Describe the analgesic effects of nicotine.

Discuss the effects of N-methyl-D-aspartate (NMDA) agonists and magnesium on central sensitization.

Describe the role of ketamine as a supplement to opioids for postoperative analgesia.

Compare the pharmacokinetics, potencies, and other characteristics of opiates for acute pain relief.

Detail the advantages of opioid antagonists for patients on long-term opioid therapy.

Perioperative Pain Therapies That Work
Pamela Flood, MD, Associate Professor of Clinical Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY

Concept: at low concentrations, general anesthetics can enhance pain sensitivity; volatile anesthetics, at one-tenth minimum alveolar concentration (MAC), inhibit nicotinic receptors (located on presynaptic terminals of descending fibers [tonic inhibition modulates pain]); nicotinic receptors present on presynaptic fibers act as gain control (activation results in increased release of epinephrine and serotonin; blocking eliminates tonic inhibitory system); question—does nicotine act as effective analgesic in early postoperative period in humans?

Clinical trials: early trials of nicotine nasal spray and nicotine transdermal system (patch) for smoking cessation showed modest analgesic effect

Initial study (Flood and Daniel, 2004): patients anesthetized with isoflurane and fentanyl infusion; randomized to receive 3 mg nicotine nasal spray or placebo while under general anesthesia (GA) during closure of abdominal fascia; patients had access to patient-controlled analgesia (PCA; morphine) for rescue; patients monitored for hemodynamic issues (eg, hypertension, tachycardia); participants—20 women undergoing hysterectomy or myomectomy through low transverse incision; fairly uniform population for height, weight, and age; all received same amount of fentanyl throughout; exclusion criteria included smoking, cardiovascular disease, and chronic pain syndromes; patients who received placebo had pain scores of 7 to 8, and those who received nicotine nasal spray had pain scores of 4 to 5 (also used significantly less morphine); patients who received nicotine had slightly lower blood pressures (statistically significant) than those who received placebo, likely due to reduced pain; analgesic effect lasted 24 hr, despite fact that pharmacokinetics of intranasal nicotine suggest much shorter effect (40 min); at 24 hr, placebo group reported pain scores of ≈5, and nicotine group reported pain scores of ≈1.5

Follow-up study: 80 women undergoing gynecologic surgery; anesthetized with intravenous (IV) fentanyl infusion; randomized to receive isoflurane or propofol (titrated to bispectral index [BIS] of ≈50); visual analog scale (VAS) pain scores primary outcome variable; patients anesthetized with isoflurane had significantly more postoperative pain (and used more morphine) than those anesthetized with propofol

Duration of effect: 40 men and women undergoing various general surgeries (no differences seen based on sex); studied effect of nicotine patch (lasting 16 hr) of varying doses (0, 5, 10, or 15 mg); followed patients for 5 days after surgery; patients who received placebo had more pain than those receiving any dose of nicotine, but no dose-dependence observed; effect continued to fifth postoperative day; less opioid use noted in those receiving nicotine, but not statistically significant

Clinical implications: another clinical trial showed benefit of nicotine for pain relief among men undergoing prostate surgery; third study (and unpublished data from speaker) showed no analgesic effect of nicotine in smokers, presumably because nicotinic receptors desensitized from long-term exposure to low concentration of nicotine; some nicotinic agonists may be useful for pain

Pain transmission in dorsal horn: pain afferents (C and A-δ fibers) release substance P, calcitonin gene-related peptide, and neurokinin A; all have final step that includes glutamate; excitatory receptors in dorsal horn include tachykinin receptors for substance P and neurokinin A and receptors for glutamate, α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA), and N-methyl-D-aspartate (NMDA); inhibitory subtypes include opioid receptors (µ, δ) and α2 adrenoreceptors (receptors for noradrenergic system and noradrenergic drugs used in epidural anesthesia, eg, clonidine)

