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NSAIDS, COX-2 Inhibitors  & Pain Management   Eric S Hsu, M.D. Department of Anesthesiology UCLA Pain Management Center
Definition of  Pain   <ul><li>“ An unpleasant  sensory  and  emotional  experience associated with  actual  or  potential ...
Classification of Pain Acute Chronic vs Duration Nociceptive Neuropathic vs Pathophysiology
Acute Pain  vs.  Chronic Pain Acute Chronic <ul><li>Usually accompanied by obvious tissue damage </li></ul><ul><li>Increas...
Classification of Pain <ul><li>Pain that arises from a stimulus that is outside  of the nervous system </li></ul><ul><li>P...
Classification of Pain by Pathophysiology Mixed   Type ( eg, Postoperative pain, chronic back pain) Nociceptive Pain Neuro...
Cyclooxygenase: COX-1 & COX-2   <ul><li>Constitutive </li></ul><ul><li>Present in most tissues </li></ul><ul><li>Synthesiz...
Peripheral & Central Sensitization Peripherally & Centrally Induced COX-2 Peripheral  Central  Trauma/inflammation Release...
<ul><li>Transduction </li></ul><ul><li>Transmission </li></ul><ul><li>Modulation </li></ul><ul><li>Perception </li></ul><u...
Central Sensitization COX-2 Dependent Central Modulation Woolf CJ, Salter MW. Science. 2000;288:1765-68 . C-fiber terminal...
Managing Nociceptive Pain : Multimodal Approach on Arthritis Surgical Osteotomy Arthroplasty Nonpharmacologic 1 Exercise/w...
Anti-inflammatory Effects of  Corticosteroids   <ul><li>1. Inhibition the release of  TNF-alpha, IL-1, IL-4, & IL-13 </li>...
Corticosteroids:  Potential Adverse Reactions   <ul><li>1. Fluid retention </li></ul><ul><li>2. Elevated blood pressure </...
Inhibition of Prostaglandin Biosynthesis by NSAIDs <ul><li>The first enzyme in the  prostaglandin (PG)  synthetic pathway ...
Pain Management   NSAIDs  vs. COX-2 – Specific Inhibitors Mediate inflammation, pain, and fever COX-2 – specific inhibitor...
Proposed Mechanism:   COX-1, COX-2, & COX-3 Arachidonic acid Needleman P et al.  J Rheumatol . 1997;24:6-8.  Simon LS et a...
Classification of NSAIDs as Analgesics <ul><li>Propionic acids </li></ul><ul><li>Indoleacetic acids </li></ul><ul><li>Pyrr...
Classification of NSAIDs as Analgesics <ul><li>Salicylic acids </li></ul><ul><li>Enolic acid (Oxicams) </li></ul><ul><li>N...
Classification of NSAIDs Chemical/Pharmacokinetic Subclasses <ul><li>Low potency/fast elimination </li></ul><ul><li>High p...
Pharmacology of NSAIDs <ul><li>Rapid GI absorption : peak concentrations occurring within 1-4 hours </li></ul><ul><li>High...
 
COX-2/COX-1 Selectivity Ratio <ul><li>The degree of selectivity of coxibs is measured by assaying the level of  prostaglan...
Adverse Reactions of NSAIDs <ul><li>GI : dyspepsia, gastritis, ulcer, bleeding, obstruction of small bowel </li></ul><ul><...
Aspirin vs. Other NSAIDs <ul><li>Aspirin  irreversibly inhibiting  COX-1 & COX-2 activity, the duration of effect is relat...
Acetaminophen  <ul><li>Although acetaminophen does not damage the gastric mucosa and has no platelet-aggregation toxicity,...
Acetaminophen & Hepatotoxicity <ul><li>Binding of the drug to plasma proteins is less than other NSAIDs </li></ul><ul><li>...
NSAIDs & Hepatotoxicity <ul><li>The elevations in hepatic transaminase levels induced by NSAIDs are not uncommon, although...
Risk Factors for Serious GI Complications <ul><li>History of: </li></ul><ul><ul><li>Peptic ulcer disease 2,3 </li></ul></u...
Risk of GI Complications & Death With Traditional NSAIDs   <ul><li>Risk of  GI complications  and death is  3 to10 times h...
GI Risks of NS-NSAIDs <ul><li>Quantitative assessment of safety data from randomized, controlled clinical trials, observat...
Introduction of COX-2 – Specific Inhibitors CH 3 F 3 C N N S O O NH 2 S CH 3 O O O O Celecoxib (Celebrex ® ) Rofecoxib (Vi...
COX-2 Selective Analgesics: Dosing   <ul><li>Celecoxib (Celebrex) </li></ul><ul><li>Rofecoxib (Vioxx) </li></ul><ul><li>Va...
Adjusted Hazard Estimates for Hospitalization for UGI Hemorrhage Among Elderly Using Prescribed NSAIDs   Patients Hospital...
Incidence of GDUs After 12 Weeks of Treatment Patients who are at high-risk of GI bleeding, have a history of intolerance ...
CLASS  and  VIGOR :  Symptomatic Ulcer/Ulcer   Complication Rates: Non-ASA Users VIGOR CLASS Annualized Incidence (%) Cele...
CLASS :  Clinically Significant Changes in Hct/Hgb (Decreases in Hct   10% Points and/or Hgb >2 g/dL) Diclofenac 75 mg bi...
Celecoxib: Benefits & GI Safety Studies <ul><li>Use of Celecoxib may provide </li></ul><ul><ul><li>Similar efficacy to tha...
CVD Risk Factors in Patients   General Population with & without OA OA General population without arthritis Hypertension (...
The Implications of NSAID Selectivity Adapted from Antman EM, et al.  Circulation . 2007;115:1634-1642. Bleeding Ulcer Com...
COX-2 Inhibitors & Cardiovascular System <ul><li>In clinical studies,  COX-2 inhibitors  decreased systemic prostacyclin (...
CRESCENT Trial: 24-hr Systolic BP at Baseline and Week 6 00:00=Midnight.  ABPM initiated at 09:00 ± 2 hr; morning dose adm...
Thromboembolic CV Adverse Events in CLASS (Celecoxib Study) Similar risks were  not   seen in the analogous CLASS study as...
Risk of AMI and SCD With Current Use of COX-2 Selective and NS-NSAIDs vs Remote NSAID Use Control  (remote use) Celecoxib ...
Adverse Side Effects of NSAIDs <ul><li>The three major NSAID risks-  gastrointestinal bleeding, renal failure, and congest...
