Multimodal Analgesia

Rosemary C. Polomano, PhD, RN, FAAN
Associate Professor of Pain Practice
University of Pennsylvania School of Nursing
Associate Professor of Anesthesiology and Critical
Care (Secondary)
University of Pennsylvania
Clinician Educator
Hospital of the University of Pennsylvania
polomanr@nursing.upenn.edu

Objectives
• Examine pharmacological approaches to
multimodal analgesia in targeting specifcic
peripheral and central mechanisms and
pathways for pain
• Apply Critical thinking and utilize clinical
decision making to manage and treat patients
with mixed pain
• Evaluate scientific information and
incorporate evidence-based practice
guidelines in the treatment of mixed pain with
multimodal therapies.

How Pain is Transmitted and
Processed

Immunology [XIV.Physiology of Pain: Pathways and Effects on Pain Perception • Pain is a complex process mediated by multiple pathways and mechanisms in both the peripheral and central nervous systems (PNS and CNS [spinal cord and brain]) • Fundamental characterization of pain – Nociceptive/inflammatory • Activation of pain-sensitive afferent neural pathways in response to injury – Neuropathic • Abnormal pain processing due to lesions in the PNS. New York. 6. •4 . WebMD Scientific American Medicine. 2003. NY: WebMD Corporation. Gammaitoni A. Federman DD.pain]. eds. Alvarez N. In: Dale DC. CNS or both Galer B.

numb. spinal cord. electric-shock-like. diabetic neuropathy. splitting •Location: originates in internal organs or body cavity linings. poorly localized. sharp. spastic bowel. muscle.Nociceptive Pain Somatic Pain •Complaints: constant. less well-localized in bone. motor weakness •Location: originates in injury to peripheral nerve. blood vessels. chronic hepatitis Neuropathic Pain •Complaints: shooting. bone fractures. osteoarthritis. or brain. degenerative joint/spinal disease. drains. tumor-related nerve compression. achy •Location: well-localized in skin and subcutaneous tissues. central post-stroke pain . bladder distention or spasms. pericarditis. bony metastases. rheumatoid arthritis. diffuse. phantom limb pain. connective tissues •Examples: incision pain. inflammatory bowel disease. chronic stasis ulcers Visceral Pain •Complaints: cramping. burning. deep •Examples: chest or abdominal tubes. poorly localized •Examples: radiculopathy. trigeminal neuralgia. post-herpetic neuralgia. constipation. organ metastases. hiatal hernia. intestinal distention. peripheral vascular disease.

American Society of Anesthesiologists Task Force on Pain Management. Arch Intern Med. vocational and recreational function1 • Optimize health including psychological well being1 • Improve Coping Ability and relationships with others1 1. 1997. and Treatments. Chronic Pain Section. 2001. 2. 2005. 3. Anesthesiology. with prompt adjustments in the regimen for inadequately controlled pain1.2 • Reduction of pain to acceptable levels1 • Facilitation of recovery from underlying disease or injury1 • Diminish suffering. social.Treatment Goals for Acute and Chronic Pain •Acute Pain •Chronic Pain • Early intervention. 86: 995-1004.National Pharmaceutical Council Inc. •6 . Management. • Multidisciplinary pain management3 • Reassess and adjust pain management plan as needed3 • Monitor processes and outcomes of pain management3 including pain and associated emotional distress1 • Increase/restore physical. et al. Pain: Current Understandin of Assessment.165:1574-1580.Gordon DB.

.Physiology of Pain Perception Injury • Transduction Brain • Transmission • Modulation • Perception Descending Pathway • Interpretation • Behavior Peripheral Nerve Dorsal Root Ganglion Ascending Pathways C-Fiber A-beta Fiber A-delta Fiber 7 Dorsal Horn Spinal Cord Adapted with permission from WebMD Scientific American® Medicine.

Physiology of Pain: Excitatory Mediators • Glutamate – Excitatory amino acid that acts both in the periphery and on Nmethyl-D-aspartic acid (NMDA) receptors in the dorsal horn • Substance P – Released by peripheral nerves in response to injury – Also acts in spinal cord • Prostaglandins – Mediate the inflammatory process – Sensitize nociceptors .

