Pediatric Pain Pharmacotherapy Update

Transcription

1 Pediatric Pain Pharmacotherapy Update Peter N. Johnson, Pharm.D., BCPS Assistant Professor of Pharmacy Practice University of Oklahoma College of Pharmacy Adjunct Assistant Professor of Pediatrics University of Oklahoma College of Medicine

2 Objectives 1. Compare & contrast opioids versus nonopioids 2. List indications for adjuvant agents for pain management 3. Identify risk factors for IOAS 4. Provide dosing considerations for obese & overweight children IOAS = Iatrogenic opioid abstinence syndrome

3 Therapeutic Agents

4 Which of the following properties does APAP possess? A. Analgesic B. Anti-inflammatory C. Antipyretic D. A & C E. All of the above 0% 0% 0% 0% 0% Analgesic Anti-inflammat... Antipyretic A & C All of the abo... APAP = Acetaminophen

5 PAIN WHO Step-Ladder Step 1: PAIN Non-opioid +/- Adjuvants Step 2: Weak opioids +/- Non-opioids +/- Adjuvants Step 3: Potent opioids +/-Non-opioids +/- Adjuvants PAIN FREE! Mild to moderate pain Mild pain Mod to severe pain Adopted from WHO, Accessed Feb 22, 2011.

6 Overview Characteristics Non-Opioids Opioids Advantages 1. Antipyretic & analgesic effects 2. No tolerance, dependence, or withdrawal 3. Anti-inflammatory* Disadvantages 1. Posses ceiling effect 2. Agent specific AE s 1. No ceiling effect 2. Indicated for mod to severe pain 3. Multiple routes of delivery 1. Tolerance, dependence, & withdrawal occur 2. 5 general AE s *Refers to non-steroidal anti-inflammatory meds AE = Adverse events

7 Non-Opioid Analgesics Oral Agents 1. Acetaminophen 2. Ibuprofen 3. Choline magnesium trisalicylate 4. Naproxen 5. Ketoprofen IV Agents 1. Ketorolac 2. Ibuprofen (Caldolor )* + 3. Acetaminophen (Ofirmev ) *Not to be confused with ibuprofen lysine (NeoProfen ) for treatment of patent ductus arteriosus + Not FDA approved in children

8 Oral APAP Labeling Changes FDA (1/2011) requested makers of APAP combination products to to 325 mg Additional warnings will be added to prescription containing products: - Black box warning for liver injury - Warning for allergic reactions FDA = Food and Drug Administration FDA, Pharmacist s Letter/Prescriber s Letter 2011;27:

9 APAP Opioid Combinations Combination Products Acetaminophen/ hydrocodone Acetaminophen/ codeine Acetaminophen/ oxycodone Tablet Oral Dosage Forms APAP 500 mg, hydro 2.5 mg APAP 500 mg, hydro 5 mg APAP 500, 650, 750 mg & hydro 7.5 mg APAP 500, 650, 660, 750 mg & hydro 10 mg No changes APAP 500 mg & Oxy 5 mg APAP 500 mg & Oxy 7.5 mg APAP 650 mg & Oxy 10 mg Liquid Oral Dosage Forms Elixir: APAP 500 mg & hydro 7.5 mg per 15 ml Sol: APAP 325 mg & hydro 7.5 mg per 15 ml Elixir: APAP 120 mg & Codeine 12 mg per 5 ml Susp: APAP 120 mg & Codeine 12 mg per 5 ml APAP 325 mg & oxy 5 mg per 5 ml Pediatric Dosage Handbook. 15th ed

10 IV APAP Introduction FDA approved in Nov 2010 Indications for analgesia & fever Dosing: Age/Weight Initial Dosing Max Single Dose 2-12 YO 15 mg/kg q 6 hrs 12.5 mg/kg q 4 hrs < 50 kg 15 mg/kg q 6 hrs 12.5 mg/kg q 4 hrs > 50 kg 1 g q 6 hrs 650 mg q 4 hrs Max Dose/Day 15 mg/kg/dose 75 mg/kg/day (< 3.75 g/day) 750 mg/dose 75 mg/kg/day (< 3.75 g/day) 1 g/dose 4 g/day FDA = Food and Drug Administration Ofirmev [Package Insert]. San Diego, CA. Cadence Pharmaceuticals Inc, Pharmacist s Letter/Prescriber s Letter. 2011;27:

11 Pharmacokinetics Onset: 15 min following 15 min infusion C max : - Occurs 1 hr following infusion - IV C max 70% > PO C max - AUC similar between IV & PO Half-life: 2-7 hrs IV administration assoc with liver exposure C max = Concentration maximum (i.e., peak concentration) AUC = Area under the curve Ofirmev [Package Insert]. San Diego, CA. Cadence Pharmaceuticals Inc, Pharmacist s Letter/Prescriber s Letter. 2011;27:

12 Cost Comparison Agent Vial Size AWP Cost Ibuprofen (Caldolor ) Ketorolac Acetaminophen (Ofirmev ) 400 mg 800 mg 15 mg or 30 mg $9.19 $13.13 $ mg $13.00 AWP = Average wholesale price Pharmacist s Letter/Prescriber s Letter. 2009;25: Pharmacist s Letter/Prescriber s Letter. 2011;27:

13 IV APAP: Place in Therapy 2 indications: - 2 nd IV agent approved for antipyretic effects - 3 rd IV agent approved for analgesia Similar pharmacokinetics to other routes Theoretically assoc with liver toxicity IV ketorolac IV APAP

14 Which of the following properties does APAP possess? A. Analgesic B. Anti-inflammatory C. Antipyretic D. A & C E. All of the above APAP = Acetaminophen

15 PAIN WHO Step-Ladder Step 1: PAIN Non-opioid +/- Adjuvants Step 2: Weak opioids +/- Non-opioids +/- Adjuvants Step 3: Potent opioids +/-Non-opioids +/- Adjuvants PAIN FREE! Mild to moderate pain Mild pain Mod to severe pain Adopted from WHO, Accessed Feb 22, 2011.

16 Codeine Overview Weak opioid for mild to moderate pain Prodrug (morphine) Metabolism: - Hydroxylation & O-demethylation via CYP2D6 isoenzyme - Demethylation via CYP3A3/4 Pediatric Dosage Handbook. 15th ed

17 CYP2D6 Isoenzyme of the CYP P450 system Responsible for 25-30% of metabolism Poor metabolizers: - Noted in 10% of Caucasian & African American adults & children - Assoc with analgesia Ultrafast metabolizers: - Noted in 3-40% of patients taking codeine - Assoc with toxicity Pediatric Dosage Handbook. 15th ed Kennedy MJ. Pharmacotherapy Self-Assessment Program Pediatrics., 7 th ed. MacDonald N, et.al. CMAJ 2010;182:1825.

18 Codeine Associated Fatality 2 YO (13 kg) Male: - History of obstructive sleep apnea - S/p elective adenotonsillectomy Discharged on APAP/codeine: - Codeine mg/apap 120 mg q 4-6 hrs - Child found dead on post-op Day #2 Postmortem analysis: - Codeine conc= 0.7 mg/l; MS conc= 32 ng/ml - Revealed duplicate CYP2D6 alleles MS = Morphine Ciszkowski C, et.al. N Eng J Med 2009;361:827-8.

19 Pharmacogenomic Study Morphine Concentrations Morphine + Diclofenac Group (ng/ml) (n = 48) Morphine Morphine 3- glucoronide Morphine 6- glucoronide Codeine + Diclofenac Group (ng/ml) (n = 48) patients (36%) had no detectable concentrations of morphine &/or metabolites Williams DG, et.al. Br J Anaesth 2002;12:

20 Recommendations CYP 450 polymorphisms exist Extensive metabolizers & poor metabolizers have been noted Several studies have noted poor analgesic effects Routine use of codeine containing products should not be recommended Sutters KA, et.al. Pain 2004;110: Clark E, et.al. Pediatrics 2007;119:460-7.