Parenteral NSAID: Ketorolac (Toradol) The Only Non-Opioid Parenteral Analgesic <ul><li>A  potent analgesic  but only a  mo...
COX-2 Inhibitors & NSAIDs in Spotlight <ul><li>9-30-04 :  Rofecoxib  was voluntarily withdrawn from the worldwide market d...
Efficacy: Celecoxib vs Naproxen in OA WOMAC OA Index Composite Scores at Week 12 CELEBREX is contraindicated in patients w...
Celecoxib (Celebrex): Efficacy on OA & RA <ul><ul><li>Celecoxib has been approved for the treatment of  OA  at a dose of  ...
NSAIDs & COX-2 Inhibitor :   Cardiovascular & GI Safety <ul><li>The  GI  &  CV  safety issues associated with  NSAIDs & CO...
NSAID Therapy in Post-Rofecoxib/Valdecoxib Age Gastroprotective agent + traditional NSAID Consider non-NSAID therapy Tradi...
WHO  Three Step Analgesic Ladder   Cancer Pain Management  <ul><li>1. Non-opioid analgesics & adjuvant meds </li></ul><ul>...
NSAIDs for Low Back Pain <ul><li>A  meta-analyses  of 65 randomized & double-blind controlled trials </li></ul><ul><li>NSA...
COX Inhibitors & Primary Dysmenorrheal Pain <ul><li>11 female patients  self-medicated with either  placebo ,  25 mg of th...
NSAIDs, COX-2 Inhibitors & Bone Healing Process An Ongoing Controversy <ul><li>Selective agonists of prostaglandin E recep...
Topical or Oral Ibuprofen for Chronic Knee Pain <ul><li>282 in randomized trials & 303 in preference study </li></ul><ul><...
Celecoxib Prevents Morphine-Induced Angiogenesis, Tumor Growth and Metastasis <ul><li>Two weeks of chronic  morphine  trea...
 
Opioid Pharmacology  in Pain Management <ul><li>No ceiling effect for analgesia  ( vs. NSAIDs ) </li></ul><ul><li>Dose can...
Nonpharmacologic Therapies for Low Back Pain A Joint Clinical Guideline from American College of Physicians & American Pai...
NIH Consensus Conference on Acupuncture <ul><li>There is clear efficacy of acupuncture in </li></ul><ul><li>1. Nausea & vo...
Treatment Plans for Pain Management :   Summary including   Gender & Cultural Differences in Pain <ul><li>Address comorbid...
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  1. 1. NSAIDS, COX-2 Inhibitors & Pain Management Eric S Hsu, M.D. Department of Anesthesiology UCLA Pain Management Center
  2. 2. Definition of Pain <ul><li>“ An unpleasant sensory and emotional experience associated with actual or potential tissue damage , or described in terms of such damage . ” </li></ul><ul><li>International Association for the Study of Pain (IASP) </li></ul>Merskey and Bogduk. Classification of Chronic Pain. 1994.
  3. 3. Classification of Pain Acute Chronic vs Duration Nociceptive Neuropathic vs Pathophysiology
  4. 4. Acute Pain vs. Chronic Pain Acute Chronic <ul><li>Usually accompanied by obvious tissue damage </li></ul><ul><li>Increased autonomic nervous activity </li></ul><ul><li>Pain resolves with healing of the underlying injury </li></ul><ul><li>Serves a protective function </li></ul><ul><li>Pain that extends 3 or 6 months beyond onset or beyond the expected period of healing 1 </li></ul><ul><li>Ceases to serve a protective function 2 </li></ul><ul><li>Degrades health and functional capability 2 </li></ul><ul><li>Depressed mood 3 </li></ul>vs. 1 Turk and Okifuji. Bonica’s Management of Pain. 2001. 2 Chapman and Stillman. Pain and Touch. 1996. 3 Fields. NNBN. 1991;4:83-92.
  5. 5. Classification of Pain <ul><li>Pain that arises from a stimulus that is outside of the nervous system </li></ul><ul><li>Proportionate to the stimulation of the receptor </li></ul><ul><li>When acute serves a protective function </li></ul><ul><li>Musculoskeletal disorders are a very common cause of nociceptive pain </li></ul><ul><li>Pain initiated or caused by a primary lesion or dysfunction in the nervous system </li></ul><ul><li>No nociceptive stimulation required </li></ul><ul><li>Disproportionate to the stimulation of receptor </li></ul>Nociceptive Neuropathic vs
  6. 6. Classification of Pain by Pathophysiology Mixed Type ( eg, Postoperative pain, chronic back pain) Nociceptive Pain Neuropathic Pain Visceral Abdominal Obstetrical Head Headache Orofacial Postherpetic Neuralgia Low Back Pain CRPS CRPS = complex regional pain syndrome. Central Poststroke Pain Trigeminal Neuralgia Distal Polyneuropathy (eg, diabetic, HIV) Musculoskeletal Osteoarthritis Rheumatoid Arthritis Low Back Pain Other Postoperative Cancer Pain
  7. 7. Cyclooxygenase: COX-1 & COX-2 <ul><li>Constitutive </li></ul><ul><li>Present in most tissues </li></ul><ul><li>Synthesizes PGs that regulate physiologic processes </li></ul><ul><li>Especially important in </li></ul><ul><ul><li>gastric mucosa </li></ul></ul><ul><ul><li>kidneys </li></ul></ul><ul><ul><li>platelets </li></ul></ul><ul><ul><li>vascular endothelium </li></ul></ul>COX-1 <ul><li>Inducible (in most tissues) </li></ul><ul><li>Induced mainly at sites of inflammation by cytokines </li></ul><ul><li>Synthesizes PGs that mediate inflammation, pain, and fever </li></ul><ul><li>Constitutive expression primarily in </li></ul><ul><ul><li>brain </li></ul></ul><ul><ul><li>kidneys </li></ul></ul>COX-2 Needleman P, Isakson PC. J Rheumatol . 1997;24(suppl 49):6–8 . DuBois RN et al. FASEB J . 1998;12:1063–1073.
