1. PEI Palliative Care Conference: Uncontrolled Pain in Palliative Care – An approach for when nothing seems to work ! Dr Edward J. Fitzgibbon Palliative Care Physician The Ottawa Hospital June 11 th 2015

2. Cecily Saunders “Palliative Care begins from the understanding that every patient has his or her own story, relationships and culture, and is worthy of respect as a unique individual. This respect includes giving the best available medical care and making the advances of recent decades available so that all have the best chance of using their time well”. Davies,E, Higginson, I.J. Palliative Care: the solid fact. WHO http://www.euro.who.int/document/E82931.pdf(2004)

3. Ready…..

4. Outline Pain in Palliative Care. Pathophysiology Assessment An Approach to Management Non-Opioids Co-Analgesics Opioids Cases and discussion

5. Pain Pain is defined “as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP 1979) Pain is always subjective and each individual learns the meaning of pain through their experiences of injury or disease during early life. Pain is a very personal experience and is what the patient says it is !

7. Bruera, E. et al. JAMA 2003;290:2476-2479. Cancer Pain: A Uniquely Individual Experience.

8. Barriers to Pain Management In-hospital patients with pain from non-surgical conditions are less likely to have their pain taken seriously enough to be treated. Patient/ family reluctance to report pain and/or take opioids Physician reluctance to prescribe opioids. There is a large gap between what is known and what is practiced in the treatment of all kinds of pain

9. Prevalence of Pain ALS: 40 to 60% End stage heart failure: 45 to 60% AIDS: 50% + will have neuropathic pain syndrome ESRD: 60% + Cancer: 50% of all cancer patients

10. Cancer Pain : Defining the Challenge “Cancer Pain is a mixture of acute pain, chronic pain, tumor specific pain and treatment related pain, all compounded by ongoing psychological responses of distress and suffering.” ( Fitzgibbon D.R, Loeser J.D,: Cancer Pain (2010) Lippincott Williams)

11. Prevalence Of Pain With Stages of Cancer and It’s Treatment Stage of DiseasePrevalence of Pain Active anti-cancer treatment24% to 73% Advanced Cancer58% to 86% Cured of Cancer ( in remission)21% to 46% van den Beuken-van Everdingen MH et al. Ann Oncol 2007;18(9):1437-1449 * Of the patients with pain, >1/3 rd graded their pain as moderate or severe. * Pooled prevalence of pain was > 50% in all cancer types with the highest prevalence in Head/neck cancer patients (70%; 95% CI 51-88%)

12. Cancer Pain: Multiple Causes 67% Tumor- Related 23% Treatment- Related Surgery, Chemo, XRT 10% Unrelated Bonica J. The Management of Pain. Vol. 1. Phila: Lea & Febiger; 1990. Tumor related: Compression Infiltration Destruction

13. Complexity of Cancer Pain Syndromes Frequent co-existence of multiple pain etiologies in an individual patient. Neuropathic pain -10% Somatic pain - 41% “ Mixed” pain - 49% Cherney et al 1989 Multiple sites involved: 1 site - 30% 2 sites – 39% 3+ sites – 31% Frequent Sites: Lower back 36%, Abdomen 27%, Thorax 23% Lower limbs 21%, Head 17%, pelvis 15%. Grond. Pain 64 (1996) 107-114

14. Cancer Pain Higher Pain Scores are associated with: Presence of Breakthrough Pain Neuropathic pain Lower Performance status ( KPS <70%) Younger patient ( <60yrs) More advanced disease. Cognitive impairment Caraceni. Pain 82 (1999) 263-274

15. Cancer Pain: ‘Hard to treat’ Opioid responsiveness and optimal pain control is inversely related to the presence of: Neuropathic pain. Breakthrough pain. Previous opioid exposure. Cognitive impairment and Psychological distress. Bruera. JPSM. 1989

16. Challenges in Managing Cancer Pain Features of both acute and chronic pain syndromes. Multiple sites. Multiple Pain Pathophysiologies Sick population…unstable disease. Multiple symptoms. Multiple treatments: Polypharmacy Multiple doctors! RESULT = High Probability of Patients with complex Pain Syndromes.