5 .UNIVERSITY OF PENNSYLVANIA HEALTH SYSTEM HEALTH SERVICES COMPONENT Acute Tissue Injury May Lead to Chronic Pain Stimulus (acute tissue injury) Neurotransmitter Release Glutamate. 1999. impairment Chronic pain syndrome Disability Quality of life 4 (h) 7 6 8 (days) (months) (years) Stimulationproduced analgesia 2 (min) 3 Time in Seconds (logarithmic scale) Carr DB. Lancet. aspartate Enkephalin Substance P. Calcitonin gene-related peptide Dynorphin Electrophysiological Excitatory postsynaptic Responses Sensitization Wind-up potential Calcium Nitric oxide synthase Protein kinase C Intracellular Stress Responses Cholecystokinin. Neuropeptide Y Vasoactive intestinal peptide Galanin C-fos ?Bcl-2 C-jun ?Bax Sprouting Remodeling Structural Responses ?Apoptosis/ cell death Perception Aversion Avoidance Neuropsychological Responses -3 -2 (s) -1 0 1 Suffering Allodynia. Goudas LC.353:2051-2058.

UNIVERSITY OF PENNSYLVANIA HEALTH SYSTEM HEALTH SERVICES COMPONENT Dorsal Horn Central sensitization is an increased sensibility of pain in the dorsal horn Afferent Pain Fiber Spinothalamic Tract Central sensitization leads to complex mechanisms that sustain chronic pain states Adequate Pain Control Prevents Central Sensitization .

2006. et al. Reg Anesth Pain Med. Rathmell JP.Activates dormant neurons –Sustained –Neuronal –Firing –Released of excitatory amino acids –Increased sensibility –Amplification of to pain noxious process –Peripheral Sensitization 1.Pathophysiology of Pain • Prevent development of chronic pain syndromes – Poorly managed acute pain can lead to hypersensitization and persistent pain syndrome1 –Tissue Damage –Inflammatory response –. –Central Sensitization –11 .Sensitizes active neurons –.31(4 suppl 1):1–42.

31(4 suppl 1):1-42. et al. but one that is gaining increasing attention as a therapeutic framework – Evidence-based approach incorporated into guidelines • • • American Pain Society (APS)1 American Society of Regional Anesthesia and Pain Medicine (ASRA)2 American Society of Anesthesiologists (ASA)3 1. Reg Anesth Pain Med. Gordon DB.165:1574-1580. Anesthesiology. Rathmell JP. Arch Intern Med.100:1573-1581. American Society of Anesthesiologists Task Force on Acute Pain Management. 2. . 3. opioids plus NSAIDs) – Provides a way to reduce doses—and adverse effects— of individual agents – Not a new concept. 2004.Tailoring Analgesic Regimens: Adopting a Multimodal Strategy • What is multimodal therapy? – Combines classes of drugs and techniques that target more than 1 pain mechanism (eg. et al. 2005. 2006.

Multimodal Therapy: Targeting Pain Throughout the Pathway • Different classes of agents act on different parts of the pain pathway based on their receptor targets • Multimodal regimens use these differences to improve pain control • Result is a more rational approach to pain therapy .

Anesth Analg. AANA J. 2005. Zemmel MH. with an associated decrease in opioid-induced adverse effects and increase in patient satisfaction1-3 – Opioid plus gabapentin or pregabalin reduced opioid requirements. Anesthesiology. BMC Anesthesiol. 2.42(suppl 3):iii40-iii52.74:49-60.5 1. Tiippana EM. 2007. Mathiesen O. Stephens J. et al. 4. Elia N. and opioid-induced adverse effects4. 5. et al. 2003.104:1545-1556. 2006. pain.7:6. Rheumatology. 3. et al.103:1296-1304.Multimodal Strategy: Combining Classes of Agents • Foundation of multimodal analgesia is the combination of 2 or more types of medications – Generally involves adding a second class of drug to an opioid • NSAID blocks production of inflammatory mediators • Anticonvulsant inhibits propagation of pain impulses • Significant clinical evidence shows that an opioid plus another class of agent better controls pain than opioids alone – Addition of an NSAID reduced postoperative morphine use by as much as 50%. 2007. et al. .

3 Better functional status4 Descending • Anticonvulsants • Opioids • Tricyclic/SNRI antidepressants • α2-agonist (clonidine) • Distinct from polypharmacy 1. 2007. Tiippana EM.104:1545-1556. –15 . 1985-1986. et al. 3.3 Fewer side effects2. J Bone Joint Surg Am. Reuben SS.63:1979-1984. Gottschalk A. Anesth Analg. Brit J Surg. Buvanendran A. 2002. et al. safer pain therapy1 – – – Improved quality of analgesia2. 2007.Multimodal Therapy: Clinical Advantages Peripheral Central • Local anesthetics • Anticonvulsants • TCAs • Opioids • Anti-inflammatory agents • Anticonvulsants • Opioids • Tricyclic/SNRI antidepressants • α2-agonist (clonidine) • Local anesthetics • Multimodal therapy provides a way to achieve balanced. Am Fam Physician.89:1343-1358. 2001. 2.89:446-453. Smith DS. Basse L. 4.