  8. 8. Peripheral & Central Sensitization Peripherally & Centrally Induced COX-2 Peripheral Central Trauma/inflammation Release of arachidonic acid COX-2 <ul><li>Prostaglandins E2 </li></ul>Peripheral sensitization COX-2 Samad TA, et al. Nature. 2001;410:471-5. Smith CJ, et al. Proc Natl Acad Sci USA . 1998; 95:13313-18. <ul><li>Prostaglandins </li></ul>Central sensitization Pain IL-1ß IL-6? Pain
  9. 9. <ul><li>Transduction </li></ul><ul><li>Transmission </li></ul><ul><li>Modulation </li></ul><ul><li>Perception </li></ul><ul><li>Interpretation </li></ul><ul><li>Pain Behavior </li></ul>Peripheral Nerve Ascending Pathways Adapted with permission from WebMD Scientific American ® Medicine . Physiology of Pain Perception Injury Descending Pathway Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Dorsal Horn Brain Spinal Cord
  10. 10. Central Sensitization COX-2 Dependent Central Modulation Woolf CJ, Salter MW. Science. 2000;288:1765-68 . C-fiber terminal AMPA NMDA Ca ++ Substance P Glutamate PKC P P (+) (+) (+) COX-2 induction PGE 2 (-) PGE 2 Na + Dorsal Horn Neuron
  11. 11. Managing Nociceptive Pain : Multimodal Approach on Arthritis Surgical Osteotomy Arthroplasty Nonpharmacologic 1 Exercise/weight loss Patient education Physical therapy, etc Pharmacologic 2-4 Analgesics Anti-inflammatory agents DMARDs <ul><li>RA = rheumatoid arthritis; DMARDs = disease-modifying antirheumatic drugs. </li></ul><ul><li>Harris C. Geriatrics . 1993;48:39-46. </li></ul><ul><li>Hochberg MC et al. Arthritis Rheum . 1995;38:1535-1540. </li></ul><ul><li>Hochberg MC et al. Arthritis Rheum . 1995;38:1541-1546. </li></ul><ul><li>ACR Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum . 1996;39:713-722. </li></ul>
  12. 12. Anti-inflammatory Effects of Corticosteroids <ul><li>1. Inhibition the release of TNF-alpha, IL-1, IL-4, & IL-13 </li></ul><ul><li>2. Maintain microcirculation & cell membrane integrity </li></ul><ul><li>3. ↓ the influx of inflammatory cells by inhibiting chemokines </li></ul><ul><li>4. Reduce life of certain inflammatory cells (e.g. eosinophils) by inhibiting production of IL-3, IL-5 </li></ul><ul><li>5. Up-regulate the transcription of anti-inflammatory genes </li></ul><ul><li>6. Suppress the transcription of genes involved in inflammation: cytokine genes (collagenase, nitric oxide synthase, COX-2 ,, etc.) & the genes for their receptors </li></ul><ul><li>7. Inhibit the phospholipase A2 which release AA from the cell membrane </li></ul><ul><li>8. Secondary effects by induction of enzymes that metabolize inflammatory mediators </li></ul>
  13. 13. Corticosteroids: Potential Adverse Reactions <ul><li>1. Fluid retention </li></ul><ul><li>2. Elevated blood pressure </li></ul><ul><li>3. Mood changes </li></ul><ul><li>4. Hyperglycemia </li></ul><ul><li>5. Generalized erythema and facial flushing </li></ul><ul><li>6. Menstrual irregularities </li></ul><ul><li>7. Gastric & peptic ulcer disease </li></ul><ul><li>8. Hypothalamic-pituitary-adrenal axis suppression </li></ul><ul><li>9. Cushing’s syndrome </li></ul><ul><li>10. Bone demineration </li></ul><ul><li>11. Steroid myopathy & weakness </li></ul>
  14. 14. Inhibition of Prostaglandin Biosynthesis by NSAIDs <ul><li>The first enzyme in the prostaglandin (PG) synthetic pathway is prostaglandin G/H synthase , also known as cyclooxygenase or COX </li></ul><ul><li>COX converts arachidonic acid (AA ) to the unstable intermediates PGG 2 & PGH 2 , and lead to the production of thromboxane A 2 (TXA 2 ) & a variety of prostaglandins </li></ul><ul><li>Pain that accompanies inflammation & tissue injury results from local stimulation of pain fibers & enhanced pain sensitivity ( hyperalgesia ), a consequence of ↑ excitability of central neurons in the spinal cord </li></ul><ul><li>Antihyperalgesic effects through inhibition of spinal PGs release </li></ul><ul><li>NSAIDs is usually classified as mild analgesics , particularly effective when inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli </li></ul>
  15. 15. Pain Management NSAIDs vs. COX-2 – Specific Inhibitors Mediate inflammation, pain, and fever COX-2 – specific inhibitors Protect gastroduodenal mucosa Supports platelet function COX-1 COX-2 Nonspecific NSAIDs Dubois RN et al. FASEB J . 1998;12:1063-1073. Prostaglandins Thromboxane Prostaglandins Arachidonic Acid
  16. 16. Proposed Mechanism: COX-1, COX-2, & COX-3 Arachidonic acid Needleman P et al. J Rheumatol . 1997;24:6-8. Simon LS et al. J Clin Rheumatol. 1996;2:135-40. Chandrasekharan NV et al. Proc Natl Acad Sci USA . 2002;99:13926-31. COX-2 (inducible) <ul><li>Body homeostasis </li></ul><ul><li>Stomach </li></ul><ul><li>Intestine </li></ul><ul><li>Kidney </li></ul><ul><li>Platelet </li></ul><ul><li>Inflammatory Site </li></ul><ul><li>Macrophages </li></ul><ul><li>Synoviocytes </li></ul><ul><li>Endothelial cells </li></ul>X X Selective COX-2 inhibitor COX-1 (normal constituent) X COX-3 (normal constituent) Pain Fever ?HTN ?GI <ul><li>CNS, Heart, Aorta </li></ul>Nonselective NSAID <ul><li>Normal Constituent </li></ul><ul><li>CNS </li></ul><ul><li>Kidney </li></ul><ul><li>Female U/G tract </li></ul>Glucocorticoids (block mRNA expression) X X Acetaminophen
  17. 17. Classification of NSAIDs as Analgesics <ul><li>Propionic acids </li></ul><ul><li>Indoleacetic acids </li></ul><ul><li>Pyrrolizine carboxylate </li></ul><ul><li>Heteroarylacetic acid </li></ul><ul><li>Phenylacetic acids </li></ul><ul><li>Naproxen (Alleve) </li></ul><ul><li>Ibuprofen (Motrin) </li></ul><ul><li>Ketoprofen (Orudis) </li></ul><ul><li>Oxaprozin (Daypro) </li></ul><ul><li>Flurbiprofen (Ansaid) </li></ul><ul><li>Sulindac (Clinoril) </li></ul><ul><li>Indomethacin (Indocin) </li></ul><ul><li>Etodolac (Lodine) </li></ul><ul><li>Ketorolac (Toradol) </li></ul><ul><li>Tolmetin (Tolectin) </li></ul><ul><li>Diclofenac (Voltaren, Arthrotec) </li></ul>
