SCHEDULE II DRUGS PAIN MANAGEMENT Rachel Beaty Pharm

SCHEDULE II DRUGS: PAIN MANAGEMENT Rachel Beaty, Pharm. D Clinical Pharmacy Specialist, Hematology Thursday, April 14, 2016 DEPARTMENT NAME DEPARTMENT OF PHARMACY

DISCLOSURE DECLARATION • The following declare they have no relevant financial interest in relation to this activity: • Rachel Beaty, presenter • Off-label uses of medications will be disclosed during the presentation • Brand names, kept to a minimum, are used when necessary to differentiate products DEPARTMENT NAME DEPARTMENT OF PHARMACY

LEARNING OBJECTIVES 1. Interpret common pain assessment tools and behaviors associated with pain in pediatric patients 2. Review the stepwise approach for the treatment of pain in pediatric patients 3. Describe the properties of various schedule II medications used for the treatment of pain in pediatric patients DEPARTMENT NAME DEPARTMENT OF PHARMACY

DEFINITION OF PAIN • “An unpleasant sensory and emotional experience arising from actual or potential tissue damage or described in terms of such damage” • “Sensory, emotional, cognitive, and behavioral components that are interrelated with environmental, developmental, socio-cultural, and contextual factors” • Pain in children is a public health concern • Chronic pain affects 20 - 35% of children and adolescents worldwide DEPARTMENT NAME DEPARTMENT OF PHARMACY Pain. 2008; 137: 473 -477. N Engl J Med. 1982; 306: 639 -645. Geneva: World Health Organization; 2012. Pain. 2011; 152(12): 2729– 2738. Image from: http: //contemporarypediatrics. modernmedicine. com/contemporary-pediatrics/news/neurologic-complications-influenza-children.

BARRIERS TO PAIN CONTROL IN PEDIATRICS • Barriers to pediatric pain control • Misconception that infants and children do not feel pain • Lack of routine pain assessment in children • Lack of knowledge • Fears of respiratory depression or other adverse effects of analgesic medication • Misconception that preventing pain takes too much time and effort • Joint Commission on Accreditation of Healthcare Organizations (JCAHO) considers pain “the fifth vital sign” • Chronic pain that is left unaddressed can lead to emotional and psychological scars DEPARTMENT NAME DEPARTMENT OF PHARMACY Pediatrics. 2001; 108: 793 -797. Indian J Palliat Care. 2011; 17: S 70 -S 73.

BEHAVIORS ASSOCIATED WITH PAIN Acute Pain • • • Facial expression Body movement and posture Inability to be consoled Crying Groaning Chronic Pain • • • Abnormal posturing Fear of being moved Lack of facial expression Lack of interest in surroundings Undue quietness Increased irritability Sleep disruption Low mood Anger Changes in Appetite DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Indian J Palliat Care. 2011; 17: S 70 -S 73.

PAIN ASSESSMENT • Should involve one or a combination of the following approaches: Self-reporting, validated observational measures, physiological indicators, behavioral signs, and/or parent report • Children’s self report should be the primary source • Pain is primarily an internal experience • Self reported tools: Visual analog scale (VAS), numerical rating scale, faces scale, color analogs scale (CAS), poker chip scale • Faces scales are usually preferred by children DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Can J Anaesth. 2014; 61(2): 180 -7. Pediatrics. 2010; 126: e 1168 -e 1198. Image from: http: //wongbakerfaces. org/faces-download/.

CASE TS is a 3 YO female admitted for an appendectomy. She has been crying, groaning, and unable to be consoled. Which of the following is true: A. The Wong-Baker Faces Pain Rating Scale should be used to assess the patient’s pain B. The parents should be questioned regarding whether or not they feel their child is in pain C. Her pain should be assessed utilizing the Visual Analog Scale D. These actions are indicative of a normal toddler E. Both A and B DEPARTMENT NAME DEPARTMENT OF PHARMACY

TYPES OF PAIN Pain Nociceptive Somatic Neuropathic Visceral Sensory nerve damage Well-localized Poorly-localized Sharp Stabbing Cramping Tightness Burning Tingling DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. J Pain Symptom Manage. 2011; 22(5): 899 -910. Am J Manag Care. 2006; 12: S 256 -S 262.

