had the greatest effect on that stay. Tolerance rarely develops to the constipating effect, so it does not fade with time. Treatments include prolonged-release formulations containing naloxone, and tapentadol. Peripherally acting mu antagonists methylnaltrexone and alvimopan are also used.
- If the tablet is swallowed whole, little naloxone is absorbed and analgesia works. If the tablet is crushed and injected or snorted, the opioid is immediately antagonised. Respiratory depression is the most serious opioid side effect and is usually preceded by sedation. Patients on chronic opioids develop sleep-related breathing disorders during sleep. These show as irregular breathing from both obstructive and central sleep apnoea. The Joint Commission issued a Sentinel Event Alert about this in August 2012.
- Risk factors for opioid-induced respiratory depression
- Risk factors for opioid-induced respiratory depression (continued)
- Use regional anaesthesia techniques wherever they fit the operation. Consolidate routes: remove an epidural opioid if intravenous opioids are also prescribed. Monitor ventilation continuously with pulse oximetry and capnography. Continuous positive airway pressure (CPAP) is recommended for sleep apnoea in opioid dependence. CPAP splints the airway open with a constant pressure, like air holding a tube round. Some patients fail CPAP and central sleep apnoea then emerges.
- Opioid-induced hyperalgesia (OIH) is a rare paradox: opioids make the patient more pain sensitive. It is more likely after high doses of phenanthrene opioids such as morphine. Switching to a phenylpiperidine derivative such as fentanyl may reverse it. Adding an NMDA receptor antagonist can abolish both opioid tolerance and OIH. They promote angiogenesis (new vessel growth) and inhibit apoptosis (programmed cell death). Whether these effects help or harm depends on the clinical situation.
- Morphine is the prototype opioid and the reference for all potency comparisons. Plasma half-life is about 2 hours but analgesia lasts nearer 4 to 5 hours. The liver glucuronidates it to morphine-6-glucuronide and morphine-3-glucuronide. Both metabolites are cleared by the kidney, so they build up in renal failure. Dose adjustment and side-effect monitoring are therefore necessary.
- The two morphine glucuronide metabolites
- Subcutaneous bioavailability is 78% versus 20% to 50% orally. That makes it ideal for long-term subcutaneous use in the opioid-tolerant patient. Hydromorphone-3-glucuronide is the inactive one. Neuraxial pruritus is about 5% with hydromorphone versus 11% to 77% with morphine. The CYP2D6 enzyme demethylates it into hydromorphone, which binds mu much more strongly. Extensive metabolisers report better opioid effect and fewer adverse effects than poor metabolisers.
- Codeine itself has no analgesic activity and is also an antitussive (cough suppressant). CYP2D6 converts codeine to morphine, which binds mu 200 times more tightly. In extensive metabolisers this conversion handles only 5% to 10% of codeine clearance. CYP3A4 handles most of its metabolism, producing inactive metabolites. About 11% of a dose is cleared by CYP2D6 to the minor metabolite oxymorphone. So toxicity is theoretically possible in ultrarapid metabolisers or on a CYP3A4 inhibitor.
- The figure traces codeine down its metabolic routes. Asterisks mark the active metabolites. The CYP2D6 arm to morphine is the one that produces analgesia. The other arms account for most of the drug but no pain relief.
- Codeine in poor and ultrarapid metabolisers
- Codeine metabolism phenotypes by CYP2D6 diplotype
- Two enzyme routes leave the parent drug oxycodone. The CYP3A4 route dominates and produces inactive products. The smaller CYP2D6 route makes the far more potent oxymorphone. Diltiazem and verapamil are examples of CYP3A4 inhibitors that shift the balance.
- It is considered 80 times as potent as morphine after intravenous administration. The liver metabolises it extensively to norfentanyl and other inactive products. Sufentanil is about 1,000 times as potent as morphine and is mainly used in theatre. It is very lipophilic, with a smaller volume of distribution and shorter half-life than fentanyl. Its high intrinsic potency makes it an excellent epidural choice in opioid-dependent patients. Alfentanil is about 10 times as potent as morphine and is also used mainly in theatre.