  18. 18. Classification of NSAIDs as Analgesics <ul><li>Salicylic acids </li></ul><ul><li>Enolic acid (Oxicams) </li></ul><ul><li>Naphthylalkanone </li></ul><ul><li>Anthranilic acid </li></ul><ul><li>Pyrazolone </li></ul><ul><li>Salsalate (Disalcid, Salflex) </li></ul><ul><li>Diflunisal (Dolobid) </li></ul><ul><li>Choline Magnesium Trilisate </li></ul><ul><li>Piroxicam (Feldene) </li></ul><ul><li>Meloxicam (Mobic) </li></ul><ul><li>Nabumetone (Relafen) </li></ul><ul><li>Mefenamic acid (Ponstel) </li></ul><ul><li>Meclofenamate (Meclomen) </li></ul><ul><li>Phenylbutazone (Butazolidin) </li></ul>
  19. 19. Classification of NSAIDs Chemical/Pharmacokinetic Subclasses <ul><li>Low potency/fast elimination </li></ul><ul><li>High potency/fast elimination </li></ul><ul><li>Intermediate potency/elimination </li></ul><ul><li>High potency/slow elimination </li></ul><ul><li>Salicylates : aspirin, salicylic acid </li></ul><ul><li>Propionic acid : ibuprofen </li></ul><ul><li>Anthranilic acid : mefenamic acid </li></ul><ul><li>Propionic acid : ketoprofen </li></ul><ul><li>Pyrrolizine carboxylate : ketorolac </li></ul><ul><li>Phenylacetic acid : diclofenac </li></ul><ul><li>Indoleacetic acid : indomethacin </li></ul><ul><li>Salicylates : diflunisal </li></ul><ul><li>Propionic acids : naproxen </li></ul><ul><li>Naphthylalkanone : nabumetone </li></ul><ul><li>Oxicams : meloxicam, piroxicam </li></ul>
  20. 20. Pharmacology of NSAIDs <ul><li>Rapid GI absorption : peak concentrations occurring within 1-4 hours </li></ul><ul><li>High protein binding (>90%): may compete with other drugs for binding </li></ul><ul><li>Hepatic metabolism: e.g. Celecoxib is a substrate for CYP 2C9 </li></ul><ul><li>Renal excretion </li></ul><ul><li>Marked variability in response </li></ul><ul><li>Try a new NSAID sequentially </li></ul><ul><li>Analgesic ceiling effect (vs. opioids) </li></ul><ul><li>Difference in properties among NSAIDs : </li></ul><ul><li>i.e. anti-inflammatory, antipyretic, and analgesic effects </li></ul>
  21. 22. COX-2/COX-1 Selectivity Ratio <ul><li>The degree of selectivity of coxibs is measured by assaying the level of prostaglandin production in blood </li></ul><ul><li>A measurement of selectivity of individual drugs is the IC 50 i.e. the ratio of the concentrations producing 50% inhibition of COX-1 & COX-2 </li></ul><ul><li>The larger the number of the ratio, the greater the selectivity for COX-2 & thus the greater the sparing of COX-1 enzyme systems </li></ul><ul><li>The following are ratios of some commonly used NSAIDs: </li></ul><ul><li>Rofecoxib-36, Celecoxib-7, Diclofenac-3, Indometacin-0.4 </li></ul>
  22. 23. Adverse Reactions of NSAIDs <ul><li>GI : dyspepsia, gastritis, ulcer, bleeding, obstruction of small bowel </li></ul><ul><li>Hepatic : hepatoxicity, altered live function test, jaundice </li></ul><ul><li>Renal : acute papillary necrosis; chronic interstitial disease, glomerulopathy; water retention & electrolyte balance </li></ul><ul><li>CV : CHF , reversal of effects of antihypertensive drugs e.g. more effect on ACE inhibitors than beta blockers & diuretics </li></ul><ul><li>Hematologica l : inhibits platelet cyclooxygenase, increased bleeding time, bone marrow suppression </li></ul><ul><li>CNS : headache, hallucination, seizure, tinnitus, aseptic meningitis </li></ul><ul><li>Hypersensitivity reactions : asthma, urticaria, vasomotor rhinitis </li></ul><ul><li>Effect on bone healing : controversial </li></ul>
  23. 24. Aspirin vs. Other NSAIDs <ul><li>Aspirin irreversibly inhibiting COX-1 & COX-2 activity, the duration of effect is related to the turnover rate of COX in different target tissues </li></ul><ul><li>The duration of effect of non-aspirin NSAIDs which competitively inhibit the active sites of the COX enzymes, relates more directly to the time course of drug (NSAIDs) disposition </li></ul><ul><li>The consequences of aspirin inhibition of platelet COX-1 (COX-2 is expressed only in megakaryocytes) last for the lifetime of the platelet </li></ul><ul><li>Inhibition of platelet COX-1-dependent TXA2 formation therefore is cumulative with repeated doses of aspirin (at least as low as 30 mg/day) & take roughly 8-12 days-the platelet turnover time-to recover once therapy has been stopped </li></ul>
  24. 25. Acetaminophen <ul><li>Although acetaminophen does not damage the gastric mucosa and has no platelet-aggregation toxicity, it can have chronic adverse renal or hepatic effects </li></ul><ul><li>A recent trial found that up to 44% of healthy persons who were randomized to 4 g/day of acetaminophen experienced serum alanine aminotransferase elevations greater than three times the upper normal limit compared with no elevation with placebo </li></ul><ul><li>Acetaminophen , alone or in combination, should therefore now be restricted to no more than 2 g/day </li></ul><ul><li>Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006: 296: 87-93 </li></ul><ul><li>Institute for Clinical Systems Improvement (ICSI). Assessment and Management of Chronic Pain. Bloomington: ICIS, 2005. Available from: www.icsi.org . Accessed August 30, 2007 </li></ul>
  25. 26. Acetaminophen & Hepatotoxicity <ul><li>Binding of the drug to plasma proteins is less than other NSAIDs </li></ul><ul><li>The mechanism of over dosage leads to hepatocellular injury & death : conversion to toxic N-acetyl-benzoquinoneimine ( NAPQI ) metabolite </li></ul><ul><li>NAPQI is eliminated rapidly by conjugation with glutathione ( GSH ) & further metabolized to a mercapturic acid & renal excretion </li></ul><ul><li>GSH become depleted in the setting of acetaminophen overdose </li></ul><ul><li>Hepatotoxicity may occur after ingestion of a single dose of 10-15 g of acetaminophen, doses of 20-25 g are potentially fatal </li></ul><ul><li>CYP induction (e.g. heavy alcohol consumption) or GSH depletion (e.g. fasting or malnutrition) ↑ the susceptibility to hepatic injury </li></ul><ul><li>Plasma transaminases become ↑ 12-36 hours after ingestion; clinical manifestation occur within 2-4 days of ingestion toxic doses </li></ul>