Pharmacologic Agents Affect Pain Differently BRAIN CNS PNS Peripheral Sensitization Descending Modulation Spinal Cord Dorsal Horn Local Anesthetics Topical Analgesics Anticonvulsants Tricyclic Antidepressants Opioids Anticonvulsants Opioids Tricyclic/SNRI Antidepressants Central Sensitization Anticonvulsants Opioids NMDA-Receptor Antagonists Tricyclic/SNRI Antidepressants .

Type of surgery pain Hernia 3000 Gallbladder 1500 0 Breast Pain Thoracotomy Phantom pain Stump pain 0 20 40 60 80 100 Percent with chronic (1 year) pain 17 . Br J Anaesth. Perkins FM. 2001. 2000. Kehlet H. Anesthesiology. 2.93:1123–1133.2 • • • • Inguinal hernia: 4%–40% Mastectomy: 20%–49% Thoracotomy: up to 67% Phantom limb:up to 90% – Severity of acute pain predicts chronic pain.Multimodal Analgesia for Pain Prevention • Prevent development of chronic pain syndromes – Significant number of postoperative patients develop chronic pain1.87:88–98. although causal relationship is not fully established2 1. Macrae WA.

Lazo SS. GI irritation/bleeding. New York. 2006. acetaminophen) Principle mechanism of action is prostaglandin synthesis Impaired hemostasis. acts at the mu receptor Respiratory depression.Pharmacological Therapy for Acute and Chronic Pain Medication Class Action Side Effects Opioids Agonistic effect . cardiovascular risk. include. dry mouth. interrupts some nerve conduction Local reactions at application site Alpha-2 agonists Inhibition of NE release Sedation and hypotension Brunto LL. renal toxicity Dual-mechanism Target multiple pain mechanism Similar to opioids with better GI tolerability Anticonvulsants Decrease excitability of neurons by modulating sodium channels Sleepiness. blurred vision. NY: McGraw Hill. Parker KL. GI irritation Nonopioids (NSAIDs. nausea. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. –18 . dizziness. 11th ed. constipation Local anesthetics Modulate sodium channels. fatigue Antidepressants Inhibit both NE and serotonin reuptake Vary by class.

desipramine. amitriptyline. morphine. naproxen sodium. hydrocodone. diclofenac COX-2 selective .Drug Classes for Analgesia Drug Class Drugs Treatment Considerations NSAIDs Nonselective – ibuprofen. hydromorphone.celecoxib Associated with reduced risk of GI toxicity. opioid-like drugs Oxycodone. maprotiline Slow onset to therapeutic effects and requires dose titration to pain relief and dose adjustments to minimize side effects Co-treatment of neuropathic pain and depression SNRIs Venlafaxine. methadone. increased in the elderly Bleeding with nonselective NSAIDs COX-2 selective NSAIDs have no known effect on thromboxane-induced platelet activity Opioids. tramadol Long-acting opioids provide more consistent pain relief Start low and go slow in the elderly Tricyclic antidepressants Nortriptyline. duloxetine Co-treatment of neuropathic pain and depression Anticonvulsants Gabapentin and pregabalin Requires dose titration to pain relief and dose adjustments to minimize side effects .

Implementing Multimodal Therapy: Classes of Medication Class of Agent Opioids Target Mu opioid receptors Clinical utility Mainstay for moderate to severe pain Clinical concerns Sedation Respiratory depression Constipation Nausea/vomiting Potential for tolerance –20 .

fentanyl • Remain therapeutic mainstay for moderate to severe pain management1 • Most common agents in the class act at the mu receptor1 • Agonistic effects both in peripheral nociceptors and centrally (spinal cord and descending pathway)1 • Some severe chronic neuropathic pain conditions can be successfully managed with opioid therapy4 • Prescribed as part of multimodal and interdisciplinary treatment plan2 • Considerations – Past hx of drug or alcohol abuse – Low starting dose – Dosing spread around the clock and not prn 1. New York. 21(11): 1821. eds. 2. Kalso E. Immunology [XIV. NY: McGraw Hill. NY: WebMD Corporation. 3.45(supple 9):S22. Brunto LL. Galer BS. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. Federman DD. –21 .Does Your Patient Respond to Opioids? –Examples: morphine. Lazo SS. oxycodone. 4. Current Medical Research and Opinions. Parker KL. et al. Gammaitoni A. In: Dale DC. Galer B. 2006. 11th ed. 1995. 2003:2064. 2005. 6. Alvarez N. Pain]. New York. Neurology. WebScientific American Mediicine.