NEUROPATHIC PAIN • Abnormal excitability in the peripheral nervous system (PNS) or central nervous system (CNS) that may persist after injury heals or inflammation subsides • Acute or chronic • Burning, shooting, tingling, or stabbing quality • Post-traumatic, post-surgical • Responds poorly to opioids • Complex regional pain syndrome DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Clin J Pain. 2006; 22: 443 -448. Arch Neurol. 2003; 60(11): 1524 -34.

MANAGEMENT OF NEUROPATHIC PAIN IN CHILDREN Medications listed are off label indications • No randomized controlled trials • Least invasive to most invasive stepwise approach • Identify and treat underlying cause • Start non-pharmacologic therapies to help manage comorbidities • Administer an opioid and/or non-steroidal anti-inflammatory (NSAID) if not contraindicated • If pain is localized, consider the addition of lidocaine 5% patch • Add low dose tricyclic-antidepressant (nortriptyline or amitriptyline) or gabapentin • Begin NMDA-receptor channel blocker such as ketamine or methadone. Consider addition of benzodiazepine, alpha agonist DEPARTMENT NAME DEPARTMENT OF PHARMACY Nortriptyline. Lexi-Drugs Online. Amitriptyline. Lexi-Drugs Online. Curr Opin Support Palliat Care. 2013; 7: 131 -138. Arch Neurol. 2003; 60(11): 1524 -34.

MANAGEMENT OF NEUROPATHIC PAIN IN CHILDREN WITH CANCER Reference Study Design Outcome Anghelescu DL et al. J Opioid Manag. 2011; 7: 353– 361. • Retrospective, single-center • Cancer patients over 5 years N= 41 Methadone was effective in treating both neuropathic and nociceptive pain unresponsive to other opioids (39% for neuropathic pain) Anghelescu DL et al. Pain Manag Nurs. 2011; 12: 82 – 94. • Retrospective, single center • Pediatric patients over 26 years N= 151 Presence of complex pain syndrome of mixed nociceptive and neuropathic pain following limb-sparing surgery for bone cancer Therapies included opioids, NSAIDS, acetaminophen-opioid combinations, postoperative continuous epidural infusion, anticonvulsants, and tricyclic antidepressants for neuropathic pain Anghelescu DL et al. Pediatr Blood Cancer 2011; 57: 1147– 1153. • Retrospective, single center • Pediatric patients with acute lymphoblastic leukemia over 20 years N= 498 35% experienced vincristine-associated neuropathic pain. There was no evidence gabapentin prevented recurrence of neuropathic pain at a mean dose of 15. 5 mg/kg/day. However, that dose may have been too low to show effect (usual max dose: 50 -70 mg/kg/day) Anghelescu DL et al Pain Manage Nurs. 2014; 15(1): 126131. • Retrospective, single center • Pediatric patients with neuropathic and nonneuropathic pain who were referred to the pain service over 3 years N= 323 56 (17%) had neuropathic pain Median age: 16 years (range 2. 2 -28. 3 years) Majority had solid tumor diagnosis (37 of 56; 66. 1 %) All patients with neuropathic pain received at least one pharmacologic intervention- most commonly opioids (97 %) followed by anticonvulsants, mainly gabapentin (90. 9 %) DEPARTMENT NAME DEPARTMENT OF PHARMACY Medications listed are off label indications

ANALGESICS FOR NEUROPATHIC PAIN • Gabapentin • Binds to alpha-2 -delta-1 subunit on presynaptic voltage-gated Ca 2+ channels modulates release of excitatory neurotransmitters • Dosed three times daily • Significant improvement in pain in adults with 3600 mg/day compared to placebo • Amitriptyline • Enhanced availability of monoamines within pathways that modulate descending pain • Inhibition of norepinephrine reuptake. Serotonergic and dopaminergic effects may also play a role • Dosed once daily DEPARTMENT NAME DEPARTMENT OF PHARMACY Gabapentin. Lexi-Drugs Online. Amitriptyline. Lexi-Drugs Online. Anaesthesia. 2002; 57: 451 -462. Arch Neurol. 2003; 60(11): 1524 -34.

CASE JT is a 19 YO AA male s/p treatment of Ewing’s sarcoma who is being seen in your clinic for a follow up appointment. He received vincristine as part of his chemotherapy regimen and has been complaining of tingling pain in his hands and feet for the past 2 weeks. What should you do? DEPARTMENT NAME DEPARTMENT OF PHARMACY

NOCICEPTIVE PAIN Acute Perioperative / Procedural Related Pain Chronic / Persisting Recurring DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012.

