1 DOSING STRATEGIES MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

2  GUIDELINES  BARRIERS HEALTHCARE PROFESSIONAL PATIENTS  PAIN  OPIOIDS BACKGROUND

3 GUIDELINES STEP 1 STEP 3 STEP 2 PAIN SEVERITY NON-OPIOID ANALGESICS ± ADJUVANT WEAK OPIOID ANALGESICS ± NON-OPIOID ANALGESICS ± ADJUVANT POTENT OPIOID ANALGESICS ± NON-OPIOID ANALGESICS ± ADJUVANT WALSH ET AL SUPP. CANC. THER. 2004

4  INADEQUATE ASSESSMENTS  FAILURE TO PRESCRIBE  INAPPROPRIATE OPIOID USE HEALTHCARE PROFESSIONAL PATIENTS  UNDER-REPORT  COMPLIANCE

5  LOCATION  TEMPORAL PATTERN (CP / IP)  INTENSITY  QUALITY  AGGREVAT / ALLEVIATING FACTORS  MEDICATION  IMPACT  ASSOCIATED FACTORS (ANXIETY / DEPRESSION) PAIN HISTORY

6 TEMPORAL PAIN PATTERN Incident Non-Incident Mixed Incident Non-Incident Mixed EODF Intermittent with Continuous Pain (BP) Continuous Pain Alone (CP) Continuous Pain Intermittent Pain Alone (NBP) Intermittent Pain (IP) Cancer Pain

7 PAIN PATHOPHYSIOLOGY VISCERAL SOMATIC NEUROPATHIC CANCER PAIN MIXED

8  MORPHINE (MU AGONIST)  FENTANYL (MU AGONIST)  HYDROMORPHONE (MU AGONIST)  OXYCODONE (MU AND KAPPA AGONIST)  METHADONE (MU AND DELTA AGONIST) OPIOID CHOICES

9 ADJUVANTS AND INTERVENTIONS ADJUVANTSINTERVENTIONS  ACETAMINOPHEN  BISPHOSPHONATES  CORTICOSTEROIDS  GABAPENTIN  NERVE BLOCK  KYPHOPLASTY  IRRIDIATION

10  GUIDELINES (WHO LADDER)  BARRIERS  PAIN HISTORY  OPIOIDS SUMMARY

11 PAIN EMERGENCY

12  OPIOID LOADING (OPIOID NAÏVE / EXPER.) FREQUENT SMALL DOSES SHORT ACTING OPIOID  GOALS PAIN CONTROL TOXICITY OPIOID LOADING

IV OPIOID LOADING

14  DOSE √ 1 MG MORPHINE √ 0.2 MG HYDROMORPHONE √ 20 MICGR FENTANYL  FREQUENCY √ EVERY MINUTE X 10; RESPITE 5 MIN; REPEAT IV OPIOID LOADING

SC AND ORAL OPIOID LOADING IV SC ORAL 1MG / 1 MIN 5MG / 30 MIN 2 MG / 5 MIN

16  IV ROUTE IS PREFERRED  FIXED DOSE INTERVAL STRATEGY √ 2-4 MG IV MORPHINE √ EVERY 2 HOURS UNTIL PAIN IMPROVES CARDIO-PULMONARY INSTABILITY WALSH ET AL SUPP. CANC. THER. 2004

17  ALTERNATIVE LOADING STRATEGY: ORAL  DOUBLE ORAL RESCUE DOSE (RD)  GIVE EVERY 30 MINS UNTIL PAIN CONTROL PATIENT ON CHRONIC OPIOID 2 X 5MG = 10 MG

18  TOTAL IV (SC) OPIOID PAST 24 HOURS √ ATC √ RD (FOR NON-INCIDENT PAIN)  CALCULATE THE HOURLY DOSE  LOADING √ DOSE: 1ST 2 X HOURLY THEN HOURLY DOSE √ FREQUENCY: EVERY 15 MINS PAIN CONTROL ALTERNATIVE STRATEGY: IV (SC) 24 MG/ 24HRS = 1 MG 24 MG 2 MG THEN 1 MG