mu). mu is most relevant –22 .Opioid Analgesics • Opioids – Opioids regulate pain throughout the pathway in the • Periphery—to inhibit calcium influx and activation of nociceptors • Spinal cord—to prevent release of neurotransmitters • Ascending pathway—to block transmission • Brain—to turn on the descending pathways – Endogenous opioids include endorphins and enkephalins • Work via a lock-and-key mechanism at the opioid receptor • Of 3 types of receptors (kappa. delta.

8:181-186. .–Characteristics of Immediate. Barkin Rl. 2001. Amer J Ther.and Controlled-Release Opioids – Immediate-release opioids – Quick onset of action (within minutes) Controlled-release opioids – More stable blood levels – More appropriate for – May be more appropriate for some types of acute pain and some types of BTP – Can be used for dose finding during initial treatment persistent acute pain and chronic pain because avoids peaks and troughs – Reduced end-of-dose breakthrough pain – Inconvenient repetitive dosing – Lower potential for euphoria – Peak and trough phenomenon (due to fewer peaks) when taken as prescribed – Not ideal for chronic pain – Increased end-of-dose breakthrough pain – Increased potential for – Decreased risk for side effects (fewer peaks) – Improved compliance and quality of life euphoria and adverse effects (peaks) McCarberg BH.

When you Need Mechanism of Different Action: Methadone and Ketamine .

Methadone. Just Another Opioid? • Synthetic opioid • Indicated for detoxification and treatment of opioid addiction • Increasingly used for treatment of moderate to severe pain • Mu-opioid receptor agonist (kappa and delta) • NMDA-receptor antagonist • Inhibits reuptake of norepinephrine and serotonin • At high doses. blocks potassium channels • Cost-effective .

steady state in 3-5 days.Pharmacokinetics • Rapidly absorbed by the GI tract • Quick onset of action  30 -60 minutes (PO).5-4 hr • Lipophilic – Analgesic efficacy  6-12 hours – Elimination half-life  24-36 hours • Long and highly variable (range 5-130 hours) • Eliminated through feces and produces nontoxic metabolites with minor activity – Preferred in renal insufficiency** – Takes 4days to reach steady state . 10-20 minutes (IV). peaks in 2.

Breakthrough Pain: Definition Problems • Definition is by consensus and has arbitrary quality • Basis for definition is an acute. transitory pain over controlled baseline pain • But what definitions should apply? – – – – Timing Severity Population Treatment of baseline pain 27 .

transient pain with intensity exceeding baseline –Mercadante S. 2005. Eur J Pain. or excruciating pain.Breakthrough Pain: Definition Problems • Most stringent definition – In the cancer population. 2002. breakthrough pain is a transitory. Cancer. et al. –Svendsen KB. severe. et al.9:195-206. 28 . which lasts seconds to hours and is superimposed on a baseline pain controlled to a moderate or better intensity by an opioid regimen • Very broad definition – Any severe.94:832-839.

94:832-839.Breakthrough Pain: Definition Problems • Definitional imprecision increased by use of alternative terms – Episodic pain – Incident pain – End-of-dose failure • Incident pain also considered a subtype of breakthrough pain associated with a voluntary action • End-of-dose failure not considered to be breakthrough pain by some –Mercadante S.9:195-206. 2005. –Svendsen KB. 29 . Cancer. 2002. et al. et al. Eur J Pain.

Portenoy RK. Palliat Med. 2004.94:832-839.18:177-183. et al. Hagen NA. 1990. 2002. but may last hours • Onset usually over minutes.Breakthrough Pain: Characteristics • Phenomenology usually similar to baseline pain. but large inter-individual differences • Frequency: <1 episode/day to many per hour • Most episodes brief. Cancer. Caraceni A.41:273- 30 . but varies • 50% associated with volitional action (some nonvolitional) • May be predictable or appear without warning • May appear or worsen at end-of-dosing interval (“end-of-dose failure”) –Mercadante S. et al. Pain.