NONPHARMACOLOGIC TREATMENT • Useful to prevent and treat pain • Interfere with pain transmission along ascending pain pathway by introducing other excitatory messages Nonpharmacologic Treatment Music Hypnosis Heat therapy Massage therapy Distraction Aromatherapy Physical therapy DEPARTMENT NAME DEPARTMENT OF PHARMACY Emerg Med Clin North Am. 2005; 23: 393 -414.

PHARMACOLOGIC TREATMENT: TWO-STEP STRATEGY • More effective than the three step ladder (WHO 1986) • Three step ladder • Recommended use of codeine and/or tramadol as a weak opioid for the treatment of moderate pain • Two step ladder • Mild • Acetaminophen and ibuprofen • Moderate to Severe • Opioids • Morphine-drug of choice DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012.

MEDICATIONS FOR MILD PAIN • Acetaminophen • Inhibits synthesis of prostaglandins in the CNS and blocks pain impulse generation • 10 - 15 mg/kg every 6 hours • Maximum daily dose: 75 mg/kg/day • Ibuprofen • Inhibits cyclooxygenase-1 and 2 enzymes, which results in decreased formation of prostaglandin precursors thromboxane A 2 • 10 mg/kg every 6 hours • Maximum daily dose: 40 mg/kg/day DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Mc. Neil Consumer Healthcare, 2014. Acetaminophen. Lexi-Drugs Online. Ibuprofen. Lexi-Drugs Online.

OPIOIDS FOR MODERATE-SEVERE PAIN • Use of strong opioids is recommended for the relief of moderate to severe persisting pain in children • No upper dosage limit: No ceiling analgesic effect • Appropriate dose is the one that produces pain relief for the individual child • If pain is constantly present, analgesics should be administered “around the clock” while monitoring side effects DEPARTMENT NAME DEPARTMENT OF PHARMACY Clin Perinatol. 1987; 14: 911 -30. J Invest Dermatol. 1981; 76: 147 -50. Pediatrics. 2005; 115: 1494 -500. Geneva: World Health Organization; 2012.

ROUTE OF ADMINISTRATION • Utilize simplest, most effective, and least painful route • Recommend: Oral, intravenous, subcutaneous • Continuous infusions for patients requiring more steady-state opioid concentrations • Intramuscular is not preferred due to it being painful • Rectal has unreliable bioavailability DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Reg Anesth Pain Med. 1992; 24: 438 -43. Pediatr Anaesth. 1999; 9: 321 -7. Image from: http: //www. nortongethealthy. com/prescription-safety.

GENERAL MECHANISM OF ACTION • Work at opioid (µ) receptors in the CNS and PNS • Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain • Each opioid has different affinities for different receptors • Variability in response among patients DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Lexi-Drugs Online. Image from http: //opioidanalgesics. blogspot. com/2011/03/mechanism-of-action-of-opioid. html.

OPIOID PHARMACOKINETIC DIFFERENCES • Different pharmacokinetics for different age groups • First few years of life - significant changes in absorption, distribution, metabolism, and excretion • Neonates - thinner stratum corneum and greater hydration to the epidermis compared with older children • Neonates and infants - reduced ability to metabolize medications hepatically • Different pharmacokinetics for obese children • Higher volume of distribution for lipophilic medication and increased glomerular filtration rates DEPARTMENT NAME DEPARTMENT OF PHARMACY Clin Perinatol. 1987; 14: 911 -30. J Invest Dermatol. 1981; 76: 147 -50. Pediatrics. 2005; 115: 1494 -500.

SCHEDULE II OPIOIDS • Opioids are one of the oldest drugs • Opium poppy Natural Synthetic Morphine Fentanyl Hydrocodone Methadone Oxycodone Meperidine Hydromorphone Tapentadol Oxymorphone DEPARTMENT NAME DEPARTMENT OF PHARMACY Psychosomatics. 2009; 50(2): 169 -76. Image from: http: //veryshareimg. com/opium-poppy-flower. html.