17. Assessment

18. An Approach to Managing Cancer Pain. 1.History of Cancer + History of Pain. 2.Standard assessment tools (ESAS, BPI) 3.Document pain syndromes involved. 4.…

20. Pain Assessment Tools Pain Management Made Incredibly Easy Lippincott Williams & Wilkins (2003)

23. BABBS 59 yrs NSCLCA

24. HDMContin 6 mgs q 12. Dil 2mgs q2h prn; TCA 60mgs; Laxatives; Chx ; Stemetil Previously: OxyContin 20 mgs TID & OxyIR q4h PRN Pt was taking 40mg q4h straight = 500-600mgs morph/24hrs

25. Managing Cancer Pain. 1.History of Cancer + History of Pain. 2.Standard assessment tools (ESAS, BPI) 3.Document pain syndromes involved. 4.Is cause known? – appropriate investigations. 5.Formulate Treatment plan - ‘realistic goals’. 6.Target Treatment @ Pain and Cause of Pain.

26. The Cause: Tumor Related Pain

27. After Chemo/XRT

28. Managing Cancer Pain. 1.History of Cancer + History of Pain. 2.Standard assessment tools (ESAS, BPI) 3.Document pain syndromes involved. 4.Is cause known? – appropriate investigations. 5.Formulate Treatment plan - ‘realistic goals’. 6.Target Treatment @ Pain and Cause of Pain. 7.WHO analgesic ladder.

29. The WHO Analgesic Ladder “This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective.” WHO advisory panel 2008 If Rx following the WHO ladder’ patients rated their pain relief : Good 76% Satisfactory 12% Inadequate 12% Zech DF, Grond s et al, Pain 1995;63:65-76

30. WHO Analgesic ladder : Principles of use By the mouth. Oral meds whenever possible By the clock. Continuous pain should be treated with regularly scheduled meds + breakthrough meds as needed. By the ladder. Choose step appropriate for patient’s pain. No ceiling for pure opioids as long as patient gets benefit and can tolerate side effects. For the individual. The “right dose” is the dose of the right drug that adequately relieves the patients' pain with minimum side effects With attention to detail. Successful implementation requires meticulous follow up once a new prescription is issued. Ascertain compliance, drug efficacy and side effects. Cancer pain relief, Geneva, Switzerland, WHO 1996.

31. WHO Ladder: Step 1: Non-Opioids Acetaminophen. NSAIDs Early use of CoAnalgesics

32. Acetaminophen N-Acetyl-Para-Amino-Phenol (APAP). Potent antipyretic, weak anti-inflammatory Mild to Moderate Analgesic actions...HOW?  Probable Central Cox 2 inhibitor  Serotonergic agent, acts via desc inhibitory pathways*  Blocks metabolism Cannabinoids.  Oral bioavailabitlity: 70-100%. tmax: 0.5 to 1hr, t1/2: 1.5-2hrs  CYP metabolism : 4% to toxic metabolite NAPQI.  Caution: drug interactions,(Coumadin, and EtOH.)  Max daily dose 4gm/day. Graham G G, et al. Mechanism of action of Paracetamol. Am J Ther 2005;12:46-55

33. NSAIDs Cox1 and Cox 2 inhibitors: Anti PGE2. Opioid sparing. Have both peripehral and central antihyperalgesic effects. Poor correlation between anti-nociceptive effect and anti- inflammatory effects and doses. Anti-hyperalgesic effect related to ability to cross BBB. Ceiling effect+, must individualize dose. Side effects: Renal, Cardiovascular, GI, CNS, Hypersensitivity reactions, Platelet dysfunction, Recommend: 2 week trial with close monitoring. If ineffective the can try other NSAID Burian M, Geisslinger G. Pharmacology and Therapeutics 107 (2005) 139-154

34. NSAIDs: Comparative Doses and Pharmacokinetics (Lexicomp 2013) Drug Maximum Recommended Daily Dose (mg) Time to peak levels (hr) Half life (hr) Diclofenac (ER) ( Voltaren) 2252-31-2 Indomethacin (Indocid) 2001-24.5 Ketoralac ( Toradol) I.M/ I.V: 120 P.O: 40 0.5 - 12-6 Celcoxib (Celebrex) 400311 Meloxicam ( Mobicox) 154-515-20 Ibuprofen 32001-21.8-2.5 Naproxen (Naprosyn) 15002-412-15 Naproxen sodium (Anaprox) 13751-212-13