19  ACUTE ONSET OF EXCRUCIATING PAIN OPIOID LOADING √ IV √ SC √ ORAL  SEVERELY ILL  ALTERNATE STRATEGY SUMMARY

20 OPIOID (OVERDOSE) EMERGENCY

21  INDICATIONS FOR NALOXONE: √ PATIENT UN-RESPONSIVE √ RR < 10 / MIN WITH EVIDENCE OF INADEQUATE VENTILATION (LOW OXYGEN SATURATION) TREATMENT OF OPIOID OVERDOSE

22  STOP OPIOID ADMINISTRATION  PREPARE NALOXONE: NP VIAL OF NALOXONE (0.4MG/ML) + 9 ML SALINE = 40 MICG / ML NALOXONE  FLOW-CHART PROTOCOL

23 Opioids Evaluate every 3 minutes: Responsive And RR > 10/min Observation for at least 4 hours 1 ml NP (40MICG) YES NO START OPIOIDS AT LOWER DOSE WITH ONSET OF PAIN Naloxone Infusion: Sum of Doses Given / hour Observation for at least 24 hours

24 STARTING ATC AND RD THERAPY

25 OPIOID NAÏVE IVORAL ATC1 MG / 1 H15 MG M / 12 H RD1 MG / 2 H5 MG M / 4 H RD = 5% - 15% OF 24 HR ATC DOSE

26 FRAIL / ORGAN DYSFUNCTION IVORAL ATC0.5 MG / 1 H15 MG M / 12 H RD0.5 MG / 2 H5 MG M / 4 H RD = 5% - 15% OF 24 HR ATC DOSE

27 OPIOID TITRATION FOR CONTIUOUS PAIN (NO S/E)

28

29  ASSESSMENT EVERY 24 HOURS √ PAIN SEVERITY / RELIEF √ DURATION OF RELIEF √ INTERFERENCE WITH SLEEP AND ACTIVITY √ SIDE EFFECTS TITRATION FOR PAIN CONTROL

30  NEW ATC DOSE / 24 HRS =  PAST 24 HR OPIOID DOSE + (30% TO 50%) √ ATC PAST 24 HOURS √ RD (FOR NON-INCIDENT PAIN) PAST 24H ATC DOSE TITRATION

31  PAST 24 HOURS √ ATC M = 40MG √ RD M = 5 MG (5MG X 6 = 30 MG) √ TOTAL = ATC + RD = = 70 MG EXAMPLE NEW ATC DOSE  (30% TO 50%) = (21 TO 35) 30 MG  NEW ATC / 24HRS = = 100MG / 24

32 OPIOID TITRATION INCIDENT AND NON-INCIDENT PAIN (NO S/E)

33  MILD SEDATION  NAUSEA  VOMITING  CONSTIPATION / DRY MOUTH / URINE RETENTION  VISUAL / TACTILE HALLUCINATIONS MANIFESTATIONS

34  NEW RD √ IF OLD RD < 50% RELIEF INCR. RD BY 100% √ IF OLD RD = 50% - 75% INCR. RD BY 50% √ IF 100% RELIEF BUT PAIN RETURN (0.5 HRS) INCR. RD BY 100% TITRATING RD

35  GOAL √ < 4 √ > 4 ADD THE RD TO THE ATC DOSE NON-INCIDENT PAIN  NEVER ADD RD TO ATC  PRE-EMPTIVE DOSING INCIDENT PAIN

36  DEFINITION  STRATEGIES: √ INCREASE ATC DOSE √ INCREASE ATC FREQUENCY √ INCREASE RD (50%) END OF DOSE FAILURE

37 SIDE EFFECTS

38  TOLERANCE  PROPHYLAXIS  CHECK MEDICATION / HYDRATION  ATC VS. RD  S/E SHOULD BE TREATED  DOSE LIMITING S/E (GI, CNS) SIDE EFFECTS

39  ATC = ↓ DOSE ( 30%) + SAME RD  RD = ↓ DOSE ( 50%) + ADJUVANT + SAME ATC CONTROLLED PAIN  OPIOID ROTATION  SYMPTOMATIC TREATMENT OF S/E  ADJUVANT + ↓ DOSE (30-50%) UNCONTROLLED PAIN

