Pain Syndromes and Chronic Pain Management dictated slides 19-52

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Principles of Pharmacology:

Principles of Pharmacology Consider patient’s age, associated medical problems, type of pain, & previous experience with pain Choose type of analgesia Choose route to control pain as rapidly and effectively as possible Titrate further doses based on initial response Anticipate side effects Recognize synergistic effects

PowerPoint Presentation:

NEJM 2002; 347 (14).

Agents to treat mild pain:

Agents to treat mild pain Acetaminophen Ibuprofen Choline Magnesium Salicylate Naproxen

Agents to treat moderate pain:

Agents to treat moderate pain Codeine, hydrocodone, oxycodone +/-acetaminophen Ketorolac

Agents to treat severe pain:

Agents to treat severe pain Morphine Hydromorphone Fentanyl Methadone

Adjunctive medications:

Adjunctive medications Antipyretics Anxiolytics Sedatives Antipruritics Antiemetics Antidepressants Anticonvulsants Antispasmodics


May act at the site of injury and decrease the pain associated with an inflammatory reaction (e.g. non-steroidal anti-inflammatory drugs (NSAID) such as: aspirin, ibuprofen, diclofenac ) Believed to act through inhibition of cyclo-oxygenase (COX). COX-2 is induced at sites of inflammation. Inhibition of COX-1 causes the unwanted effects of NSAID, i.e. gastrointestinal bleeding and nephrotoxicity . Selective COX-2 inhibitor are now used May alter nerve conduction (e.g. local anesthetics): block action potentials by blocking Na channels Used for surface anesthesia, infiltration, spinal or epidural anesthesia. Used in combination to steroid to reduce local swelling (injection near nerve root) Local anesthetic preferentially blocks C fiber conduction, cold decreases firing of C fibers, ischemia blocks first the large myelinated fibers Analgesics


Analgesics May modify transmission in the dorsal horn (e.g. opioids : endorphin, enkephalin , dynorphin ) Opioids act on G-protein coupled receptors: Mu, Delta and Kappa Opioid agonists reduce neuronal excitability (by increasing potassium conductance) and inhibit neurotransmitter release (by decreasing presynaptic calcium influx) May affect the central component and the emotional aspects of pain (e.g. opioids , antidepressant) Problems of tolerance and dependence

Non-opioid Analgesics:

Non-opioid Analgesics Mild to moderate pain No side effects of respiratory depression Highly effective when combined with opioids Acetaminophen NSAIDs COX-2 inhibitors Aspirin


Acetaminophen Antipyretic Mild analgesic Administer PO or PR Infant dose: 10-15 mg/kg/dose every 6-8 hr Pediatric Oral dose: 10-15 mg/kg/dose every 4 hr Adult dose: 650 mg-1000 mg/dose Onset 30 minutes


Acetaminophen Per rectum dose 40 mg/kg once followed by 20 mg/kg/dose every 6 hours Uptake is delayed and variable Peak absorption is 60-120 minutes Unreliable to cut suppositories Maximum daily dosing Infants: 60-75 mg/kg/day <60 kg: 100 mg/kg/day >60 kg: 4 grams/day


Ofirmev Indicated for the management of mild to moderate pain; management of moderate to severe pain with adjunctive opioid analgesics; and reduction of fever For adults and children ≥2 years old

Side Effects of Acetaminophen:

Side Effects of Acetaminophen Generally a good safety profile Do not use in hepatic failure Causes hepatic failure in overdose Infant drops are MORE concentrated than the children’s suspension Infant’s Acetaminophen 80 mg/0.8 mL Children’s Acetaminophen 160 mg/5 mL


NSAIDs Antipyretic Analgesic for mild to moderate pain Anti-inflammatory COX inhibitor  Prostaglandin inhibitor Platelet aggregation inhibitor

NSAIDs: Ibuprofen:

NSAIDs: Ibuprofen Dose 6-10 mg/kg/dose every 6 hours Adult dose 400-600 mg/dose every 6 hours Onset 30-45 minutes Maximum daily dosing <60 kg: 40 mg/kg >60 kg: 2400 mg May use higher doses in rheumatologic disease

NSAIDs: Ketorolac:

NSAIDs: Ketorolac Intravenous NSAID (also available P.O.) Dose 0.5 mg/kg/dose every 6 hours Onset 10 minutes Maximum I.V. dose 30 mg every 6 hours Monitor renal function Do not use more than 5 days Significant increase in side effects after 5 days

Side Effects of NSAIDs:

Side Effects of NSAIDs Gastritis Prolonged use increases risk of GI bleed Still rare in pediatric patients compared to adults NSAID use contraindicated in ulcer disease Nephropathy (ATN) Bleeding from platelet anti-aggregation Increased risk versus benefit post-tonsillectomy NSAID use contraindicated in active bleeding Delayed bone healing?