30:296-301. 2005. 31 . et al. Pharmacol Ther.Characteristics of Breakthrough Pain Characteristic Average Range Time to peak severity 3-5 minutes 10 seconds to 180 minutes Severity Severe or excruciating Mild to excruciating Duration 15-30 minutes 1 second to more than 24 hours Number of episodes per day 1-5 Less than 1 to 3600 Precipitated by event 55%-60% 52%-77% Predictable 50%-60% 41%-81% –Bennett D.

. Hagen. Pain.UNIVERSITY OF PENNSYLVANIA HEALTH SYSTEM HEALTH SERVICES COMPONENT Components of Chronic Pain Around-the-clock medication Breakthrough pain Portenoy . 1990.41:273-281.

2007. 2007.23:223- 233.29:588-601. . Wagstaff AJ. 2007. 2006. et al. Drugs.Comparison of Oral Transmucosal Fentanyl Citrate to Fentanyl Buccal Tablet –Simpson DM.. Slatkin NE. Portenoy RK. et al...66:2387-2395. Curr Med Res Opin. J Support Oncol. Clin Ther. Blick SK.5:327-334. et al.

Oral Transmucosal Opioids • Sublingual preparations: • Fentanyl sublingual (Abstral™) .

Intranasal Opioids • Intranasal fentanyl spray (Instanyl™) • Fentanyl nasal spray (PecFent™) .

Fentanyl Buccal Soluble Film (Onsolis®) –Inactive layer –Mucoadhesive (drug) layer –Delivery through the buccal mucosa –Mucosal surface –200 mcg –400 mcg –600 mcg –800 mcg –1200 mcg .

–37 . Pain Manag Nurs. reducing their numbers DuPen A. 2007.8:113-121.Is this Patient Developing Tolerance or Is Pain Worsening? • Opioid tolerance is a “shift to the right” in the dose-response curve – Higher dose required over time to maintain the same level of analgesia • Tolerance can be pharmacokinetic… – Drug or concomitant medications upregulate metabolic pathways that remove opioids from the body • …or pharmacodynamic – Desensitization • Physiological changes to the opioid receptors – Downregulation • Internalization of opioid receptors by endocytosis.

et al. –38 . 1994. 2. 9:462-473. Compton MA. 1999. set in motion anti-analgesic or hyperalgesic processes • Pain-free animals made tolerant to morphine have significantly decreased tolerance to pain1 • Opioid “tolerance” may not be a downregulation of analgesic systems. but an upregulation of hyperalgesic systems2 1. Laulin JP.Could Your Patient have Opioidinduced Hyperalgesia (OIH)? • Increased sensitivity to pain resulting from opiate administration • Opioids.89:631-636. in addition to providing analgesia. Pain Symptom Manage. Neuroscience.

Differentiating OlH from Other
Conditions
Condition

Nature of Pain

Presentation or Onset
of Pain

Response to
Opioid

Opioid Induced
Hyperalgesia

Increased sensitivity to pain; diffuse
pain, extending beyond the
distribution of pre-existing pain;
allodynia may be present

Abrupt onset with rapid
opioid escalation or highdose opioid administration

Pain worsens

Worsening Pain
Pathology

Localized to site of pre-existing pain
or new site of pathology

Variable, depending on
source of pain

Pain improves

Opioid Tolerance

Localized to site of pre-existing pain

Gradual onset

Pain improves

Opioid Withdrawal

Increased sensitivity to pain; diffuse,
extending beyond the distribution of
pre-existing pain

Abrupt with short-acting
opioids or antagonist
administration; gradual with
long-acting opioids

Pain improves

Opioid Addictive
Disease

Increased sensitivity to pain; diffuse,
may extend beyond the distribution
of pre-existing pain.

Gradual onset

Pain may improve
but functionality
may worsen

Pseudoaddiction

Localized to site or pre-existing
pain.

Variable, depending on
source of pain

Pain improves

Table adapted from Mitra 2008.
Compton, P. The OIH paradox: Can opioids make pain worse? Pain treatment topics. http://pain-topics.org/pdf/Compton-OIH-Paradox.pdf.
August 20, 2008. Accessed July 14, 2009.