Off label use in pediatrics < 2 years FENTANYL • Availability: Injectable solution, *buccal tab, *lozenge, and *transdermal patch • Rapid onset, brief duration of action • Starting dose for children 1 - 12 years • IV injection: 1 - 2 mcg/kg/dose every 30 - 60 minutes • IV infusion: 1 mcg/kg/hr • Clinical pearls: • • • 70 -100 x more potent than intravenous morphine Prolonged half-life with continuous infusion Side effect of rapid administration may produce chest wall rigidity Boxed Warning: CYP 3 A 4 interactions The parenteral preparation may be given intranasal *Should only be used in opioid tolerant patients DEPARTMENT NAME DEPARTMENT OF PHARMACY Fentanyl. Lexi-Drugs Online. Anesthesiology. 1996; 85: 1268 -75. Geneva: World Health Organization; 2012. Image from: http: //www. thepoisonreview. com/2011/06/30/whole-fentanyl-patch-ingestion-expect-the-worst/.

HYDROCODONE Off label use in pediatrics < 2 years • Availability: • Formulated with acetaminophen; capsule, oral elixir, oral solution, oral tablet • Also available as an ER abuse deterrent tablet • Starting dose children 2 - 13 years • 0. 1 - 0. 2 mg/kg/dose every 4 - 6 hours • Clinical pearls: • Rescheduled from Schedule III to Schedule II August 2014 • Since April 2014: ≤ 325 mg acetaminophen • Boxed Warning: CYP 3 A 4 interactions DEPARTMENT NAME DEPARTMENT OF PHARMACY Hydrocodone. Lexi-Drugs Online.

HYDROMORPHONE Off label use in pediatrics • Availability: Tablet, suspension, injectable solution, suppository • Starting dose for children 1 - 12 years • IV injection: 0. 015 mg/kg/dose every 3 - 6 hrs • Oral: 0. 03 -0. 08 mg/kg/dose every 3 - 4 hrs • Clinical pearls: • 5 x more potent than intravenous morphine • Preferred for patients in renal failure due to decreased amount of metabolites DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Hydromorphone. Lexi-Drugs Online. Pediatr Clin North Am. 2005; 995 -1027.

Off label use in pediatrics METHADONE • Availability: Tablet, suspension, injectable solution • Starting dose for children 1 - 12 years • Oral: 0. 1 - 0. 2 mg/kg/dose every 4 hrs for first 2 - 3 doses, then every 6 - 12 hrs • IV: 0. 1 -0. 2 mg/kg/dose every 4 hrs for first 2 -3 doses, then every 6 - 12 hrs • Clinical pearls: • • • Long half life and slow peak - steady state concentrations may take 12 days Weak N-methyl-D-aspartate (NMDA) receptor antagonism CYP 3 A 4 interactions Boxed Warning: QT prolongation Structurally similar to verapamil - calcium channel blockade DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Pharmacotherapy. 2002; 22: 1196 -9. Methadone. Lexi-Drugs Online.

Off label use in pediatrics MORPHINE • Availability: Immediate release tablet, controlled release tablet, suspension, sublingual tablet, suppository, injectable solution • Starting dose for children 1 - 12 years • Oral: 0. 2 – 0. 5 mg/kg/dose every 4 hrs • IV: 0. 1 – 0. 2 mg/kg/dose every 4 hrs • Clinical pearls: • Metabolized by glucuronidation to morphine-6 -glucuronide (active) and morphine-3 -glucuronide (inactive) • Neonates: Reduced ability to produce morphine-6 -glucuronide • Renally eliminated • Half life 1 - 3 hours in older children; 10 - 20 hours in preterm neonates • Hypotension DEPARTMENT NAME DEPARTMENT OF PHARMACY Morphine. Lexi-Drugs Online. N Eng J Med. 2002; 347: 1094 -103. Pediatr Clin North Am. 2005; 995 -1027. Geneva: World Health Organization; 2012.

OXYCODONE Off label use in pediatrics • Availability: Immediate release tablet, extended release tablet, suspension • Starting dose for children 1 - 12 years • Oral: 0. 125 – 0. 2 mg/kg/dose every 4 hrs • Clinical pearls: • Most potent oral opioid • Boxed Warning: CYP 3 A 4 interactions • Partially metabolized to an active metabolite, oxymorphone, via CYP 2 D 6 pathway • Slow or ultra-fast metabolizers may experience reduced or enhanced analgesia and dose-related side-effects DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Oxycodone. Lexi-Drugs Online.

OPIOID HYPERSENSITIVITY Phenanthrenes Phenylpiperidines Phenylheptanones Morphine Hydromorphone Codeine Hydrocodone Oxycodone Fentanyl Remifentanyl Methadone • Cross-reactivity between agents of same structural class • Investigate allergies DEPARTMENT NAME DEPARTMENT OF PHARMACY PAAPA. 2012; 25(1): 17.