  26. 27. NSAIDs & Hepatotoxicity <ul><li>The elevations in hepatic transaminase levels induced by NSAIDs are not uncommon, although it occurs more often in patients with juvenile rheumatoid arthritis or systemic lupus erythematosis </li></ul><ul><li>Overt liver failure has been reported following use of many NSAIDs, including diclofenac, flurbiprofen, and sulindac </li></ul><ul><li>Sulindac has been associated with the highest incidence of cholestasis </li></ul><ul><li>All patients should be evaluated within 8-12 weeks treatment of NSAIDs </li></ul><ul><li>Garcia Rodriguez LA et al. Acute liver injury associated with NSAIDs and the role of risk factors. Arch Intern Med 1994; 154: 311-316 </li></ul><ul><li>Walker AM. Quantitative studies of the risk of serious hepatic injury in persons using NSAIDs. Arthritis Rheum 1997; 40: 201-208 </li></ul><ul><li>Helfgott SM et al. Diclofenac associated hepatotoxicity. JAMA 1990; 264: 2660-2662 </li></ul>
  27. 28. Risk Factors for Serious GI Complications <ul><li>History of: </li></ul><ul><ul><li>Peptic ulcer disease 2,3 </li></ul></ul><ul><ul><li>Upper GI bleeding 2,3 </li></ul></ul><ul><ul><li>GI hospitalization 1 </li></ul></ul><ul><li>Arthritis-related disability 1,3 </li></ul><ul><li>High-dose or multiple NSAIDs 1 </li></ul><ul><li>Older age 1-3 </li></ul><ul><li>Concurrent prednisone use 1 </li></ul><ul><li>Prior GI side effect 1 </li></ul><ul><li>History of cardiovascular disease 2,3 </li></ul><ul><li>Concomitant use of H 2 antagonists/antacids 1,3,4 </li></ul><ul><li>Fries JF. J Rheumatol . 1991;18:6–10. 2. Silverstein FE, et al. Ann Intern Med . 1995;123:241–249. 3. Simon LS, et al. Fam Med . 1996;28:204–210. 4. Singh G, et al. Arch Intern Med . 1996;156:1530–1536. </li></ul>
  28. 29. Risk of GI Complications & Death With Traditional NSAIDs <ul><li>Risk of GI complications and death is 3 to10 times higher in users of traditional NSAIDs vs. non-NSAID users </li></ul><ul><li> 107,000 hospitalizations and 16,500 deaths annually related to traditional NSAID use among people with arthritis </li></ul><ul><li>Even 1 week of traditional NSAID use can cause ulcers </li></ul>1. Hawkey CJ. BMJ . 1990;300:278-84. 2. Gabriel SE, et al. Ann Intern Med . 1991;115:787-96. 3. Henry D, et al. BMJ. 1996;312:1563-66. 4. Griffin MR, et al. Ann Intern Med. 1991;114:257-63. 5. Langman MJS, et al. Lancet. 1994;343:1075-78. 6. Singh G. Am J Med . 1998;105 (suppl 1B):31S-38S. 7. Goldstein JL, et al. Am J Gastroenterol . In press.
  29. 30. GI Risks of NS-NSAIDs <ul><li>Quantitative assessment of safety data from randomized, controlled clinical trials, observational studies, case-control studies, and case series </li></ul><ul><li>With at least 2 months of NSAID or ASA treatment: </li></ul><ul><ul><li>1 in 5 patients will have endoscopic ulcer </li></ul></ul><ul><ul><li>1 in 70 patients will have a symptomatic ulcer </li></ul></ul><ul><ul><li>1 in 150 patients will have a bleeding ulcer </li></ul></ul><ul><ul><li>1 in 1200 patients will die of a bleeding ulcer </li></ul></ul>Tramèr MR, et al. Pain . 2000;85:169-182.
  30. 31. Introduction of COX-2 – Specific Inhibitors CH 3 F 3 C N N S O O NH 2 S CH 3 O O O O Celecoxib (Celebrex ® ) Rofecoxib (Vioxx ® ) Valdecoxib (Bextra ® ) N O CH 3 S NH 2 O O Sulfone-based Sulfonamide-based Sulfonamide-based
  31. 32. COX-2 Selective Analgesics: Dosing <ul><li>Celecoxib (Celebrex) </li></ul><ul><li>Rofecoxib (Vioxx) </li></ul><ul><li>Valdecoxib (Bextra) </li></ul><ul><li>Dose 200-400 mg </li></ul><ul><li>Interval 12-24 hrs </li></ul><ul><li>Dose 12.5-50 mg </li></ul><ul><li>Interval 24 hrs </li></ul><ul><li>Dose 10-20 mg </li></ul><ul><li>Interval 12-24 hrs </li></ul>
  32. 33. Adjusted Hazard Estimates for Hospitalization for UGI Hemorrhage Among Elderly Using Prescribed NSAIDs Patients Hospitalized (%) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 60 120 180 240 295 Time From index Date (days) Mamdani et al. BMJ. 2002;325:624-627. Observational Study Nonselective NSAIDs 4.0 (2.3 to 6.9) Diclofenac + misoprostol 3.0 (1.7 to 5.6) Rofecoxib 1.9 (1.3 to 2.8) Celecoxib 1.0 (0.7 to 1.6) Controls 1.0 Rate ratio (95% CI)
  33. 34. Incidence of GDUs After 12 Weeks of Treatment Patients who are at high-risk of GI bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs, may be appropriate candidates for CELEBREX. CELEBREX should be administered at the lowest effective dose. ND=not done. * P <.001 vs all other treatments. 1. Data on file. Pfizer Inc., New York, NY; 2. Simon LS et al. JAMA . 1999;282:1921-1928. Pooled Analysis 0 5 10 15 20 25 30 Placebo 100 400 OA patients 1 (n=1215) RA patients 2 (n=1149) 50 200 Naproxen (500 mg BID) Celecoxib (mg BID) Patients with ulcer (%) * ND ND *
  34. 35. CLASS and VIGOR : Symptomatic Ulcer/Ulcer Complication Rates: Non-ASA Users VIGOR CLASS Annualized Incidence (%) Celecoxib 400 mg bid Nonselective NSAIDs Rofecoxib 50 mg qd Naproxen 500 mg bid Annual Incidence (%) 52% reduction 53% reduction P <.001 P ≤.05 Arthritis Advisory Committee; February 7, 2001. Available at http://www.fda.gov/ohrms/dockets/ac/ Silverstein et al JAMA ;2000. 284:1247-1255 Bombardier et al. N Engl J Med . 2000; 343: 1520-1528. CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib; in patients who have demonstrated allergic-type reactions to sulfonamides; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or other NSAIDs.