40 CHRONIC DOSING

41  PARENTERAL ATC PAST 24 HOURS  MULTIPLY BY 3 (FOR MORPHINE)  ORAL ATC 24 HOUR DOSE  DIVIDED ACCORDING TO DOSING FREQUENCY  FOLLOW UP 48 HOURS ORAL CONVERSION & CHRONIC DOSING

42  PAST 24 HR ATC IV MORPHINE DOSE = 30MG  ORAL ATC = 30 X 3 = 90 MG / 24 HRS  IF SRM ( / 12 HRS) = 90 / 2 = 45 MG / 12 HRS  IF SRM ( / 8 HRS) = 90 / 3 = 30 MG / 8 HRS  IF IRM ( / 4 HRS ) = 90 / 6 = 15 MG / 4 HOURS EXAMPLE

43  PAIN EMERGENCY  OPIOID OVERDOSE  START OPIOID THERAPY  TITRATE OPIOIDS (ATC & RD)  STARTING LONG TERM REGIMEN SUMMARY

44 SPECIAL SITUATIONS

45  ASSESS CAREFULLY / CONSULT CAREGIVER  ENSURE CONTINUOUS ANALGESIA EVEN IF PATIENT UNABLE TO COMMUNICATE  ALTERNATE ROUTES  GIVE SPECIFIC ORDERS NOT TO WITH HOLD OPIOIDS EVEN IN FALLING BP OR CHANGING BREATHING RATES PAIN CONTROL IN THE ACTIVELY DYING

46  REQUIRED DOSAGE USUALLY HIGHER  MONITORING COMPLIANCE AND SUPERVISION  ONE PHYSICIAN / SHORT Rx / METHADONE  DRUG TESTING SUBSTANCE ABUSE HISTORY

47  ATC PAIN WELL CONTROLLED DURING THE NIGHT BUT POORLY CONTROLLED BY DAY √ INCREASE DAY TIME DOSE ONLY  RD FOR INCIDENT PAIN CONTROLLED BY DAY WAKE THE PATIENT BY NIGHT √ A SINGLE LONG ACTING DOSE AT BED TIME √ DOUBLE RD DIURNAL PAIN PATTERN

48  EXTEND DOSING INTERVAL  REDUCE DOSAGE FRAIL / ELDERLY / ORGAN IMPAIRMENT  DO NOT STOP OPIOID ABRUPTLY  ↓ DOSAGE BY % EVERY DAY  MAINTAIN RD OPIOID DOSE REDUCTION

49 QUESTIONS

50 CASE 1 52 YEAR OLD MALE WITH PANCREATIC CANCER AND SEVERE ABDOMINAL PAIN (10 NRS ) ON SR MORPHINE 30 MG TWICE DAILY PHYSICAL EXAMINATION:EPIGASTRIC MASS, NO REBOUND TENDERNESS, NO ASCITES, NO JAUNDICE.HE IS DOUBLED OVER IN A FETAL POSITION WHICH RELIEVES HIS PAIN SLIGHTLY KUB:UNREMARKABLE CT SCAN ABDOMEN ; LARGE UPPER ABDOMINAL AND CELIAC LYMPH NODES COMPRESSING MESENTERIC VESSELS

51 CASE 1 TREATMENT DOUBLE SR MORPHINE TO 60 MG TWICE DAILY, PROVIDE A RESCUE OF 20 MG EVERY 4 HOURS AS NEEDED IMMEDIATE CELIAC BLOCK METHADONE SWITCH SINCE MORPHINE IS NOT EFFECTIVE,START WITH 10 MG EVERY 3 HOURS AS NEEDED PARENTERAL MORPHINE 1MG EVERY MINUTE FOR 10 MINUTES WITH 5 MINUTE RESPITE REPEAT UNTIL PAIN CONTROL OR 30 MG HYDROMORPHONE 0.4 MG EVERY 5 MG SC

52 CASE 1 HE HAS SIGNIFICANT PAIN RELIEF WITH 9 MG OF IV MORPHINE

53 CASE 1:ADJUSTED OPIOID DOSE MORPHINE 2MG PER HOUR CONTINUOUS IV AND 2MG EVERY 2 HOURS AS NEEDED MORPHINE 4 MG CONTINUOUS AND 4 MG EVERY 2 HOURS AS NEEDED MORPHINE IMMEDIATE RELEASE 30-40MG EVERY 4 HOURS BY MOUTH AND 15-30MG EVERY 4 HOURS AS NEEDED METHADONE 0.4MG CONTINUOUS AND 0.4MG EVERY 2-3 HOURS AS NEEDED FENTANYL TRANSDERMAL 100MCG /HOUR PATCH AND ORAL MORPHINE RESCUE