–39

Moving to a Multimodal Strategy:
Dual-mechanism Analgesics
• A single medication with dual mechanisms
of action
– First in class: tramadol

• Newest dual-mechanism agent is tapentadol
– Acts on mu opioid receptors and inhibits reuptake of NE1
– Clinical trial experience
• Comparable to oxycodone in acute pain (bunionectomy)2
and in more chronic pain (up to 90 days in joint or
back pain)3
• Comparable or better pain relief than morphine in dental
surgery4
• Main side effects similar to conventional opioids
(GI, CNS), but significantly better GI profile, including
lower rate of constipation3,5

– May be associated with less tolerance1
– May be useful in patients with opioid sensitivity
4. Kleinert R, et al. J Pain. 2006;7(4 suppl 2):S44 Abstract 773.
1. Tzschentke TM et al. Drugs Future. 2006;31:1053-1061.
th
2. Oh C, et al. Presented at: American Pain Society’s 27th Annual Scientific 5. Hartrick C, et al. Presented at: American Pain Society’s 27 Annual
Scientific Meeting. 2008. Abstract 222.
Meeting. 2008.Abstract 229.
3. Oh C, et al. Presented at: American Pain Society’s 27th Annual Scientific
Meeting. 2008. Abstract 226.

–40

Tapentadol IR: Efficacy and Safety
Profile
• Nausea, vomiting and constipation were significantly
less likely with tapentadol IR
• Pain intensity showed similar efficacy for tapentadol
IR and oxycodone

1. Hale M, et al. Curr Med Res Opin. 2009;25:1095-1104.
2. Hartrick C, et al. Clinic Ther. 2009; 31:260-271.

–41

3. Poster 306. Buynak R. 2009. Poster 301. 2009. 2009. Etropolski M. Buynak R. Poster 293. Presented at: American Pain Society’s 28th Annual Scientific Meeting. Presented at: American Pain Society’s 28th Annual Scientific Meeting. et al. –42 . et al.Tapentadol ER: Improved Tolerability –Incidences of Treatment Emergent Events for Tapentadol ER and Oxycodone CR 40% Tapentadol ER 35% Oxycodone CR 25% ents –Pati 30% 20% 15% 10% 5% 0% Nausea Vomiting Constipation Dizziness Somnolence 1. Presented at: American Pain Society’s 28th Annual Scientific Meeting. 2. et al.

Implementing Multimodal Therapy: Classes of Medication Class of Agent Opioids NSAIDs Target Mu opioid receptors Prostaglandins Clinical utility Mainstay for moderate to severe pain First-line adjunct to opioids Sedation Renal impairment Clinical concerns Respiratory depression Constipation Liver impairment Nausea/vomiting GI bleeding/ ulcers Potential for tolerance Hemostasis CV risk –43 .

Classes of Pain Medications: Nonopioids • Nonsteroidal anti-inflammatory drugs (NSAIDS) – Examples: celecoxib. ketorolac – Anti-inflammatory and analgesic effects – Principal mechanism of action: inhibition of prostaglandin synthesis – Activity at peripheral nociceptors and in spinal cord – Side effects due in part to selectivity for cyclooxygenase-2 • • • • Impaired hemostasis (nonselective) GI irritation/bleeding (nonselective) Cardiovascular risk Renal toxicity • Acetaminophen – – – – Analgesic but not anti-inflammatory Less potent than NSAIDs Lacks adverse effects of NSAIDs Hepatotoxic in overdose –44 .

2. ASRA. Data on file. Vancouver.2: – Median Tmax of regular release formulation is ~45 to 60 minutes – Mean Cmax of ~10 mcg/mL (with up to 1/3rd below the therapeutic level) – Bioavailability (AUC) – 87% (tablets) to 93% (elixir) – First pass hepatic exposure • Rectal Acetaminophen3: – Median Tmax – 200 minutes – Mean Cmax of 4 to 9 mcg/mL with most failing to achieve the therapeutic level of 10 mcg/mL – Bioavailability – 50 to 80% with erratic and unpredictable absorption • IV Acetaminophen1: – Median Tmax by end of 15-minute infusion – Mean Cmax of ~27 mcg/mL with all patients above the therapeutic level – 100% bioavailability 1: Schutz et al. Canada.34(5):425-431.. Inc. April 19-22. Nielson HW. J Paediatr Child Health 1998. Poster presentation. 2010. . 2007. et al. 3: Coulthard KP.Comparative Acetaminophen Pharmacokinetics (1000 mg) • Oral Acetaminophen1. Cadence Pharmaceuticals. Schroder M.

Implementing Multimodal Therapy: Classes of Medication Class of Agent Opioids NSAIDs Local anesthetics Target Mu opioid receptors Prostaglandins Sodium channels Clinical utility Mainstay for moderate to severe pain First-line adjunct to opioids Differential (sensory) blockade Sedation Renal impairment Allergic reactions Clinical concerns Respiratory depression Constipation Liver impairment Nausea/vomiting GI bleeding/ ulcers Potential for tolerance Hemostasis CV risk –46 .

but leaves motor function unaffected – Some nerves are more readily blocked than others. Parker KL. 2006. depending on size and myelination • Interrupts pain input at the nerve roots • Associated with few adverse effects Brunton LL. may produce differential—also known as sensory—block – Interrupts some nerve conduction. Lazo SS. NY: McGraw Hill. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. New York. 11th ed.Classes of Pain Medications: Local Anesthetics Examples: lidocaine. –47 . bupivacaine • Modulate sodium channels • When administered peripherally.