Central sensitization: blocked by NMDA antagonists; mediated by repetitive C-fiber activation; includes enhancement of nociceptive and non-nociceptive stimulation (ie, hyperalgesia, allodynia, spontaneous pain); activation of NMDA receptors through afferent input important; many studies have looked at NMDA blockade for preventive analgesia; results mixed; 24 studies reviewed in meta-analysis; only 58% showed positive effect; other NMDA antagonists (eg, dextromethorphan [also nicotinic antagonist]) in clinical use, but only 67% of studies showed benefit; no studies of magnesium for preemptive analgesia have shown benefit; some ketamine, dextromethorphan, or magnesium should be available during postoperative period because of ongoing sensitization and negative stimulus

Postoperative ketamine: study of patients undergoing thoracotomy—found large reduction in PCA requests (over 72 hr) by patients receiving low-dose PCA morphine with ketamine (5 mg per bolus) vs those receiving larger dose of morphine alone; no reports of psychomimetic effects; ketamine especially efficacious in opioid- tolerant patients; patients receiving ketamine had lower pain scores, even though other group received more morphine; recent study—looked at 26 opioid-tolerant patients undergoing lumbar fusion; patients given ketamine, 0.2 mg/kg on induction, and 2 µg/kg per hour for 24 hr vs placebo; ketamine group had lower pain scores immediately after surgery, during subsequent 24 hr, and during physical therapy (PT); another study— looked at cervical and lumbar spine surgeries; patients received placebo, low-dose ketamine (42 µg/kg per hour), or higher-dose ketamine (83 µg/kg per hour); pain scores relatively low; only higher dose of ketamine had effect, which lasted entire study period (10 days); similarly, VAS score at movement relatively low, but only higher dose of ketamine associated with considerably reduced scores; fentanyl requirement for breakthrough pain lower with both doses of ketamine; pediatric study—84 children (2-12 yr of age) received morphine on induction and ketamine (0.25 mg/kg bolus) or saline; concluded no benefit associated with ketamine; however, pain scores for patients who received only morphine were higher (difference not statistically significant) at most time points, compared to those who received morphine plus ketamine; postoperative morphine requirement higher in group not receiving ketamine; number of postoperative analgesia requirements also higher; no psychotomimetic episodes or problems with vomiting

Ketamine and magnesium: both block NMDA channel; some evidence of synergy; study—looked at amount of magnesium and NMDA required to block channel; when used in combination, extremely small concentrations have large effect (profoundly synergistic); implications for management of postoperative pain (more research needed)

Methadone: multimodal drug (r-stereoisomer is µ-opioid receptor agonist, s-stereoisomer potent NMDA antagonist); efficacy may result from combined effect; clinical study found profound synergy between methadone and ketamine; other NMDA antagonists—eg, dextromethorphan, memantine; case reports of dramatically reduced neuropathic pain and cancer pain with memantine; clinical trials needed

The Role and Method of Delivery of Opiates for Acute Pain Relief
Steven L. Shafer, MD, Professor of Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY

Introduction: problems with toxicity, but effective for pain relief; many opioids available; not identical or interchangeable; all have distinguishing characteristics; most clinicians familiar with fentanyl and morphine, but much to learn about other opioids (eg, time course, perioperative use, choice for best advantage); differences in pharmacokinetics (particularly rate of onset and offset), potency, and other characteristics

Morphine: endogenous ligand (neurotransmitter); slow rise to peak effect (≈90 min after bolus injection); because of slow peak, difficult to titrate every 1 or 2 min; metabolizes to morphine-6-glucuronide (active metabolite; in intrathecal space, 150 times more potent than morphine; crosses intrathecal space so slowly that it contributes nothing to acute morphine analgesia; in patients with normal renal function on long-term therapy, contributes one-third of total analgesia; patients in renal failure can become toxic from accumulation over time); directly releases histamine; some data suggest morphine not fully efficacious