21 Adjuvant Agents

22 Adjuvant Agent Indications Type of Pain Neuropathic pain Bone pain Burn pain Agents Selective serotonin reuptake inhibitors Tricyclic antidepressants Anti-epileptics NSAIDs Radiopharmaceuticals Antihistamines Corticosteroids Anti-epileptics Ketamine Benzodiazepines Clonidine/dexmedetomidine Tricyclic antidepressants NSAIDs = Non steroidal anti-inflammatory agents

23 Iatrogenic Opioid Abstinence Syndrome

24 Which of the following are risk factors of opioid withdrawal? A. High dose, extended duration B. Low dose, extended duration C. High dose, short duration D. Low dose, short duration High dose, ext... 0% 0% 0% 0% Low dose, exte... High dose, sho... Low dose, shor...

25 Definitions Term Physiologic Dependence (Withdrawal) Psychological Dependence Addiction Description Signs & Symptoms that manifest following abrupt discontinuation of sedatives/analgesics Need for substance for euphoric effects Complex pattern of behavior associated with abuse of a substance Addiction & psychological dependence are rare with acute pain syndrome Tobias JD. Crit Care Med 2000;28:

26 IOAS Overview Noted in 35-57% of critically-ill pts receiving sedative & analgesic agents Symptoms associated with a number of different consequences: - morbidity - hospital stay - Patient/caregiver discomfort IOAS = Iatrogenic opioid abstience syndrome Fonsmark L, et.al. Crit Care Med 1999;27: Katz R, et.al. Crit Care Med 1994;22: Cammarano WB, et.al. Crit Care Med 1998;26: Dominguez KD, et.al. Ann Pharmacother 2003;37:473-7.

27 Fentanyl Exposure as Risk Factor Total Dose < 2.5 mg/kg > 2.5 mg/kg Fentanyl Duration < 9 days > 9 days Withdrawal (n = 13) No Withdrawal (n = 10) % prediction: Duration of 5 days or fentanyl dose > 1.5 mg/kg 100% prediction: Duration of 9 days or fentanyl dose > 2.5 mg/kg Katz R, et.al. Crit Care Med 1994;22:763-7.

28 Opioids: Risk Factor Summary - Cumulative dose - Duration Concomitant use of NMB s Mechanical ventilation for > 7 days Acute respiratory distress syndrome Extracorporeal life support > 5 days NMB s = Neuromusclar blockers Katz R, et.al. Crit Care Med 1994;22: Fonsmark L, et.al. Crit Care Med 1999;27:196-9.

29 IOAS Treatment Algorithm Low Risk Moderate Risk High Risk Cumulative fentanyl dose <1.5 mg/kg Infusion duration: 5 d 1. < 3 d: D/C if pt on low dose d: - Taper by 10-15% q 6-8 hrs - Taper by 25-50% q day Tobias JD. Crit Care Med 2000;28: Honey BL, et.al. Ann Pharmaother 2009;43: Cumulative fentanyl dose >1.5 mg/kg Infusion duration: >5 d Prevention/Treatment of Withdrawal 1. Taper continuous infusion (20%) every 12 h 2. Initiate oral methadone & enteral benzodiazepine Cumulative fentanyl dose >2.5 mg/kg Infusion duration: >9 d 1. Taper continuous infusion over 2-4 wks 2. Initiate oral methadone & enteral benzodiazepines Alternative agents: 1. Phenobarbital 2. NMDA antagonists (e.g., ketamine) 3. α 2 agonists (e.g. dexmedetomidine, clonidine) 4. Opioid antagonists (e.g. naloxone)

30 Tapering: Withdrawal Outside ICU - Acute: 10-20% per day - Chronic: 10% q 3-5 days Consider converting to long-acting agent Use of opioids for controlled detoxification: - Methadone restricted for opioid detox - Approved through FDA/DEA for IOAS - Accepted for use in pain control Schuckit M. Harrison s Online: Chapter 388; Opioid drug abuse and dependence. Klipa D, et al. Applied Therapeutics: 2009; Pain and its management.

31 Which of the following are risk factors of opioid withdrawal? A. High dose, extended duration B. Low dose, extended duration C. High dose, short duration D. Low dose, short duration

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33 What initial dose of IV morphine would you recommend for an 8 YO M (wt = 81 kg) for post-op pain? A. 1 mg B. 4 mg C. 8 mg D. 16 mg 0% 0% 0% 0% 1 mg 4 mg 8 mg 16 mg

34 Obesity/Overweight Categories BMI percentile (%) CDC definition AAP Expert Committee < 85 th % Healthy weight Healthy weight 85 th - 94 th % Overweight Overweight > 95 th % Obese Obese > 99 th % N/A Severe obesity BMI = kg/m 2 BMI % based on sex, weight & height Barlow SE, et al. Pediatrics 2007;120:S Centers for Disease Control, 2008.