- Tissue and plasma esterases degrade it rapidly, giving a half-life of 10 to 20 minutes. It pairs with propofol as total intravenous anaesthesia, especially in neurosurgery. Remifentanil by patient-controlled analgesia has been used successfully in labouring women. It is a second-line option when neuraxial analgesia is contraindicated or has failed. The disadvantage is that stopping the infusion loses analgesia almost immediately. There is also evidence that remifentanil infusions may cause opioid-induced hyperalgesia.
- Meperidine is a synthetic phenylpiperidine mu agonist with a short half-life. Normeperidine has a 12 to 16 hour half-life, so repeated dosing lets it accumulate. Total daily intravenous dose in a healthy adult should not exceed 600 mg per day. It should not be given for longer than 48 hours. The authors do not recommend meperidine for intravenous patient-controlled analgesia. It is contraindicated with monoamine oxidase inhibitors.
- Gut absorption is good, with bioavailability around 80%. The liver metabolises it by cytochrome P450 to inactive metabolites cleared in bile and urine. Elimination half-life is 22 hours; a single dose gives 3 to 6 hours of analgesia. Slow release back into the blood stretches the half-life to as long as 128 hours. Analgesia then lasts 8 to 12 hours instead of 3 to 6. Variation in OPRM1, the mu-1 opioid receptor gene, alters the receptor itself.
- Conversion ratios from morphine to methadone
- The conversion is curvilinear: the ratio changes as the morphine dose rises. Below 100 mg of oral morphine a day, the ratio is 3 to 1. At 300 to 600 mg it is 10 to 1, and above 1,000 mg it reaches 20 to 1. Interactions are graded from documented clinical effects down to predicted only. Ciprofloxacin, diazepam, acute ethanol and fluconazole raise methadone levels. Inhibiting metabolism risks toxicity; inducing it risks poor analgesia or withdrawal.
- Methadone drug interactions - Increase Methadone Concentration/Effects
- Methadone drug interactions - Decrease Methadone Concentration/Effects
- Opioid rotation means swapping to a different opioid to restore analgesic sensitivity. It works in the highly tolerant patient, and methadone is a common choice. Cross-tolerance is incomplete: tolerance to one opioid is not full tolerance to another. So the calculated equianalgesic dose of the new opioid is always lower than expected. A pain service must also lead a change of institutional culture, not just staff a rota. The goal is to raise relief of pain and suffering to a primary goal of patient care.
- It is also a kappa receptor antagonist and an ORL1 agonist. Intravenous elimination half-life is 1.2 to 7.2 hours, mean 2.2 hours. CYP3A4 in the liver converts buprenorphine to norbuprenorphine. Both are then rapidly conjugated to their 3-glucuronides in a phase II reaction. The adult parenteral dose is 300 micrograms, equivalent to 10 mg of morphine. The recommended dosing interval is every 6 hours.
- A novel off-label route is applying buprenorphine perineurally with local anaesthetic. The mix combines a long-acting local anaesthetic with clonidine and dexamethasone. This four-drug combination is called multimodal perineural analgesia. It is reported to give upward of 40 hours of analgesia at brachial and lumbar plexuses. A long-acting local anaesthetic alone gives under 12 to 16 hours. It suits situations where placing a continuous perineural catheter is not possible.
- Both combine mu receptor agonism with monoamine reuptake inhibition. Tramadol is a prodrug metabolised by CYP2D6 to O-desmethyltramadol, called M1. M1 has 200 times greater mu affinity, greater potency and a longer half-life than tramadol. So 5% to 15% of the population with reduced CYP2D6 activity get weaker analgesia. Poor metaboliser frequency is 8% in Whites, 2% to 7% in African Americans, 0% to 0.5% in Asians. Its metabolism also escapes drug interactions at the CYP2D6 enzyme.
- It comes as 50 mg tablets. The recommended adult dose is 50 to 100 mg orally every 4 to 6 hours. Do not exceed 400 mg in 24 hours. It comes as 50 mg, 75 mg and 100 mg tablets, dosed every 4 to 6 hours. Do not exceed 700 mg on the first day, or 600 mg per day after that. Tapentadol immediate release 50 and 75 mg matches oxycodone immediate release 10 mg.