35. WHO Ladder: Step 2 ‘Weak’ Opioids Codeine Tramadol Tapentadol Early use of appropriate Co analgesic

36. Tramadol Unique, Atypical opioid. Analgeisa=Codeine 4-phenyl-piperidine analogue of Codeine. Partial μ opioid receptor agonist + Serotonin and Norepinephrine reuptake inhibitor. Oral bioavailaibility: 68 – 90%* ( *rpt dosing) Metabolism : Hepatic CYP 2D6.active metabolites (M1) Renal excretion……..dose reduce in CKD. ?Better tolerated in elderly…? Marketing hype. Dosing: 50mg o.d. increase to maximum 400mg/d. Available as Tramacet, + IR and ER formulations

37. WHO Ladder: Step 3 ‘Stronger’ Opioids Morphine Hydromorphone Fentanyl Oxycodone Early use of appropriate Co analgesic

38. © 2011 American Society of Anesthesiologists, Inc. Published by American Society of Anesthesiologists, Inc. 3 Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior. Al-Hasani, Ream; Bruchas, Michael Anesthesiology. 115(6):1363-1381, December 2011. DOI: 10.1097/ALN.0b013e318238bba6 Fig. 1. Sites of action of opioid analgesics. The gray pathway shows the sites of action on the pain transmission pathway from periphery to central nervous system. The red pathway shows the actions on pain-modulating neurons in the midbrain and medulla. GABA = [gamma]-aminobutyric acid; MOR = [mu] opioid receptor.

39. Essential Discussion of Opioids Discuss the implications of the use of opioids. Patients and family members are fearful of impending death, addiction, tolerance, and nothing left for ‘later.’ Discuss the most common side effects. Nausea - tolerance. Constipation – rarely tolerance. Drowsiness especially when initiating therapy or increasing the dose – and tolerance. – Drowsiness may be related to pain relief.

40. Central Nervous SystemPeripheral ↑ Analgesia ↑ Euphoria* ↑ Sedation ↓ Respiratory rate ↓Cough reflex ↑ Miosis ↑ Truncal rigidity ** ↑ Nausea and vomiting Behavioural restlessness. * addiction potential ** esp Fentanyl/ Sufentanyl Gastrointestinal system: ↑Constipation ↓Gastric motility ↓Digestion in small intestine ↓Peristaltic waves in the colon ↑Constriction of biliary sphincter ↑Esophageal reflux Other Smooth Muscle: ↑Depression of Renal function ↓Uterine tone ↑Urinary retention Skin: ↑Itching and sweating ↑Flushing of face/neck. Cardiovascular System: ↓Blood Pressure + heart rate Immune System: ↓Lymphocyte function ↓Cytotoxic activity of natural killer cells Organ System Effects of Morphine and it`s Surrogates Al-Hasani, Ream et al. Anesthesiology. 115(6):1363-1381, Dec 2011. Molecular Mechanisms of Opioid receptor-dependant signaling and behaviour.

41. Factors Associated with Successful Opioid Therapy Age and weight (pharmacokinetic/pharmacodynamic differences) Severity and Pathophysiology of pain Severity, nature, extent of disease. Allergies or drug intolerances Psychological factors + History of addiction (CAGE) Response to previous opioid therapy ( patient’s preference) Co existing disease ( cardiovascular, Pulmonary, GI etc) Renal and Liver function Drug Route: PO / IV/ SQ/ TD / IT etc. Pharmacodynamic Factors and Pharmacologic Interactions Fitzgibbon D, et al. Lippincott, Cancer Pain, 2010

42. Onset + Duration of Opioid Analgesia DrugRouteOnset of analgesia (minutes) Time to Max Analgesia Duration of action (hours) Morphine + other short acting opioids Oral30 – 40 minutes 1 to 1.5 hours 3 to 5 hours SQ10 -15 minutes 30 to 40 minutes 4 hours IV5 - 8 minutes10 to 20 minutes 3 to 4 hours FentanylBuccal3 to 5 5- 10 min60 minutes SQ 2 to 3 5-10 min60 mins IV1 to 2 5-8 min60 mins (McCaffery & Pasero 1999)

43. Equianalgesic Tables “ When changing opioids, caution must be exercised because the equianalgesic dose ratios that are found on widely available published tables largely represent average data from controlled single-dose studies in selected populations. The ratios fail to account for the incomplete cross tolerance, which would render the new drug more potent than anticipated”. Enting RH et al : A prospective study evaluating the response of patients with unrelieved cancer pain to parenteral opioids. Cancer 94:3049-3056, 2002.