Fentanyl: “pharmacologically clean,” compared to morphine; efficacy of opioids for analgesia based on efficacy of fentanyl series (by definition, considered 100% efficacious); first of fentanyl class of opioids; available in large variety of forms; initially offered as Sublimaze, generic fentanyl later became available in transdermal, submucosal, and sublingual forms; 20 mL vial costs ≈$0.70; overall pharmacokinetics much slower than those of morphine, but levels peak in brain ≈4 min after bolus injected; rapid offset driven by rapid blood-brain equilibration (in contrast to morphine, which has slow blood-brain equilibration)

Hydromorphone: attempt to “fix” problems associated with morphine and thebaine derivatives; rapid onset (≈10 min); does not release histamine; 8 times more potent than morphine; no active metabolite; good choice for PCA; faster offset kinetics than fentanyl in first 30 min; study showed no difference in outcomes when compared to morphine for PCA

Sufentanil: 10 times more potent than fentanyl; context-sensitive half-time faster than that of fentanyl; pharmacokinetics—slower than hydromorphone, fentanyl, and morphine during first 30 min and slower than hydromorphone and morphine over 24 hr; blood-brain equilibration rate results in peak effect between that of fentanyl (4 min) and that of hydromorphone (10 min); by ≈2 hr after bolus, neither sufentanil nor fentanyl present in active quantities in brain

Context-sensitive half-time: time required for drug levels (in effect site) to fall by 50% once drug discontinued (after having achieved constant concentration in plasma); dependent on agent and duration of exposure

Meperidine: according to speaker, “not a good analgesic”; no role in management of pain; problems include toxic metabolite (normeperidine; causes seizures); renally excreted; potent negative inotrope; causes tachycardia (developed as anticholinergic); adverse effects of drug interactions include monoamine oxidase (MAO) syndrome (when combined with MAO inhibitors); useful for shivering; good local anesthetic; peaks ≈8 min after onset; effect-site concentration decreases to 40% of peak in 2 hr

Alfentanil: less potent than fentanyl; rapid onset (peaks ≈90 sec after bolus injection); large dose causes patient to “turn to stone” for brief period; useful when placing retrobulbar blocks; rapid offset (mostly eliminated within 20 min after bolus)

Remifentanil: rapid onset; extremely rapid metabolism due to ester properties (not substrate for plasma esterases, eg, butylcholinesterase); not influenced by hepatic or renal disease; neostigmine does not affect kinetics; even neonates and premature infants have sufficient esterase metabolism (modest decrease in elderly); 50% effect-site decrement curves show maximum concentration at ≈2 min; does not accumulate with continued dosing

Methadone: “least utilized important drug in anesthesia”; give 10 to 15 mg before beginning procedure (almost routine in speaker’s practice); terminal half-life ≈1 day; do not send patient home on methadone (for acute use only); combination product (l-methadone is opioid agonist; d-methadone is NMDA antagonist); onset indistinguishable from that of hydromorphone (peaks in ≈10 min); doses rarely exceed 20 mg in acute perioperative setting; initial offset faster than expected; initially, concentrations fall relatively quickly, but hepatic metabolism associated with long half-life (potential problems with repeated doses)

Opioid antagonists: alvimopan—restricted to gut; charged nitrogen prevents passage through blood-brain barrier; methylnaltrexone—also contains charged nitrogen; additional comments—both drugs effective for managing opioid-induced constipation; neither drug reverses opioid analgesia; opioid analgesia mediated in brain and spinal cord; adverse effects of opioids—angiogenic (cancer patients on high-dose opioids more likely to die of cancer earlier); several studies suggest patients who receive perioperative opioids more likely to have cancer recurrence than those who have regional anesthetic and do not require opioids; suggests those on long-term opioids should also take peripheral opioid antagonist; ventilatory depression another side effect of opioids; Manzke (2003) found 5-hydroxytriptamine-4(a) [5HT4(a)] receptor agonist averts opioid-induced ventilatory depression without loss of analgesia; future—combinations of opioids with peripherally acting opioid antagonists may become standard