- Advantages of tapentadol over tramadol
Biased Opioid Ligands
- TRV-130, oliceridine, is the putative G-protein biased compound. The FDA approved it in August 2020 for moderate to severe acute pain. One milligram intravenously is reported equianalgesic to 5 mg of intravenous morphine. Adult dosing is 1 to 2 mg intravenously every 1 to 3 hours as needed. Do not exceed 27 mg in any 24-hour period. The liver metabolises it extensively by CYP3A4 and CYP2D6 to inactive products.
- Two signalling pathways after receptor activation
- The figure contrasts a conventional opioid with a mu G-protein selective modulator. Conventional agonists recruit both arms of the signalling system. A biased agonist preferentially activates the G-protein arm. ORAEs in the figure means opioid-related adverse events.
- Oliceridine also shows reward-enhancing effects similar to morphine and oxycodone. Their benefit comes from inhibiting cyclooxygenase (COX) enzymes types 1 and 2. COX converts arachidonic acid into prostaglandin H2. Prostaglandin E2 is the key mediator of both peripheral and central pain sensitisation. They sensitise nociceptors to other mediators such as histamine and bradykinin. Think of them as turning up the gain on the microphone rather than making the sound.
Nonopioid Analgesic Adjuncts
- COX-1 versus COX-2
- They are opioid sparing, meaning less opioid is needed for the same relief. That reduces opioid side effects such as postoperative nausea, vomiting and sedation. Ketorolac is the commonly used parenteral NSAID in multimodal perioperative care. The optimal dose is 15 to 30 mg intravenously every 6 to 8 hours. It should not be used beyond 5 days. In 2020 the FDA approved intravenous meloxicam, 30 to 60 mg once daily, COX-2 preferential.
- That kidney risk rises with hypovolaemia, congestive heart failure and chronic renal insufficiency. COX-2 selective inhibitors were developed to reduce these problems. Celecoxib is the COX-2 specific inhibitor available in the United States. Celecoxib is the only COX-2 specific drug currently available there for acute postoperative pain. Recommended oral loading dose is 400 mg. Then 200 mg orally every 12 hours for several days.
- Short-term parecoxib and valdecoxib after coronary bypass raised thromboembolic events. The authors do not recommend a COX-2 inhibitor in known coronary or cerebrovascular disease. Prostaglandins matter for renal blood flow, sodium excretion and glomerular filtration. So both traditional NSAIDs and COX-2 inhibitors can cause fluid retention and hypertension. Both COX-1 and COX-2 play significant roles in bone fusion after a fracture. Whether COX-2 inhibitors do the same after orthopaedic procedures is still controversial.
- Paracetamol (acetaminophen) is a para-aminophenol derivative. It acts mainly centrally on the COX enzyme with minimal peripheral action. It may act at the TRPV1 receptor, the capsaicin and heat sensor. In adults, 2 g of oral paracetamol is equivalent to 200 mg of celecoxib. Intravenous paracetamol was released in the US in November 2010. It comes as a 1 g in 100 mL infusion given over 15 minutes through a peripheral line.
- Nonopioid analgesic adult dosing guidelines
- Ketamine and dextromethorphan are the two NMDA receptor antagonists used as adjuncts. Intravenous loading dose is 1 mcg/kg over 10 to 20 minutes. Maintenance is 0.2 to 0.7 mcg/kg per hour. Intramuscular premedication is 2.5 mcg/kg. Spinal 0.1 to 0.2 mcg/kg, epidural 1 to 2 mcg/kg, peripheral nerve block 1 mcg/kg. Buccal and intranasal are both 1 to 2 mcg/kg.
- Used for up to 48 hours after surgery, it can cut opioid use by upward of 40%. No major complications have been reported after 48 hours of continuous infusion. ASRA consensus guidelines define low dose as a bolus of 0.35 mg/kg or less. But ketamine 1 mg/mL with morphine 1 mg/mL by PCA after abdominal surgery did not improve relief. In morphine-resistant pain, a bolus of ketamine 250 mcg/kg plus morphine 15 mcg/kg did help. The ideal PCA morphine to ketamine ratio is 1 to 1 with an 8-minute lockout.