44. Equianalgesic Table DrugS/C (IV)P.O. Morphine10mgs20mg Hydromorphone 2mgs 4mg Oxycodone N/A10 to 15mg Codeine60mgs120mg Fentanyl100 to 125 mcg sc TramadolN/A150mg Merperidine75mgs300mgs MethadoneN/A2mgs

46. Top 10 drugs most frequently reported as causing harm as a consequence of medication error ISMP 2006 #1: Insulin ( 54 ) #2: Morphine ( 43 ) #3: Hydromorphone ( 32 )*** #4: Heparin (unfractionated) ( 19 ) #5: Fentanyl ( 11 ) #6: Warfarin ( 10 ) #7: Furosemide ( 9 ) #8: Dalteparin‡ ( 7 ) #9: Metoprolol‡ ( 7 ) #10:Ramipril‡ ( 7 ) These 10 drugs accounted for 199 of 465 harmful medication incidents that were reported to ISMP Canada over a 5-year period (2001 to 2005).

47. 5 mg

48. Hydromorphone 2013 ISMP Canada Safety Bulletin Vol 13 (10) Nov 4 th 2013. All opioid medications require attention to ensure patient safety. HYDROmorphone, a potent opioid, is the most common medication associated with harmful medication incidents voluntarily reported to ISMP Canada. From January 2000 to September 2013, ISMP Canada received 233 incidents involving HYDROmorphone with an outcome of harm or death via AnalyzeERR®* and individual practitioner reports. Medical examiners identified 3 specific risk factors for harm with HDM: 1: continued presence of high-dose HYDROmorphone in patient care areas leading to ten-fold overdoses. 2: Excessive starting doses of HYDROmorphone, and 3: inconsistent monitoring of patients receiving opioids

49. Time To Rehabilitate Morphine “The Gold standard” ESMO 2012 2012:ESMO Clinical Practice Guidelines. Ripamonti C.I, et al. Management of cancer pain: ESMO clinical practice Guidelines. Annals of Oncology 23 (Suppl):vii139-vii154, 2012. ``The opioid of first choice for moderate to severe cancer pain is oral morphine.`` There is no evidence...that other opioids are superior to morphine in terms of efficacy and tolerability. 2012: Evidence based recommendations from the EAPC. Caraceni A, et al Lancet Oncol 2012;13:e58-68. ``The data show no important differences between Morphine, Oxycodone and Hydromorphone.... any of them could be first choice. ``

50. Hydromorphone Vs Morphine “In conclusion there is evidence to support the efficacy and tolerability of hydromorphone for moderate to severe cancer pain as an alternative to morphine and oxycodone, while there is NO evidence to demonstrate it’s superiority or inferiority in comparison with Morphine as the first choice opioid for the same indication. Pigni A et al, Palliative Medicine 25(5) 471 -477 (2010) Quigley C. Cochrane Database Syste Rev 2002 ( updated 2009)

51. MorphineHydromorphone Named after Morpheus - God of dreams Gold standard Alkaloid from opium Commercially sold 1827 Opiate/Narcotic Dihydromorphinone Morphine Derivative - semi synthetic Hydrogenated ketone Opiate/Narcotic Clinical use - 1926

52. Pharmacology: Morphine Vs Hydromorphone MorphineHydromorphone Bioavailability25-35% Oral30 -40% Oral Protein Binding30-40%20% MetabolismHepatic Metabolites (major)M3G, M6GH3G, H6G Half-life2-3 hours ExcretionRenal Route PO/IV/IM/SC/IT/PR Potency15

53. 2 The Metabolism of Opioid Agents and the Clinical Impact of Their Active Metabolites. Smith, Howard Clinical Journal of Pain. 27(9):824-838, November/December 2011. Major Opioid Metabolites

54. Pharmacologic properties attributable to M3G, M6G, and H3G (Care beyond cure p 52, 4 th 2010) M3G ( + H3G) Central agitation Hallucinations Myoclonus Convulsions Coma Hyperalgesia M6G ( + H6G) Sedation Nausea Respiratory depression Coma Analgesic effect Factors that may increase accumulation of Morphine/HDM metabolites Age > 70yrs. Renal failure ( factors that may ppt RF : urinary obstruction, Meds e.g. NSAIDs, ACE etc, cancers: MM, Lymphoma] Dehydration Rapid + substantial increases in opioid doses Long term use.