COX-2 inhibitors:

COX-2 inhibitors Selectively inhibits Cyclooxygenase-2 which reduces risk of gastric irritation and bleeding Same risk for nephropathy as non-selective COX inhibitors Shown to have increased cardiovascular events in adults More studies needed in pediatric patients COX-2 inhibitors used in rheumatologic diseases

Principles of Opioid Use:

Principles of Opioid Use Work at opioid (mu) receptors in the CNS and peripheral nervous system Each opioid has different affinities for different receptors, so there is variability in response among patients

Side Effects of Opioids:

Side Effects of Opioids All opioids have side effects that should be anticipated & managed Respiratory depression Nausea, vomiting Constipation Pruritis Urinary retention

Opioid Pharmacokinetics:

Opioid Pharmacokinetics Codeine 70% bioavailability from oral dosing 25% plasma protein-bound Metabolized to morphine (10%) and norcodeine Excreted in urine as inactive forms Half-life 2.5-2.5 hours


Codeine Oral analgesic (also anti-tussive) Weak opioid Used often in conjunction with acetaminophen to increase analgesic effect Metabolized in the liver and demethylated to morphine Some patients ineffectively convert codeine to morphine so no analgesia is achieved Dose 0.5-1 mg/kg every 4-6 hours


Oxycodone Oral analgesic Mild to moderate pain Hepatic metabolism to noroxycodone and oxymorphone Can be given alone or in combination with acetaminophen Dose 0.05-0.2 mg/kg every 4-6 hours Dosage same for Hydrocodone Maximum 5-10 mg every 4-6 hours

Opioid Pharmacokinetics:

Opioid Pharmacokinetics Morphine First-pass metabolism results in poor and unpredictable bioavailability from oral dosing 30% plasma protein-bound Detoxification by glucuronidation in liver Prolonged clearance and lower clearance rates in infants Half-life decreases with increasing age High inter-individual variability Available orally, sublingually, subcutaneously, intravenous, rectally, intrathecally Moderate to severe pain Use in caution with renal failure


Morphine Oral form comes in an immediate and sustained release Immediate: 0.3 mg/kg q 3-4 hr Sustained release: 20-35 kg: 10-15 mg q 8-12hr 35-50 kg: 15-30 mg q 8-12 hr Duration of I.V. analgesia 2-4 hours Dose dependent on formulation I.V. Dose 0.05-0.2 mg/kg/dose every 2-4 hours Infusion: 0.03 mg/kg/hr Onset 5-10 minutes Side effect of significant histamine release

Opioid Pharmacokinetics:

Opioid Pharmacokinetics Fentanyl Highly lipophilic, redistributes into muscle/fat 80 - 85% plasma protein-bound 90% metabolized in the liver to inactive metabolites Half-life much shorter in infants and young children with higher clearance


Fentanyl Available intravenous, buccal tab, lozenge and transdermal patch Use buccal tabs, lozenges and patch only in opioid tolerant patients Severe pain Rapid onset, brief duration of action With continuous infusion, longer duration of action I.V. Dose : 0.5-1 mcg/kg/dose every 30-60 minutes Infusion: 0.5-2 mcg/kg/hr Side effect of rapid administration may produce glottic and chest wall rigidity Careful observation, CRM and immediate availability of airway equipment and skills

Opioid Pharmacokinetics:

Opioid Pharmacokinetics Methadone Highly lipophilic, redistributes into muscle/fat 80 - 85% plasma protein-bound 90% metabolized in the liver and eliminated in the urine (<10% unchanged) Half-life shorter in children than adults Very long half-life with slow peak Good for steady level of analgesia Accumulates slowly and takes days to reach steady state PO : 0.1-0.2 mg/kg q 6-12 hr IV: 0.1 mg/kg q 6-12 hr


Hydromorphone 5 x more potent than Morphine (IV) Used in patients with renal insufficiency PO: 0.04-0.08 mg/kg q 3-4 hr IV: 0.02 mg/kg q 2-4 hr Infusion: 0.006 mg/kg/hr

Patient Controlled Analgesia (PCA):

Patient Controlled Analgesia (PCA) Programmable pump that allows patient control of intravenous analgesia Patient can choose when to deliver a dose of opioid and achieve relief quickly Inherent safety in the PCA: patient will fall asleep when over sedated and is unlikely to administer too much drug Teaching is integral and essential

When to use PCA:

When to use PCA Useful for sickle cell vaso-occlusive episodes, postoperative pain, cancer pain, palliative care Take patient’s age, maturity, and medical condition into the decision Bray et al (1996) compared morphine infusion and PCA in children Children over 5 able to use PCA Children between 5-8 years showed no difference in analgesia Children over 8 years had better analgesia with PCA

How to set up a PCA:

How to set up a PCA Loading dose if patient is in pain so that there is a therapeutic serum level to start Basal infusion rate can deliver continuous background dose of opioid to maintain therapeutic level Patient demand dose is the dose administered with each patient activation of the pump (usually small) Lockout interval (5-10 min) prevents a second PCA dose before the previous bolus has taken effect (important to prevent overdosing) Maximum hourly limit can be set based on the average hourly use of morphine Sedation and vital sign assessment is mandatory

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