- Dextromethorphan is the d-isomer of the codeine analogue levorphanol. It is a noncompetitive NMDA antagonist long used as a cough suppressant. Analgesia is likely mediated entirely through its NMDA antagonism. Oral metabolism produces dextrorphan, which causes most of the side effects. Oral 150 mg before surgery cut PCA morphine needs after abdominal hysterectomy. It triggers histamine release and comes mainly as oral liquid, so it is used less than ketamine.
- Clonidine (half-life 9 to 12 hours) and dexmedetomidine (half-life 2 hours) are the two agents. Oral 5 mcg/kg before knee surgery cut PCA morphine use and postoperative nausea and vomiting. Oral 3 to 5 mcg/kg plus transdermal 0.2 mg/24 h halved PCA morphine after prostatectomy. Intrathecal clonidine 25 mcg with bupivacaine 15 mg and morphine 250 mcg helped knee replacement. That combination cut postoperative morphine use and improved 24-hour pain scores. With a local anaesthetic, clonidine 0.5 to 1.0 mcg/kg may improve and prolong perineural blocks.
- Dexmedetomidine is a potent, highly selective alpha-2 adrenoreceptor agonist. It shows cardioprotective, neuroprotective and renoprotective effects against hypoxic injury. It provides sedation without significant respiratory depression, plus opioid-sparing analgesia. Part of a multimodal protocol for intraoperative and postoperative analgesia. It decreases central nervous system sympathetic outflow in a dose-dependent way. The two most frequent adverse effects are bradycardia and hypotension.
- Dexmedetomidine dosing guidelines
- Gabapentin and pregabalin are alpha-2 delta subunit calcium channel ligands. Their licensed uses are partial-onset seizures and neuropathic pain such as postherpetic neuralgia. Growing evidence supports perioperative use to reduce postoperative pain and opioid use. In a retrospective hip and knee arthroplasty study, over 300 mg of gabapentin raised risk. In the opioid-naive patient, preoperative gabapentin should rarely exceed 300 mg orally. A meta-analysis of 281 trials with 24,682 patients found lower pain scores at 6 hours.
- Gabapentin binds the alpha-2 delta subunit of voltage-gated P/Q type calcium channels. Those channels sit on the synaptic bulb of presynaptic neurons. Calcium entering after a pain-evoked action potential triggers vesicle fusion. Vesicle fusion releases transmitters into the dorsal horn. Gabapentin may inhibit that step and also activate descending noradrenergic pathways.
- Absorption of gabapentin versus pregabalin
- Given intravenously, lidocaine is analgesic, antihyperalgesic and anti-inflammatory. It also acts on G protein-coupled receptors, NMDA receptors and the glycinergic system. A bolus of 1.5 to 2.0 mg/kg followed by 1.5 to 2 mg/kg per hour has been recommended. The target serum concentration is 1 to 5 micrograms per mL. Above 5 micrograms per mL, cardiovascular and central nervous system toxicity appear. Stopping more than 60 minutes before skin closure was compared with running past closure.
- If a peripheral nerve block is needed, do not perform it immediately. Wait at least 6 hours after the lidocaine infusion is stopped. Six hours is roughly four half-lives of the drug. Four half-lives leaves only about 6% of the original level. This rule protects against additive local anaesthetic toxicity. The authors' opinion is that the perineural dose should not exceed 1 to 2 mg.
- Recent meta-analyses support perioperative intravenous magnesium as an analgesic adjunct. It decreases pain scores and is opioid sparing in the first 24 hours after surgery. In 50 patients having scoliosis surgery, magnesium plus low-dose ketamine was tested. Magnesium bolus was 50 mg/kg over 30 minutes, then 8 mg/kg per hour. Ketamine bolus was 0.2 mg/kg, then 0.15 mg/kg per hour. Compared with ketamine alone, the pair reduced postoperative morphine consumption.