55. Key Principles of Opioid Use DOSE: look at the effect !!! NOT at the milligrams. The desired effect is pain relief with tolerable or manageable side effects. Adequate trial by dose titration. Increase the dose up to the appearance of limiting side effects. ( Effect OR Toxicity) Genetics of opioid receptors-variants determine analgesic response to a greater degree than differences in opioid metabolism and clearance = Individualise treatment plan

56. Rationalizing Opioid Rotations British Journal of Clinical Pharmacology Volume 75, Issue 1, pages 60-78, 14 DEC 2012 DOI: 10.1111/j.1365-2125.2012.04317.x Volume 75, Issue 1,

57. Oxycodone Morphine like – but not ‘morphine’. Twice the potency of morphine (1.5 to 2) Combined product – Oxycodone 5 mg + acetaminophen 325 mg. Oxycocet, Percocet, Percodan, endone, endocet. Limited to 12 pills per day due to acetaminophen (325mg/tab). Expected duration of action 4 hours. Pure Oxycodone – Peak time to effect 60 minutes Partially Active metabolites. Noroxycodone + oxymorphone ? Less toxic in renal failure Long Acting – OxyNeo 10, 20, 40 & 80mgs. Currently NO parenteral formulation in Canada.

58. Fentanyl NOT morphine like. Inactive when swallowed. Hepatic metabolism- metabolites are inactive + non-toxic Renal excretion; < 10% of unchanged drug excreted in urine. ? Safer in hepatic + renal failure. Absorbed buccally, sublingually, subcutaneously, intravenously. 75 times more potent than morphine. VERY short acting. SC dose peak time to effect 15-20mins. SC dose duration of action 40-60 mins.

59. Long Acting Preparations Establish the dose. Calculate the appropriate breakthrough dose. Be aware of the slow rise in serum values. Peak time to effect is about 8 hours. However, provides constant opioid release. Improved compliance and QoL. Not Indicated as First Option in Acute Pain !

60. Transdermal Fentanyl Fentanyl TD duration of action ~72 hours. Slow onset of action when initiated. Cachectic patients may require patch changes q48hours. Apply above the waist. Apply to an area that is well perfused. Do not apply over a hairy area. Do not shave - but clip if necessary. Ensure good adhesion. Dose dependent on surface area. Rotate patch sites.

61. Managing Cancer Pain. 1.History of Cancer + History of Pain. 2.Standard assessment tools (ESAS, BPI) 3.Document pain syndromes involved. 4.Is cause known? – appropriate investigations. 5.Formulate Treatment plan - ‘realistic goals’. 6.Target Treatment @ Pain and Cause of Pain. 7.WHO analgesic ladder. 8.Early use of Co-Analgesics: Multi-Modal Analgesia

62. Mellar P. Davis 13 - Cancer painSupportive Oncology null 2011 122 - 135 Synaptic Nociceptive Receptors and Transmitters: **** Potential Targets for Multimodal Analgesics.

63. Targets for Multimodal Analgesia Mechanism Opioid Receptors Prostaglandin synthesis Na + ion influx Ca + ion influx NMDA receptor Cannabinoid receptors ?.............................. Medication options mu opioid agonists Cox -2 inhibitors/ NSAIDs Na + channel blocker ( Lidocaine) Ca + channel blocker ( Gabapentoids) NMDA-r antagonist ( e.g. ketamine) DTHC,

64. Tricyclic Antidepressants. TCA’s First line adjuvant in NCP. Actions: Monoamine reuptake inhibition Na + and Ca ++ channel blocker Antihistaminergic Weak NMDA receptor antagonist Response rate: 51-87% in cancer pain Sindrup, Pain (1999) ;83: 389-400

65. Antidepressants as Analgesics Reuptake inhibition of Norepinephrine + Serotonin Norepinephrine Serotonin ExamplesAmitriptylline Nortriptylline Impiramine DesipramineSSRIs Trazadone Analgesic efficacy NNT 1.7 (1.4-2.6) 3.2 ( 2.6-5) 6.7 (3.5-9) Antichol side effects ++ + +/- Sindrup Pain 1999;83: 389-400

66. University of Ottawa Institute of Palliative Care Tricyclic Antidepressants Nortriptylline / Amitriptylline Start:10 mg/day Titrate:3 – 7 days by 10 – 25 mg/day Max:usual antidepressant dose Limited by side effects Alternatives – Venlafaxine – Duloxetine – SSRIs of limited use.