GENERAL SIDE EFFECTS OF OPIOIDS Respiratory Depression Urinary Retention Nausea / Vomiting Opioids Pruritus Sedation Constipation DEPARTMENT NAME DEPARTMENT OF PHARMACY Lexi-Drugs Online. Pediatr Clin North Am. 2005; 995 -1027. Geneva: World Health Organization; 2012.

SUPPORTIVE THERAPY • Constipation: Prevention is Key • Bowel regimen: Polyethylene glycol, docusate, bisacodyl, senna, lactulose, magnesium citrate, oral naloxone • Sedation: Switch to another agent • Consider psychostimulant: Methylphenidate, dextro-amphetamie, caffeine • Nausea/vomiting • Antiemetics: Ondansetron, promethazine • Pruritus • Diphenhydramine, hydroxyzine, low-dose naloxone infusion DEPARTMENT NAME DEPARTMENT OF PHARMACY Lexi-Drugs Online. Pediatr Clin North Am. 2005; 995 -1027.

OTHER SCHEDULE II PAIN MEDICATIONS • Meperidine • Tapentadol DEPARTMENT NAME DEPARTMENT OF PHARMACY

Off label use in pediatrics MEPERIDINE • Not indicated or recommended for treatment of pain in pediatric patients • Availability: Tablet, solution, injectable solution • Low bioavailability, short duration of action, formation of an active metabolite • Risk of seizures with accumulation of active metabolite normeperidine • Higher risk with oral administration: First-pass metabolism decreases efficacy while increasing normeperidine concentrations • American Pain Society recommends restricting the use of meperidine in adults to 600 mg/day and for < 48 hours • Use in children: Drug induced rigors (off label indication), allergic to other analgesics DEPARTMENT NAME DEPARTMENT OF PHARMACY J Pediatr Pharmacol Ther. 2011; 16(3): 185 -190. Meperidine. Lexi-Drugs Online.

Off label use in pediatrics TAPENTADOL • Indications: Moderate-severe acute pain in adults • Availability: Immediate release tablets, extended release tablets • µ opioid agonist and norepinephrine reuptake inhibitor • Clinical pearls: • • Lower affinity to µ opioid receptor than morphine Less opioid receptor mediated side effects- nausea, constipation 1/3 analgesic potency as morphine Norepinephrine reuptake inhibition also contributes to analgesia DEPARTMENT NAME DEPARTMENT OF PHARMACY Anesth Prog. 2013; 60: 178 -187. Clinical trials. gov: NCT 01134536.

TAPENTADOL PEDIATRIC TRIAL Children 6 - < 18 years after scheduled surgical procedures • An efficacy and safety study of tapentadol in the treatment of post-operative acute pain requiring opioid treatment in pediatric participants Tapentadol 1 mg/kg single dose < 20 kg: 4 mg/m. L ≥ 20 kg: 20 mg/m. L • Multi-center, single-arm, open-label, single-dose trial • Primary outcome: Pharmacokinetic profile and the number of patients with adverse events DEPARTMENT NAME DEPARTMENT OF PHARMACY Clinical trials. gov: NCT 01134536.

PATIENT CONTROLLED ANALGESIA (PCA) • Programmable pump that allows patient control of intravenous analgesia • Patient can choose when to deliver a dose of opioid and achieve relief quickly • Inherent safety in the PCA - patient will fall asleep when over sedated and is unlikely to administer too much drug • Teaching is integral and essential DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Image from: http: //www. kroslakent. com/cgi-bin/shop/pid_1837. htm.

Randomized PCA DOSING TRIAL • • Higher demand dose with low constant infusion (HDLI) Total opioid utilization: Pediatrics: 3. 7 ± 1. 0 mg/kg Adults: 11. 6 ± 2. 6 mg/kg Lower demand dose with higher constant infusion (LDHI) Total opioid utilization: Pediatrics: 5. 8 ± 2. 2 mg/kg Adults: 4. 7 ± 0. 9 mg/kg 38 total patients with sickle cell disease enrolled Reduction in pain intensity during PCA treatment observed in both groups Time to improvement did not differ Hospital durations were similar for children in both groups DEPARTMENT NAME DEPARTMENT OF PHARMACY Am Jour Hematol. 2011; 86(12): E 70 -E 73