- They inhibit cytosolic phospholipase A2, upstream of the lipoxygenase and COX enzymes. The antiemetic mechanism is less clear but appears to be centrally mediated. The recommended preoperative intravenous dose is 0.11 to 0.2 mg/kg. Rapid administration causes perineal irritation in 50% to 70% of people. So dilute it in 50 mL of normal saline and give over 10 minutes before surgery. High-dose dexamethasone with a proton pump inhibitor suits the opioid-tolerant patient.
Patient-Controlled Analgesia
- The commonest PCA drugs in the United States are morphine, hydromorphone and fentanyl. In an otherwise healthy adult, use an incremental dose of 1 to 2 mg of morphine. Pair it with an 8 to 10 minute lockout. The authors do not recommend a background infusion in the opioid-naive patient. Reserve background infusions for patients with chronic malignant or non-malignant pain. Also for patients with persistent pain who have failed a trial of incremental dosing.
- The five variables of any PCA mode
- Patient-controlled analgesia dose ranges
- Relative risk factors for patient-controlled analgesia
- Also closed head injury, altered mental status and lactating mothers. If more than two risk factors are present, avoid the standard PCA regimen. Where they match, the catheter is congruent: bupivacaine 0.05-0.1% or ropivacaine 0.1-0.2%. Opioid is optional there: fentanyl 2-5 mcg/mL, morphine 0.1 mg/mL or hydromorphone 0.02 mg/mL. Where they do not match, the table flags incongruency and calls it not ideal. For incongruent catheters a hydrophilic opioid is required to reach the right segments.
- PCA opioid side effects: nausea, vomiting, pruritus, sedation, respiratory depression, confusion. For nausea and vomiting, combine dopamine, serotonin and NK1 antagonists as guidelines advise. Glucocorticoids, anticholinergics and antihistamines are also used, with nonpharmacologic measures. An alpha-2 agonist such as dexmedetomidine is both analgesic and antiemetic. For pruritus use diphenhydramine, hydroxyzine, low-dose naloxone or nalbuphine. Add an NMDA antagonist or an alpha-2 delta calcium channel ligand.
Neuraxial Analgesia
- Discovery of spinal opioid analgesia
- Meta-analysis found epidural analgesia superior to systemically given opioids. Thoracic catheters are recommended for thoracic and upper abdominal surgery. Continue at least 2 to 4 days; under 24 hours gives no cardiovascular advantage. Epidural opioids relieve pain without significant sympatholysis or motor block. Morphine has greater spinal cord bioavailability than alfentanil or fentanyl. Local anaesthetic and opioid act synergistically, and block the surgical stress response.
- Determinants of epidural efficacy
- The green oval marks the insertion region for thoracic surgery. The blue oval marks the region for upper abdominal surgery. The pink oval marks the region for lower abdominal surgery. The principle is congruency: the catheter sits at the level of the incision.
- Hydrophilic versus lipophilic epidural opioids
- They place the epidural congruent with the surgical incision. As a rule the infusion is simply local anaesthetic with no opioid. This particularly benefits patients who cannot tolerate pruritus and other opioid effects. Sufentanil is the epidural opioid of choice for patients on over 250 mg/day oral morphine. A systemic opioid such as a PCA must not be combined with a neuraxial opioid. Epidural morphine plus intravenous PCA morphine is the specific example to avoid.
- Adult epidural catheter dosing by incision level - Surgical Dermatome
- Adult epidural catheter dosing by incision level - Column 2
- Adult epidural catheter dosing by incision level - Column 3
- Do not exceed 400 mg of epidural bupivacaine in 24 hours. You may consider clonidine 1 to 2 mcg/mL in the epidural mixture. Hypotension, bradycardia and sedation are common above 14 mcg per hour of clonidine. Clonidine at 2 mcg/mL can be combined with an opioid and a local anaesthetic. Ropivacaine 0.2% with fentanyl 5 mcg/mL and clonidine 2 mcg/mL was studied after knee replacement. Infused at 3 to 7 mL per hour it caused no significant sedation.