  35. 36. CLASS : Clinically Significant Changes in Hct/Hgb (Decreases in Hct  10% Points and/or Hgb >2 g/dL) Diclofenac 75 mg bid Ibuprofen 800 mg tid Most common side effects with CELEBREX are dyspepsia, diarrhea, and abdominal pain, and are generally mild to moderate. * P  .05 nonselective NSAIDs vs celecoxib. Pincus et al. Ann Rheum Dis. 2002;61(suppl 1):137(THU0266). Celecoxib 400 mg bid % of Patients 0 2 4 6 8 10 Non-ASA Users ASA Users * * * *
  36. 37. Celecoxib: Benefits & GI Safety Studies <ul><li>Use of Celecoxib may provide </li></ul><ul><ul><li>Similar efficacy to that of NS-NSAIDs 1-3 </li></ul></ul><ul><ul><li>Improved GI safety profiles ≤1 week and up to 6 months 1 </li></ul></ul><ul><ul><li>Improved GI tolerability 1 </li></ul></ul><ul><ul><li>Longer time to clinically significant GI events 2 </li></ul></ul><ul><ul><li>Significantly less decrease in hematocrit 2 </li></ul></ul><ul><ul><li>Significant reduction in number of lower bowel lesions 3 </li></ul></ul>1. FDA Arthritis Advisory Committee Hearing. February 7, 2001; Gaithersburg, MD; 2. Pincus et al. Ann Rheum Dis. 2002;61(suppl 1):137(THU0266); 3. Data on file. USPI Celebrex Pfizer Inc, New York, NY. As with all NSAIDs, CELEBREX should be used with caution in patients with fluid retention, hypertension, or heart failure. NSAIDs may diminish the effect of ACE inhibitors & can reduce the natriuretic effect of furosemide & thiazides.
  37. 38. CVD Risk Factors in Patients General Population with & without OA OA General population without arthritis Hypertension (>140/90 mm Hg) Total Cholesterol ( ≥240 mg/dL ) Diabetes (MD diagnosed) % of Population Singh G et al. Am J Manag Care. 2002;8:S383-S391.
  38. 39. The Implications of NSAID Selectivity Adapted from Antman EM, et al. Circulation . 2007;115:1634-1642. Bleeding Ulcer Complications Degree of Selectivity Blood Pressure Increase Discontinuation Thrombosis, Myocardial Infarction Etoricoxib Celecoxib Diclofenac Rofecoxib Naproxen Ibuprofen Discontinuation Cardiovascular Risk Gastrointestinal Risk COX-2 COX-1
  39. 40. COX-2 Inhibitors & Cardiovascular System <ul><li>In clinical studies, COX-2 inhibitors decreased systemic prostacyclin ( PGL 2 ) production in healthy volunteers. </li></ul><ul><li>Specific COX-2 inhibitors that do not inhibit platelet COX-1 might unfavorably alter the thromboxane (TxA 2 )-prostacyclin balance by inhibiting COX-2 dependent synthesis of vasoprotective prostacyclin in endothelial cells </li></ul><ul><li>↑ risk of cardiovascular complication ? </li></ul><ul><li>Hinz B, Brune K. Cyclooxygenase-2: 10 years later. </li></ul><ul><li>J Pharmacol Exp Ther 2002; 200(2):367-375 </li></ul>
  40. 41. CRESCENT Trial: 24-hr Systolic BP at Baseline and Week 6 00:00=Midnight. ABPM initiated at 09:00 ± 2 hr; morning dose administered within 5 min of initiating ABPM. 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm Hg 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm Hg 120 125 130 135 140 145 00:00 04:00 08:00 12:00 16:00 20:00 Time of Day mm hg Celecoxib Rofecoxib Naproxen Baseline Week 6 Daytime Adapted from Sowers JR, et al. Arch Intern Med . 2005;165:161-168. Daytime Daytime
  41. 42. Thromboembolic CV Adverse Events in CLASS (Celecoxib Study) Similar risks were not seen in the analogous CLASS study as they were with VIGOR. Adapted from White WB, et al. Am J Cardiol. 2002;89:425-430. Non-ASA Users ASA Users Days Days P =0.899 P =0.947 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 4.0 0 40 80 120 160 200 240 280 320 360 40 80 120 160 200 240 280 320 360 Celecoxib 400 mg BID (n=882) % of Patients NSAIDs (n=857) Celecoxib 400 mg BID (n=3105) NSAIDs (n=3124) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.5 5.0 4.0 0
  42. 43. Risk of AMI and SCD With Current Use of COX-2 Selective and NS-NSAIDs vs Remote NSAID Use Control (remote use) Celecoxib Ibuprofen Naproxen Rofecoxib >25 mg Other NSAIDs Indomethacin Diclofenac Adjusted † Odds Ratio (95% CI) 1.00 (reference) 0.86 (0.69-1.07) 1.09 (0.99-1.21) 1.18 (1.04-1.35) 1.16 (1.04-1.30) 1.33 (1.09-1.63) 1.69 (0.97-2.93) P =.01 P <.01 P =.005 Rofecoxib  25 mg 1.29 (0.93-1.79) P =.06 AMI=acute myocardial infarction; SCD=sudden cardiac death. † Adjusted for age, gender, health plan region, medical history, smoking, and medication use. Adapted from Graham DJ, et al. Lancet . 2005;365:475-481. P <.01 3.15 (1.14-8.75)
  43. 44. Adverse Side Effects of NSAIDs <ul><li>The three major NSAID risks- gastrointestinal bleeding, renal failure, and congestive heart failure- with increasing age is an important factor </li></ul><ul><li>In an average primary care group of 100, 000 , with 3500 over-65s taking NSAIDs, there will be 18 hospital admissions every year for upper GI bleeding, 10 for acute renal failure, and 22 for congestive heart failure. </li></ul><ul><li>The majority of the renal and heart failure cases would be age> 75 , NSAIDs uncover existing disease problems, dose-responsive relationship, and there are particularly association with NSAIDs with longer half-lives </li></ul><ul><li>Bandolier 2000 More on NSAID adverse effects. Online available: http://www.jr2.ox.ac.uk/bandolier/band79/b79-6.html#Heading8 4 Aug 2004 </li></ul>
  44. 45. Parenteral NSAID: Ketorolac (Toradol) The Only Non-Opioid Parenteral Analgesic <ul><li>A potent analgesic but only a moderately effective anti-inflammatory drug </li></ul><ul><li>No tolerance, withdrawal, or respiratory depression </li></ul><ul><li>Achieving peak plasma concentration in 30-50 minute </li></ul><ul><li>Elimination half life of 4-6 hours . The rate of elimination is reduced in elderly & in renal failure. </li></ul><ul><li>Inhibit platelet aggregation & promote gastric ulceration </li></ul><ul><li>Recommend to start with 30 mg , then 15 mg q 6 hours prn up to 48 hours to minimize potential significant side effects </li></ul>