Retrospective Review PCA DOSING TRIAL #2 HDLI Total morphine: 222. 71 mg Total length of PCA: 4. 9 days Total hospital days: 5. 03 days LDHI Total morphine 355. 58 mg Total length of PCA: 6. 16 days Total hospital days: 7. 18 days • 26 patients 11 -18 years with sickle cell pain crisis • Total morphine and length of hospital stay less in high demand/low basal infusion DEPARTMENT NAME DEPARTMENT OF PHARMACY J of Pediatr Nurs. 1998; 13(1): 15 -19

Descriptive Design PCA TRIAL #3 • • • HDLI No significant change in pain rating scale Morphine: 1. 1 -1. 2 mg/kg/day LDHI Significant reduction in pain rating scale Morphine: 0. 3 -1 mg/kg/day Nursing controlled analgesia: high scheduled and low infusion No significant change in pain rating scale Morphine: 1. 1 -2. 4 mg/kg/day 13 hospitalized pediatric sickle cell patients > 8 years Amount of morphine administered was not significantly different Patients had significantly lower pain scores in LDHI group DEPARTMENT NAME DEPARTMENT OF PHARMACY J Pain Manag. 2008; 2(1): 179 -190.

MONITOR PATIENTS RECEIVING OPIOIDS • Close observation of all patients receiving opioids • Routine vital signs • Sedation scales when indicated • Particular close attention to patients • History of obstructive sleep apnea • Craniofacial anomalies • Infants who are younger than 6 months or older infants with history of apnea or prematurity • Opioid-naïve patients with continuous infusions DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012.

BREAKTHROUGH PAIN • Sudden onset, occurs for short periods of time and is severe • Distinguish between end-of-dose pain episodes, incident pain related to movement or procedure, and breakthrough pain is needed • Children with persisting pain should receive regular medication to control pain and appropriate medication for breakthrough pain DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012.

NALOXONE • Mechanism of action • Opioid antagonist that competes and displaces opioids at opioid receptor sites • Dose • 0. 1 mg/kg/dose (max: 2 mg) every 3 minutes IV, IM, Sub. Q, intraosseous (off-label), endotracheal (off-label) • 4 mg intranasal spray ; 1 mg per nostril of 1 mg/m. L injection (off-label) • Clinical pearls: • Caution to avoid withdrawal syndrome after prolonged administration of opioids and in opioid tolerant children, cardiovascular disease, post-operative patients • May be given continuously for treatment of opioid induced pruritus (off-label) • Dose: 0. 25 mcg/kg/hour DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Naloxone. Lexi-Drugs Online. Image from: https: //www. statnews. com/2015/11/18/fda-nasal-spray-overdose/.

PROLONGED RELEASE VS. IMMEDIATE RELEASE • Immediate release: First line • Prolonged release: Recommended to be available if patient can afford medication • Insufficient evidence to support prolonged release over immediate release morphine. Studies in adults showed that immediate and prolonged release morphine formulations are equivalent for pain relief DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Cochrane Database Syst Rev. 2007; 4: 1 -57.

OPIOID SWITCHING AND ROTATION • Opioid Switching - changing to an alternative opioid because of an inadequate analgesic effect and/or dose-limiting side-effects and to improve outcomes • Recommended in presence of inadequate analgesic effect with intolerable side -effects • Utilize the equianalgesic dosing table • Opioid Rotation - changing between different opioids in a set schedule to prevent potential adverse effects and limit dose escalation • Routine rotation of opioids is not recommended • Optimal titration of opioids before switching to another agent DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012 J Pain Sympton Manage. 2009; 38(3): 418 -425

CONVERTING BETWEEN OPIOIDS • General process for switching opioids • Determine 24 -hr opioid requirement • Calculate equianalgesic dose of new opioid • Convert to desired formulation of new opioid • Incomplete cross-tolerance • Tolerance to opioids does not occur to the same extent with each drug • If goal is true equianalgesic conversion, reduce dose by ~20% when switching from one opioid to another DEPARTMENT NAME DEPARTMENT OF PHARMACY

EQUIANALGESIC DOSING Agent Approximate Equianalgesic Dose (mg) IV PO Morphine 10 30 Hydromorphone 1. 5 7. 5 Fentanyl 0. 1 -- -- 20 Oxycodone DEPARTMENT NAME DEPARTMENT OF PHARMACY Lexi-Drugs Online.