- Morphine, hydromorphone, meperidine, methadone, fentanyl and sufentanil are all used. Labour analgesia uses sufentanil 2.5 to 5 mcg. Caesarean section uses morphine 100 mcg; clonidine 60 mcg adds duration but also sedation. For total knee and hip replacement, morphine 100 mcg has been recommended for inpatients. The authors avoid intrathecal morphine and use motor-sparing peripheral nerve blocks instead. For thoracotomy and major abdominal surgery, doses above 300 mcg sharply raise side effects.
- Hydrophilic opioids such as morphine penetrate the spinal cord itself. They cross the dura slowly, bind epidural fat poorly and enter plasma slowly. Delayed respiratory depression is more common with them, from rostral spread up the fluid. Lipophilic opioids such as fentanyl bind nonspecific receptors in the white matter. They are quickly taken up by epidural fat and enter the circulation fast. So they have rapid onset, short duration and a narrow band of analgesia.
- Intrathecal analgesia dosing by procedure
- Intrathecal analgesia dosing by procedure (continued)
- A direct comparison exists between the two hydrophilic intrathecal options. Intrathecal hydromorphone 50 to 100 mcg approximates intrathecal morphine 100 to 200 mcg. Other intrathecal side effects are nausea, vomiting, urinary retention and pruritus. Additives include alpha-2 agonists, NSAIDs, NMDA antagonists and acetylcholinesterase inhibitors. Intrathecal clonidine is synergistic with spinal local anaesthetics. It prolongs sensory and motor block and causes less urinary retention than morphine.
- Other intrathecal dosing guidelines
- Clonidine 15 to 45 mcg improves the quality of spinal blockade in outpatient surgery. Clonidine side effects rise significantly above intrathecal doses of 150 mcg. Epinephrine is dosed 0.1 to 0.6 mg. It causes a dose-related delay in return of motor function and of micturition. Those reports include both accidental and intentional administration. The same is true for acetylcholinesterase inhibitors, NMDA antagonists and adenosine.
The Opioid-Dependent Patient
- The ASA definition was pain of a duration or intensity that harms function or well-being. Treatment may need anxiolytics, antidepressants, anticonvulsants and antiarrhythmics. Since the late 1990s chronic opioid prescribing rose dramatically, led by the United States. One reason was more compassionate treatment of cancer pain in longer-surviving patients. The much larger reason was willingness to treat non-malignant pain such as osteoarthritis. Long-term consequences include physical dependence and withdrawal on stopping abruptly.
- Chronic primary and chronic secondary pain
- Three waves of the opioid crisis
- Since 1999 more than 600,000 people in the United States and Canada have died from overdose. CDC data estimate 75,673 opioid overdose deaths in the 12 months ending April 2021. The figure the year before was 56,064. This is the backdrop against which every opioid prescription is now written. It is use of 60 mg or more of oral morphine equivalent per day. That intake must have continued for 7 days or longer.
- Physical dependence is a physiologic state of adaptation to a psychoactive substance. That produces hypertension, tachycardia, sweating, abdominal cramping and diarrhoea. Rising doses may instead reflect worsening disease, or opioid-induced hyperalgesia. So an escalating requirement is a question, not an automatic diagnosis of tolerance. Innate tolerance is a genetically predetermined sensitivity to a drug. Restore analgesia at more than 50% below the predicted equianalgesic dose.
- Types of acquired tolerance
- The American Society of Addiction Medicine calls addiction a treatable chronic medical disease. Pharmacologic: opioid weaning before or after surgery, plus multimodal opioid-sparing analgesia. Procedural: peripheral nerve neuromodulation and transcutaneous electrical nerve stimulation. Also continuous perineural blocks and peripheral nerve cryoneurolysis, plus acupuncture. Nonpharmacologic: electronic pain-coping applications and sensory therapy such as music. Acute pain care in opioid-dependent patients is unpredictable and often disjointed.
The Transitional Pain Service
- Interventions a transitional pain service may provide
- Two staffing models for a transitional pain service
- It compared orthopaedic surgery patients before and after a TPS was set up. Implementing the service significantly reduced overall opioid use after orthopaedic surgery. An economic analysis of the low-intensity model showed a positive economic impact. A TPS need not be separate; it can sit inside an existing perioperative surgical home. First categorise the patient as opioid naive, exposed or tolerant. Consult a perioperative pain specialist before surgery in high-risk patients.