  45. 46. COX-2 Inhibitors & NSAIDs in Spotlight <ul><li>9-30-04 : Rofecoxib was voluntarily withdrawn from the worldwide market due to increased CV risk for rofecoxib versus placebo in the APPROVe trial, an adenomatous polyp prevention study. </li></ul><ul><li>4-8-05 : FDA pressured Pfizer into pulling its Bextra from the market due to concerns about potential heart and skin dangers posed by Bextra. Pfizer reported sales of Bextra of $1.29 billion, Celebrex of $3.3 billion (out of total $52.52 billion company sales) in 2004. </li></ul><ul><li>4-8-05 : FDA took sweeping action to address the health risks of widely used painkillers ( NSAIDs ), calling companies to include sterner “ black box” warning of cardiovascular & gastrointestinal risks on labels. </li></ul>
  46. 47. Efficacy: Celecoxib vs Naproxen in OA WOMAC OA Index Composite Scores at Week 12 CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib; in patients who have demonstrated allergic-type reactions to sulfonamides; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or NSAIDs. * P <.05 vs placebo. WOMAC=Western Ontario and McMaster Universities. Bensen et al. Mayo Clin Proc . 1999;74:1095-1105. Placebo (n=203) Celecoxib 100 mg bid (n=197) Naproxen 500 mg bid (n=198) Greater Improvement Mean Improvement From Baseline
  47. 48. Celecoxib (Celebrex): Efficacy on OA & RA <ul><ul><li>Celecoxib has been approved for the treatment of OA at a dose of 100 mg bid/200 mg qd 1 </li></ul></ul><ul><ul><li>Celecoxib has been approved for the treatment of adult RA at a dose of up to 100-200 mg bid 1 </li></ul></ul><ul><li>All above approved doses of Celebrex have comparable efficacy with naproxen 500 mg bid 2,3 </li></ul>1. CELEBREX ® (celecoxib capsules) [package insert]. New York, NY: Pfizer Inc; 2002; 2. Bensen et al. Mayo Clin Proc. 1999;74:1095-1105; 3 . Simon et al. JAMA. 1999;282:1921-1928 . CELEBREX is contraindicated in patients with known hypersensitivity to celecoxib; in patients who have demonstrated allergic-type reactions to sulfonamides ; and in patients who have experienced asthma, urticaria, or allergic-type reactions after taking ASA or NSAIDs.
  48. 49. NSAIDs & COX-2 Inhibitor : Cardiovascular & GI Safety <ul><li>The GI & CV safety issues associated with NSAIDs & COX-2 specific inhibitors are an ever-changing landscape </li></ul><ul><li>Aspirin alone or in combination with another NSAID , or COX-2 inhibitor is a risk factor for GI events e.g. ulcer, bleeding etc. </li></ul><ul><li>CV effects of COX-2 inhibitors have been recognized </li></ul><ul><li>- avoid COX-2 inhibitors in patients with CV risk & those requiring aspirin </li></ul><ul><li>♫ Clinical data supports Naproxen (neutral for MI risk) as an NSAID of choice for pain management in patients with CV risk factors </li></ul><ul><li>It’s important to consider gastroprotective options in patients taking NSAIDs + PPIs significantly reduce the risk for GI complications </li></ul><ul><li>US FDA Arthritis Advisory Committee, 2005; Graham DJ, JAMA 2006 </li></ul>
  49. 50. NSAID Therapy in Post-Rofecoxib/Valdecoxib Age Gastroprotective agent + traditional NSAID Consider non-NSAID therapy Traditional NSAID +PPI Consider non-NSAID therapy Cardiovascular risk (consider aspirin) Traditional NSAID + PPI or Coxib +PPI Consider non-NSAID Traditional NSAID No cardiovascular risk (no aspirin) NSAID GI risk No/low NSAID GI risk Risk
  50. 51. WHO Three Step Analgesic Ladder Cancer Pain Management <ul><li>1. Non-opioid analgesics & adjuvant meds </li></ul><ul><li>2. Weak opioid analgesics plus 1 st step </li></ul><ul><li>3. Strong opioid analgesics plus 1 st & 2 nd ( Consider transdermal delivery or IV, subcutaneous PCA ) </li></ul><ul><li>Add on : Neuraxial drug delivery system, stimulatory, nerve block, neurolysis & ablative interventions </li></ul><ul><li>How about starting with ladder 3 in severe cancer pain? </li></ul>
  51. 52. NSAIDs for Low Back Pain <ul><li>A meta-analyses of 65 randomized & double-blind controlled trials </li></ul><ul><li>NSAIDs are effective for short-term symptomatic relief in acute & chronic back pain without sciatica . However, effect sizes are small </li></ul><ul><li>No specific type of NSAID is more effective than others </li></ul><ul><li>Selective COX-2 inhibitors showed fewer side effects compared to traditional NSAIDs in the RCT trials. However, COX-2 inhibitors are associated with increased CV risks in specific patient populations </li></ul><ul><li>Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Non-steroid anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev. 2008 Jan 23; (1): CD000396 </li></ul>
  52. 53. COX Inhibitors & Primary Dysmenorrheal Pain <ul><li>11 female patients self-medicated with either placebo , 25 mg of the COX-2 specific inhibitor rofecoxib , 50 mg of nonselective COX inhibitor diclofenac , or 7.5 mg of COX-2 selective inhibitor meloxicam , over 4 menstrual cycles </li></ul><ul><li>Pain was assessed by McGill Pain Questionnaire & a VAS </li></ul><ul><li>Results : Rofecoxib & diclofenac both decreased the duration of pain compared with placebo, 50% or more pain relief after each capsule </li></ul><ul><li>Meloxicam was not as effective as rofecoxib & diclofenac; 50% or more pain relief only after the third & fourth capsules vs. placebo </li></ul><ul><li>Chantler I, Mitchell D, Fuller A. The effect of three COX inhibitors on intensity of primary dysmenorrheic pain. Clin J Pain. 2008 Jan; 24(1): 39-44 </li></ul>