PARENTERAL AND ORAL EQUIANALGESIC DOSES Opioid (Parenteral : Oral) Morphine 1: 2 – 1: 3 Hydromorphone 1: 2 – 1: 5 Methadone 1: 1 – 1: 2 Example: 2 mg IV morphine = 4 to 6 mg PO morphine DEPARTMENT NAME DEPARTMENT OF PHARMACY Geneva: World Health Organization; 2012. Lexi-Drugs Online.

EXAMPLE CONVERSION Hydromorphone PCA Continuous 0. 06 mg/hr + demand 0. 2 mg q 10 min PRN Patient has received 12 demand doses in past 24 hr Convert to equianalgesic oral morphine regimen DEPARTMENT NAME DEPARTMENT OF PHARMACY

CASE BC is a 15 yo male with Hb. SS admitted to the floor with a VOC. He was started on a morphine PCA but has been complaining of itching. Which of the following is appropriate: A. B. C. D. Order a low dose naloxone infusion for the patient Switch the PCA from morphine to hydromorphone Scheduled hydroxyzine to be given with the morphine Any of the above DEPARTMENT NAME DEPARTMENT OF PHARMACY

TOLERANCE, DEPENDENCE, ADDICTION • Tolerance: Body becomes accustomed to certain doses of the medicine and needs a higher dose to obtain the same effect • Patients who receive synthetic opioids are more likely to develop tolerance • Treatment: Increase the dose, decrease the interval, switch agents • Dependence: Behavioral and cognitive phenomenon including a strong desire to take the psychoactive drug • Addiction: Persistent need to obtain an opioid medication for its euphoric effects, which often involves criminal activity to obtain the agent DEPARTMENT NAME DEPARTMENT OF PHARMACY Crit Care Med. 2000; 28: 2122 -32. Geneva: World Health Organization; 2012.

WITHDRAWAL • Withdrawal signs/symptoms: Tachypnea, tachycardia, fever, sweating, hypertension, diarrhea • 35 -52% of critically ill children and infants develop withdrawal due to long-term opioid use • Risk for withdrawal increases with long duration and high dosages of opioids • To prevent: Taper opioid dose • 7 - 14 days: Decrease by 10 - 20% of original dose every 8 hours • > 14 days: Decrease dose by 10 - 20% of original dose weekly DEPARTMENT NAME DEPARTMENT OF PHARMACY Ann Pharmacother. 2009; 431506 -11. Geneva: World Health Organization; 2012. Image from http: //www. roxyaddict. com/blog/.

REASSESSMENT OF PAIN • How did the intervention impact the patient’s report of pain (or behavior)? • Is the patient experiencing adverse effects from opioids? • Constipation - modify bowel regimen • Pruritus with continuous opioid - low-dose naloxone drip • Does patient require adjunctive agent in addition to opioids? DEPARTMENT NAME DEPARTMENT OF PHARMACY

CASE EF is an 18 -yr old patient with refractory rhabdomyosarcoma who is currently on palliative chemotherapy and was admitted for worsening pain. His current pain medications include: Hydromorphone PCA and Methadone PO. The provider initiated gabapentin for tingling/burning sensations in lower extremities and the oral methadone dose was increased 2 days ago, but patient’s pain is still not controlled. She wants to increase the methadone dose. What do you tell her? DEPARTMENT NAME DEPARTMENT OF PHARMACY

CASE Patient AB is a 18 yo female who is followed in your clinic for sickle cell disease. Of note, she has missed the majority of her appointments over the past two years. Based on your exam and AB’s report of her pain, she needs a pain medication for as-needed treatment of pain at home. The patient states she responds well to Lortab®, you should A. Have the MD write a prescription for Lortab®, as it is a Schedule-II medication and requires a triplicate prescription B. Inform the patient that Lortab® is formulated with 500 mg acetaminophen and is no longer available C. Call Lortab® in to the patient’s pharmacy D. None of the above DEPARTMENT NAME DEPARTMENT OF PHARMACY

SUMMARY • Pain is subjective – not all patients are alike • Pain should be assessed and managed consistently and with an interdisciplinary approach • A two-step approach to treating pain should be employed • Selection of primary and adjunctive agents for pain depends on medication properties… and the patient! DEPARTMENT NAME DEPARTMENT OF PHARMACY

COMMENTS/QUESTIONS? DEPARTMENT NAME