35 NHANES Obesity Prevalence % NHANES = National Health & Nutrition Examination Survey Ogden CL, et al. JAMA 2008;299: Centers for Disease Control, 2008.

36 95 th percentile 9 YO F w/ BMI of 23 would be classified as obese 15 YO w/ BMI 23 of would be classified as healthy weight 85 th percentile 5 th percentile

37 Overweight/Obese Admissions % 20 % th% 90-94th% 95-96th% 97-98th% >99th% 33.1% (278/839) admissions were patients 5-12 YOA w/ BMI > 85 th % Miller JL, et al. Ann Pharmacother 2010;44:35-42.

38 Wt-Based Dosing (mg/kg, mg/m 2 ) Most common dosing scheme for meds in children Method accounts for wt-based clearance Potential for over-dosing or under-dosing in overweight children Bartelink IH et.al. Clin Pharmacokinet 2006;45:

39 Medication Errors in Pediatrics Higher error rate vs adults: - Division of total daily dose - Individualized, weight-based dosing - Variations in dosing recommendations - Choice of correct concentration/dosage form - Familiarity with pediatric & adult dosing recommendations Dose errors (most common) Kaushal R, et al. JAMA 2001;285:

40 Dosing Error Evaluation Group Overdose errors 1 Underdose errors 2 * * Overweight group 2 Control group 3 * * * P = * P = Total mg/kg/day or mg/kg/dose < 90% of minimum pediatric dose or adult dose 2 Children with BMI > 85 th percentile 3 Children with BMI < 85 th percentile Miller JL, et al. Ann Pharmacother 2010;44:35-42.

41 Pharmacokinetic Changes Absorption No change Distribution adipose tissue lean body mass α 1 glycoprotein activity Metabolism Phase I reactions or unchanged Phase II reactions Elimination kidney size total body clearance & glomerular filtration rate Lee JB, et al. Orthopedics 2006; 29: 984. Wurtz R, et al. Clin Infect Dis 1997; 25: Blouin RA, et al. Antimicrob Agents Chemother 1982; 21: Blouin RA., et al. Applied Therapeutics 1992;

42 Wt-Based Correction Factors Wt-based correction factors (CF) 1 : - Dose = CF (ABW- IBW) + IBW - Proposed for aminoglycosides (CF=0.4), fluoroquinolones (CF=0.45), β-lactams (CF=0.3) Limited data evaluating PK changes in 5 obese children (cefazolin & tobramycin) 2 CF= Correction factors ABW = Actual body weight IBW = Ideal body weight PK = Pharmacokinetics Pai MP et.al. Pharmacotherapy 2007;27: Koshida R et.al. Pharmaceutical Research 1989;6:

43 What initial dose of IV morphine would you recommend for an 8 YO M (wt = 81 kg) for A. 1 mg B. 4 mg C. 8 mg D. 16 mg post-op pain?

44 Recommendations < 40 kg > 40 kg 1. < 40 kg: Utilize weight-based dosing 1. Utilize weight-based dosing 2. If > adult dose, utilize adult dosing guidelines Consider lipophilicity of the agent Consider pharmacokinetic analysis whenever possible Johnson PN, et.al. Accessed Feb 16, 2011.

45 Conclusions 1. Recognition of opioid & non-opioid properties & updates 2. Specific roles for adjuvant agents exist 3. IOAS is often misunderstood & has specific risk factors 4. Analgesic agents in overweight children may require adjustment IOAS = Iatrogenic opioid abstinence syndrome

46 Pediatric Pain Pharmacotherapy Update Peter N. Johnson, Pharm.D., BCPS Assistant Professor of Pharmacy Practice University of Oklahoma College of Pharmacy Adjunct Assistant Professor of Pediatrics University of Oklahoma College of Medicine