  53. 54. NSAIDs, COX-2 Inhibitors & Bone Healing Process An Ongoing Controversy <ul><li>Selective agonists of prostaglandin E receptors ( EP2 & EP4 ) stimulate bone repair </li></ul><ul><li>NSAIDs inhibit bone formation & prevent heterotopic ossification after hip arthroplasties or surgical fixed fractures </li></ul><ul><li>Pain management with NSAIDs or COX-2 selective inhibitors after fractures may delay the fracture healing process , but the majority of present knowledge is based on experimental data and retrospective studies </li></ul><ul><li>The data acquired so far is suggestive to recommend alternative pain treatment modalities in clinical situations where impaired bone healing is a problem , e.g. when treating non-unions of fractures, arthrodesis or osteotomies </li></ul><ul><li>Vuolteenaho K, Moilanen T, Moilanen E. Non-Steroid Anti-Inflammatory Drugs, Cyclooxygenase-2 and the Bone Healing Process. Basic & Clinical Pharmacology & Toxicology. 2007; 102: 10-14 </li></ul>
  54. 55. Topical or Oral Ibuprofen for Chronic Knee Pain <ul><li>282 in randomized trials & 303 in preference study </li></ul><ul><li>WOMAC (Western Ontario & McMaster Universities) osteoarthritis index </li></ul><ul><li>More participants changed treatments because of adverse effects in oral group </li></ul><ul><li>More participants changed treatment because of ineffectiveness in the topical group </li></ul><ul><li>Advice to use oral or topical preparations has an equivalent effect on knee pain over one year , and there are more minor side effects with oral NSAIDs </li></ul><ul><li>Topical NSAIDs may be a useful alternative to oral NSAIDs </li></ul><ul><li>Unerwood, M, Ashby D, Cross P, Hennessy E, Letley L, Martin J, Mt-Isa S, Parsons S, Vickers M, Whyte K. Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomized controlled trial & patient preference study. BMJ 2008; 336: 138-142 </li></ul>
  55. 56. Celecoxib Prevents Morphine-Induced Angiogenesis, Tumor Growth and Metastasis <ul><li>Two weeks of chronic morphine treatment at clinically relevant doses may stimulate COX-2 & PGE2 & angiogenesis in breast tumors in mice model. This is accompanied by increased tumor weight & increased metastasis & reduced survival. </li></ul><ul><li>Co-administration of celecoxib prevents these morphine-induced effects. </li></ul><ul><li>Morphine & celecoxib together provided better analgesia than either alone </li></ul><ul><li>Clinical trials of this combination for chronic & severe pain in cancer are warranted </li></ul><ul><li>Farooqui M, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumor growth, metastasis and mortality, without compromising analgesia. British Journal of Cancer 2007; 97: 1523-1531 </li></ul>
  56. 58. Opioid Pharmacology in Pain Management <ul><li>No ceiling effect for analgesia ( vs. NSAIDs ) </li></ul><ul><li>Dose can be escalated until limiting side effects are reached, then consider switching to an alternative opioid medication </li></ul><ul><li>Be careful with acetaminophen dosage with compounded opioids (weak opioids in WHO step 2 ladder) to minimize hepatotoxicity </li></ul><ul><li>Incomplete cross-tolerance among different opioids helps to explain the utility of opioid rotation in pain management </li></ul><ul><li>Wide range of patient response to individual opioids for pain control </li></ul><ul><li>No fixed opioid therapy, needs to titrate the dose </li></ul>
  57. 59. Nonpharmacologic Therapies for Low Back Pain A Joint Clinical Guideline from American College of Physicians & American Pain Society <ul><li>Systemic review of English-language studies through MEDLINE (Nov 2006) & Cochrane Database of Systematic Reviews (2006, Issue 4) </li></ul><ul><li>Chronic or subacute (>4 weeks’ duration) low back pain : good evidence that cognitive-behavioral therapy, exercise, spinal manipulation, and interdisciplinary rehabilitation are all moderately effective </li></ul><ul><li>Chronic low back pain : fair evidence that acupuncture, message, yoga (Viniyoga), & functional restoration are effective </li></ul><ul><li>Acute low back pain (<4 weeks’ duration ): only superficial heat with good evidence for moderate benefits; spinal manipulation with fair evidence for moderate benefits </li></ul><ul><li>Sciatica : evidence is insufficient to evaluate the efficacy of therapies </li></ul><ul><li>Chou R, Huffman LH ; Ann Intern Med. 2007 Oct 2; 147(7): 492-504 </li></ul><ul><li>American Pain Society; American College of Physicians </li></ul>
  58. 60. NIH Consensus Conference on Acupuncture <ul><li>There is clear efficacy of acupuncture in </li></ul><ul><li>1. Nausea & vomiting related to chemotherapy </li></ul><ul><li>2. Adult postoperative pain </li></ul><ul><li>3. Postoperative dental pain </li></ul><ul><li>There are reasonable studies showing that the use of acupuncture resulted in satisfactory treatment in </li></ul><ul><li>Addiction, stroke rehab, headache, menstrual cramps, tennis elbow, myofascial pain, fibromyalgia, asthma, osteoarthritis, low back pain, carpal tunnel syndrome </li></ul><ul><li>Acupuncture as a therapeutic intervention is widely practiced in the United States (JAMA 1998) </li></ul>
  59. 61. Treatment Plans for Pain Management : Summary including Gender & Cultural Differences in Pain <ul><li>Address comorbid conditions </li></ul><ul><li>Gender & cultural differences </li></ul><ul><li>Improve activity & function </li></ul><ul><li>Be cautious with polypharmacy </li></ul><ul><li>Consider interventional approach </li></ul><ul><li>Complementary & Alternative Treatment </li></ul>Better Quality of Life

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