54 CASE 2 70 YEAR OLD MALE WITH ADVANCED COLON CANCER AND PAINFUL LIVER METASTASES LESS THAN 25% RESPONSE THE MORPHINE SR 60MG TWICE DAILY AND 20MG OF IMMEDIATE RELEASE EVERY 4 HOURS LABORATORY:NORMAL CREATININE AND BILIRUBIN CT SCAN ABDOMEN: MULTIPLE LIVER METASTASES, DISTENDED LIVER, MILD INTRAHEPATIC BILE DUCT DILATATION

55 CASE 2:TREATMENT INCREASE THE SR MORPHINE TO 120MG EVERY 12 HOURS AND ADJUST THE RESCUE DOSE TO 40MG EVERY 4 HOURS IMMEDIATE CELIAC BLOCK INCREASE THE SR MORPHINE TO 160MG TWICE DAILY AND ADJUST THE RESCUE TO 60 MG EVERY 4 HOURS TRANSDERMAL FENTANYL 100MCG /H PATCH WITH 60MG MORPHINE RESCUE OR 400MCG FENTANYL RESCUE HEPATIC RADIATION HEPATIC ARTERY EMBOLIZATION

56 CASE 3 35 YEAR OLD WITH METASTATIC BREAST CANCER TO BONE WITH PAIN LEVEL 6 (NRS) AND MILD CONFUSION ASSOCIATED WITH VIVID DREAMS MEDICATIONS:SR OXYCODONE 40MG TWICE DAILY AND IR OXYCODONE 15 MG EVERY 4 HOURS AS NEEDED, 3 DOSES IN LAST DAY:MIRTAZAPINE 15MG AT NIGHT,LORAZEPAM AS NEEDED,2 DOSES PER DAY ON AVERAGE, LAXATIVES

57 CASE 3 PHYSICAL EXAMINATION: NO FOCAL NEUROLOGIC DEFICITS LABORATORY: NORMAL CALCIUM, CREATININE AND BILIRUBIN

58 CASE 3:TREATMENT START HALOPERIDOL 1MG EVERY 12 HOURS AND AS NEEDED EVERY 4 HOURS STOP MIRTAZAPINE AND REDUCE OR ELIMINATE LORAZEPAM START KETOROLAC 15MG SC EVERY 6-8 HOURS AND REDUCE SR OXYCODONE TO 20 MG EVERY 12 HOURS, MAINTAIN RESCUE DOSES SWITCH TO MORPHINE IMMEDIATE RELEASE 15 MG EVERY 4 HOURS ATC FENTANYL TRANSDERMAL 50MCG / HOUR WITH BUCCAL FENTANYL 200MCG EVERY 2 HOURS AS NEEDED

59 CASE 3 YOU SWITCH TO MORPHINE IR 15 MG EVERY 4 HOURS WITH IMPROVED PAIN AND COGNITION.THE VIVID DREAMS RESOLVE YOU THEN CONVERT TO SR MORPHINE 45MG (15MG PLUS 30MG) WITH RESCUE DOSES AND DISCHARGE HER HOME TWO WEEKS LATER SHE PRESENTS CONFUSED WITH MYOCLONUS AND A RESPIRATORY RATE OF 8

60 CASE 3 : TREATMENT SWITCH BACK TO EQUIVALENT SR OXYCODONE DOSES MRI THE BRAIN AND PLACE HER ON DEXAMETHASONE CHECK SERUM CALCIUM,ET-CO2 AND CREATININE, STOP NASIDS IF SHE WAS ON THEM USE HALOPERIDOL 1MG EVERY 4 HOURS AS NEEDED FOR CONFUSION IMMEDIATELY START NALOXONE 40MCG IV EVERY 3 MINUTES UNTIL RESPIRATION >10 AND MYOCLONUS RESOLVES