A Clinical Guide to Neuropathic Pain. Clin J Pain. Galer BS. Pain. 4. 2000. 1999. 3. Topical (lidocaine patch 5%)1. Rowbotham MC. Dworkin RH. Perander J. –48 .3 Transdermal (fentanyl patch)4 Peripheral tissue activity Applied directly over painful site Minimal systemic absorption Systemic AEs rare Systemic activity Applied away from painful site Serum levels necessary Systemic AEs common Argoff CE.16(2 suppl):S62-S66. 2. Friedman E. Galer BS.80:533-538. Pharmaceutica. 1999. Duragesic [package insert].Tropical vs Transdermal Medication Delivery Systems 1.2. 2000:61-64.

4. Lidoderm (lidocaine patch 5%) [package insert]. 2002. –49 . 2000:61-64. et al. 6. In: Programs and Abstracts of the 8th World Congress on Pain. Alvarez NA. Clin J Pain. Pain.16(2 suppl):S62-S66.65:39-44. et al. Galer BS. et al. Galer BS. Rowbotham MC. 3. et al.3 – 12 h on. Programs and Abstracts of the IASP 10th World Congress on Pain. A Clinical Guide to Neuropathic Pain. 1996. 8.80:533-538.Lidocaine Patch 5% • Lidocaine 5% in pliable patch1 • Up to 3 patches applied once daily directly over painful site2. 2002. et al. Abstract 274.36:236-240. Ann Pharmacother. 2. Abstract 175-P171. 5. Pain. Rowbotham MC. 7. 1999. et al. 2000. Argoff CE. 12 h off (FDA-approved label) – Recently published data indicate 4 patches (18–24 h) safe • Efficacy demonstrated in 3 randomized controlled trials on PHN3-5 • Drug interactions and systemic side effects unlikely6-8 – Most common side effect: application-site sensitivity • Clinically insignificant serum lidocaine levels7 • Mechanical barrier decreases allodynia4 1. 1996. Gammaitoni AR.

sedation.Implementing Multimodal Therapy: Classes of Medication Class of Agent Opioids NSAIDs Local anesthetics Anticonvulsants Target Mu opioid receptors Prostaglandins Sodium channels Sodium and calcium channels Clinical utility Mainstay for moderate to severe pain First-line adjunct to opioids Differential (sensory) blockade Becoming first-line adjunct in acute pain and first-line therapy for chronic pain Sedation Renal impairment Allergic reactions CNS-related adverse effects. including dizziness. and fatigue Clinical concerns Respiratory depression Constipation Liver impairment Nausea/vomiting GI bleeding/ ulcers Potential for tolerance Hemostasis CV risk –50 .

pregabalin. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 2006. and fatigue Brunto LL. including sleepiness. dizziness. –51 . New York.Classes of Pain Medications: Anticonvulsants –Examples: gabapentin. 11th ed. Parker KL. lamotrigine • Decrease excitability of neurons by modulating sodium channels. do not act on GABA • Emerging as top-line adjunct in acute pain and first-line therapy in chronic pain • Adverse effects/limitations – Most common adverse effects are CNS related. NY: McGraw Hill. Lazo SS.

• HIV-associated neuropathy – lamotrigine • Trigeminal neuralgia – carbamazepine* – lamotrigine – oxcarbazepine • Central poststroke pain – lamotrigine .Anticonvulsant Drugs for Neuropathic Pain Disorders • Postherpetic neuralgia – gabapentin* – pregabalin * • Diabetic neuropathy – carbamazepine – phenytoin – gabapentin – lamotrigine – pregabalin * *Approved by FDA for this use. HIV = human immunodeficiency virus.

sedation.–Implementing Multimodal Therapy: Classes of Medication Class of Agent Target Clinical utility Clinical concerns NSAIDs Local anesthetics Mu opioid receptors Prostaglandins Sodium channels Mainstay for moderate to severe pain First-line adjunct to opioids Sedation Renal impairment Opioids Respiratory depression Constipation Liver impairment Nausea/vomiting GI bleeding/ ulcers Potential for tolerance Hemostasis Anticonvulsants Antidepressants Sodium and calcium channels Serotonin Differential (sensory) blockade Becoming first-line adjunct in acute pain and first-line therapy for chronic pain First-line therapy in chronic pain Allergic reactions CNS-related adverse effects. including dizziness. and fatigue Limited analgesic effect of serotoninspecific agents Norepinephrine Limited application in acute pain CV risk –53 .