- Opioid-naive, opioid-exposed and opioid-tolerant patients
Management of the Opioid-Dependent Patient
- Clinicians should query their state's prescription drug monitoring program. A Patient Activity Report confirms the drug, dose and dispensing date. It also names the patient, the prescribing physician and the pharmacy. The risk from preoperative opioids is dose dependent, so the category predicts trouble. They have higher readmission rates, greater costs and increased mortality. Identifying modifiable risks before surgery can improve the outcome.
- The O-NET categories of preoperative opioid use
- Patients are stratified further by comorbidities and by type of surgery. The O-NET category is only the starting point. A tolerant patient having minor surgery is not the same risk as one having major surgery. Use the figure to place a patient before writing the plan.
- Perioperative management of the patient taking preoperative opioids
- The responsibility rests with the surgical team, preoperative staff and the anaesthesia team. Where available, the transitional pain service evaluates them first. Then the anaesthesia team simply has to be innovative on the spot. Use regional analgesia, neuraxial or peripheral nerve blockade, wherever appropriate. Opioids nevertheless remain the mainstay of perioperative pain management here. An adequate opioid dose must be maintained to avoid precipitating withdrawal.
- Start by determining the patient's baseline opioid requirement and continue it. Opioid-dependent patients need 30% to 100% more opioid than opioid-naive patients. Keep fentanyl patches on, unless major surgery or sepsis risk demands an infusion instead. Over 200 mg of methadone a day can prolong the QT interval, risking torsades de pointes. Patients on buprenorphine may continue it, supplemented with morphine or fentanyl. Add gabapentinoids, an NSAID or COX-2 inhibitor, paracetamol, ketamine and magnesium.
- Both gabapentin and pregabalin bind the alpha-2 delta subunit of P/Q-type calcium channels. Celecoxib 400 mg orally 2 hours before surgery cuts pain and opioid requirement. Its interaction with the endocannabinoid system, TRPV1 and NMDA may help here specifically. Adult dose above 50 kg is 1,000 mg intravenously every 6 hours. The recommended preoperative intravenous dose is 0.11 to 0.2 mg/kg. Doses as high as 0.2 mg/kg have been used within multimodal strategies.
- Intraoperative care needs prudent use of fentanyl, morphine or hydromorphone. The goals are anaesthesia, postoperative analgesia and preventing withdrawal. Exact guidelines do not exist, but doses may need to be 30% to 50% higher than in naive patients. Opioid rotation works because a new opioid binds a different receptor subtype. Following the cancer pain model, use less than 50% of the calculated equianalgesic dose. Before discharge, a pain-trained physician or pharmacist should convert to an oral regimen.
- Reversing neuromuscular blockade near the end and letting the patient breathe is informative. A respiratory rate over 20 with widely dilated pupils means more opioid is needed. Titrate to 12 to 14 breaths per minute and a moderately small pupil before waking. Intravenous lidocaine suits abdominal surgery, or when regional anaesthesia is contraindicated. Its indirect NMDA blockade through protein kinase C inhibition makes it useful here. Since magnesium and ketamine bind different NMDA sites, together they may be superadditive.
- Protein kinase C activation of the NMDA receptor is critical in developing opioid tolerance. Blocking NMDA with ketamine reverses morphine tolerance and restores its effect. Recommended intraoperative dose is 0.5 mg/kg as a bolus at the start of the case. Then 10 mcg/kg per minute as an infusion for the duration of the case. Low-dose ketamine may continue postoperatively for up to 48 hours without serious complications. Dexmedetomidine and clonidine have moderate analgesic and opioid-sparing effects.
- A PCA with a basal plus demand dose prevents both withdrawal and breakthrough pain. For a patient on 90 mg oral morphine a day, the basal rate works out at 1.25 mg per hour. The demand dose is half the hourly rate, about 0.6 mg, with a 10-minute lockout. Program hourly or 4-hour dose limits into the PCA to increase safety. Monitor constantly for oversedation and respiratory depression. Regional anaesthesia is highly recommended; low-dose ketamine may continue postoperatively.