and drowsiness Brunto LL. nausea.Classes of Pain Medications: Antidepressants • Tricyclics Examples: amytriptyline. 2006. agitation. desipramine – Inhibit both norepinephrine (NE) and serotonin reuptake to varying degrees – Possess other properties (eg. bupropion – Selective serotonin reuptake inhibitors (SSRIs) have not been shown to be particularly effective as pain therapy Adverse effects vary by class of agent. constipation. –54 . duloxetine. 11th ed. Parker KL. nortriptyline. New York. NY: McGraw Hill. Lazo SS. dizziness. blurred vision. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. and include dry mouth. local anesthetic-like activity) • SNRIs (serotonin norepinephrine reuptake inhibitors) Examples: venlafaxine.

2006. . Goodman & Gillman’s The Pharmacological Basis of Therapeutics.Tricyclic Antidepressants: Adverse Effects • Commonly reported AEs (generally anticholinergic): – – – – – – – – – Blurred vision Cognitive changes Constipation Dry mouth Orthostatic hypotension Sedation Sexual dysfunction Tachycardia Urinary retention –Most AEs • Amitriptyline • Doxepin • Imipramine • Nortriptyline • Desipramine –Fewest AEs –55 Brunto LL. Parker KL. NY: McGraw Hill. 11th ed. Lazo SS. New York.

3 – Aggressively manage AEs of analgesics1. Pain Manag Nurs. Dunwoody CJ. Pain Manag Nurs.9:S22-32. et al. Krenzischek DA. 2008. Polomano RC. et al.9:S11-21. avoiding gaps in analgesia2-4 – Institute proper assessment and monitoring practices2.4 – Remain informed about novel dual-mechanism analgesics and drug delivery systems1.2. 2008. et al. 2008. Pain Manag Nurs.2.2. Pain Manag Nurs. 2. 2008. 3.Multimodal Strategy: Implications for Nursing Practice • Effective and safe practices with multimodal strategies require that nurses: – Understand the rationale for combining analgesics1.4 • Mechanisms of action and pharmacodynamics • Synergistic and AEs – Ensure timely administration of all analgesics. et al.4 1.4 – Be knowledgeable about classes of analgesics1. Polomano RC.9:S3-10.9:S33-41. –56 . 4.2.

–57 . 2008. Pain Manag Nurs. et al.Drug Therapy of Chronic Pain: Implications for Future Practice • Multimodal therapy will continue to evolve through use of novel agents and technologies – Dual-mechanism agents • Increased knowledge of the physiology of pain and pharmacotherapy helps nurses safely and effectively understand and administer multimodal analgesia – Focused assessments and reassessments – More consistent and reliable dosing to reduce analgesic gaps – More options to advocate for individual patient’s treatment needs Polomano RC.9:S33-41.

Anesth Analg.Individualizing Pain Therapy: Practice Factors • Pain protocols – Consider what constitutes best clinical care • Protocols are useful tools to direct care. 2007. 58 . Vila H Jr. 2.105:10-12. 2005. not the number Treat the PATIENT. not the number • Evidence shows that the incidence of opioid-induced adverse effects increases significantly after implementing a policy to titrate opioids to a specific numeric rating scale (NRS) number1. Kehlet H. White PF. Anesth Analg.2 1.101:474-480. et al. but nurses must also apply their clinical judgment – Treat the patient.

Multimodal Analgesia For Acute Pain • Acute postoperative pain remains significantly undertreated and is associated with substantial shortand long-term consequences • Despite multiple guidance documents. barriers to the successful management of acute and chronic pain still remain • Multimodal analgesia and the avoidance of “analgesic gaps” are central to effective management of postoperative pain • Emerging treatment options may assist in removing barriers to optimal postoperative pain management .

not a symptom • “Rational” polypharmacy is often necessary • combining peripheral and central nervous system agents enhances pain relief • Treatment goals include: • balancing efficacy.Multimodal Analgesia For Chronic Pain • Chronic neuropathic pain is a disease. and tolerability • reducing baseline pain and pain exacerbations • improving function and QOL • New agents and new uses for existing agents offer additional treatment options . safety.