- The authors do not recommend neuraxial opioids in this population. Deliver the baseline opioid and breakthrough opioid systemically instead. Never give opioids by multiple routes at once, because of respiratory depression risk. A physician versed in equianalgesic dosing should ideally be involved. Opioid use disorder (OUD) is treated with specific FDA-approved medications. The abbreviation MOUD means medication treatment of opioid use disorder.
Special Populations
- Patients on maintenance methadone should continue that dose perioperatively. Or divided into three doses at 8-hour intervals for better analgesia. Respiratory depression is a further risk because of the long half-life. In the United States buprenorphine is approved for acute pain, OUD and chronic pain. It is a partial mu agonist, kappa antagonist and nociceptin (ORL-1) agonist. That ceiling makes it potentially safer than methadone for treating OUD.
- The chemical change is replacing the n-methyl group with a methylcyclopropyl group. It is used in alcohol- and opioid-dependent patients motivated to stay abstinent. It comes as a once-daily 50 mg oral dose. Or a monthly 380 mg depot injection in a biodegradable matrix. Hold the oral formulation for 3 days before surgery. Ideally schedule surgery at least 4 weeks after the last depot naltrexone dose.
Organization of Perioperative Pain Management Services
- Effective management is crucial to good perioperative care and recovery. Poor control means longer stay, poor sleep and slower first ambulation. It means cardiopulmonary and thromboembolic complications, and higher costs. There is good evidence on how often pain is inadequately controlled. The incidence of moderate to severe pain in surgical patients is about 25% to 40%. Inadequate control also raises the risk of chronic postsurgical pain.
- Guiding principles for acute perioperative pain management
- Prevalence of chronic postsurgical pain by operation
- Considerable barriers challenge acute pain teams working across the continuum of care. Limited reimbursement for postoperative care discourages setting up a service. It does that by improving outcome, speeding recovery and enabling earlier discharge. It provides direct patient care such as running epidural and regional catheter infusions. It educates physicians, nurses and caregivers to assess and manage pain competently. Ideally it spans the preoperative to postoperative phases as a continuum.
- Treating postoperative pain purely as incision pain misses other contributors. Many elective patients already have chronic pain from degenerative disease or malignancy. That pre-existing pain intensifies what they feel after surgery. Patients often accept pain as a natural consequence of surgery, so they never report it. Personal experience and stories from friends and relatives shape expectations. Opiophobia, the fear of opioids, makes patients refuse effective treatment.
- Pain management therefore begins preoperatively with patient education. Education relieves the anxiety, apprehension and fear surrounding surgery. It lets the team understand the patient's specific fears and concerns. Education is also how you change other caregivers' attitudes to treating pain. Depending on institutional needs, the team may include acute pain fellows. Other anaesthesiologists must be available so supervision never lapses.
- Building a perioperative pain management service
Conclusion and Key Points
- Standardised acute pain strategies belong in every enhanced recovery protocol. They should use opioids judiciously and add procedure-specific techniques. Evidence-based opioid stewardship reduces opioid-related adverse drug events. Communication, cooperation and collaboration among providers is paramount. The cost of ignoring pain runs to billions of dollars, and the cost in suffering is immeasurable.
- Inadequate pain relief causes real morbidity and delays recovery and return to activity. Tissue injury drives neuroplastic change, giving peripheral and central sensitization. Traditional analgesia targets perception only; multimodal care targets all four elements. Opioid differences come from mu, delta and kappa G protein-coupled receptors. NSAID benefit comes from inhibiting cyclooxygenase types 1 and 2. Avoid a COX-2 inhibitor in known coronary artery or cerebrovascular disease.
- PCA has five variables: bolus, incremental dose, lockout, background infusion, hourly limits. A typical healthy adult regimen is 1 to 2 mg morphine with an 8 to 10 minute lockout. Opioid-sparing therapy plus oximetry and capnography reduce respiratory depression risk. The opioid-dependent patient is often identified moments before surgery. Tailor an individual anaesthetic combining regional with general anaesthesia. A successful service needs institutional commitment and a pain-trained physician leader.
- References
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- Barash, Cullen, and Stoelting's Clinical Anesthesia, 9th Edition