67. Gabapentoids Pregabalin + Gabapentin. α 2 -δ calcium channel(N)blocker..widespread throughout PNS and CNS Atypical anticonvulsants. Effective in neuropathic pain: DPN, PHN, Incisional injury, Inflammatory injury, APS: Opioid sparing (periop). Generalized Anxiety Disorder ( mood stabiliser). Sleep modulating drug. (Noor M.Gajraj. Anesth Analg 2007;105:1805-15)

68. © 2007 by International Anesthesia Research Society. Published by Lippincott Williams & Wilkins, Inc.3. Pregabalin: Its Pharmacology and Use in Pain Management. Gajraj, Noor; MD, FRCA Anesthesia & Analgesia. 105(6):1805-1815, December 2007.

69. .4. Pregabalin: Its Pharmacology and Use in Pain Management.Gajraj, Noor; MD, FRCA. Anesthesia & Analgesia. 105(6):1805-1815, December 2007. Comparison of Gabapentin and Pregabalin

70. Morphine Oxycodone Hydromorphone Fentanyl +/- adjuvants Acetaminophen ASA NSAIDs +/- Adjuvants Combined meds Codeine Tramadol Oxycodone with acetaminophen Modified “WHO” Ladder Adapted from The WHO 3 Step Analgesic Ladder, Cancer Pain Relief, 2nd Edition, WHO Increasing Pain Mild Pain 1-3 Moderate Pain 4-6 Severe Pain 7-10 Methadone Ketamine Lidocaine Neuraxial Options CADDs

71. Managing Cancer Pain. 1.History of Cancer + History of Pain. 2.Standard assessment tools (ESAS, BPI) 3.Document pain syndromes involved. 4.Is cause known? – appropriate investigations. 5.Formulate Treatment plan - ‘realistic goals’. 6.Target Treatment @ Pain and Cause of Pain. 7.WHO analgesic ladder. 8.Early use of Co-Analgesics: Multi-Modal Analgesia 9.Balance treatment efficacy/side effects /cost. 10.Set dose and time limits for review.

72. Case: OPN 63yo lady with 2 week hx of gradually worsening low back pain. 5/10, worse at night + with standing. Phx: Breast cancer 2005. Rx SX Chemo Xrt Dhx: Metoprolol, Acetaminophen 3gm/d. Ahx: nil known------ “nervous about narcotics” Psy/Soc hx: CAGE –ve. Exam: Well, localized tenderness D6/7, no neuro deficit. Next steps………….

73. Case OPN contd…. Impression: Predominantly somatic pain Investigations: XRay/ Labs – Met D6 Treatment: Step2 WHO ladder. Codeine/ Tramadol/ Morphine all reasonable Laxative prescription…… Consider coanalgesics ( await KFT) Refer Onc – restaging / PXRT,Bisphos etc..

74. Case : HW HW 56 yo man with NSCLC, hepatic + bone mets+ Presents with increasing pain (R) hip,, escalating opioid intake, nausea, drowsy, myoclonic++ Dhx: HDM Contin 12mg q 8hr + HDM 4mg prn, used 6 prns in past 24hrs ( Total HDM 60mg po/d). Gabapentin 600mg t.id. Exam: PPS 50%. Dry+, drowsy, mumbling, anxious, Myoclonic jerks, CAM+ Tender ++R hip, unable to weight bear.

75. Case :HW Imp: Uncontrolled pain + Delirium Dehydrated, Opioid toxic, ? Op induced hyperalgesia X-rays: bone mets (R) Femur++. Labs-Ca/LFTs Rx: IV Fluids, Haloperidol 1mg sq stat + q 12hr d/c HDM Contin + po prn ( total oral HDM prev 24h=60mg). ↓Hydromorphone SQ 3 mg q 4hr straight ( = 40%↓), prn 2mg sq q 1hr prn…check effect. Consult: Rad Onc ?PXRT. Consider ortho referral After 24hrs IVF + haldol, delirium ↓ but still CAM+ Opioid rotation…..options Fentanyl / Morphine.

76. Case : HW 1)Continue Rehydration + Haloperidol 2)Calculate MEDD = 18mg HDM sq/d straight + 12mg prn = 30mg parenteral HDM/d = 300mg MEDD. 3) Reduce MEDD x 25-50%, ( we chose 180mg/d ) 4)Morphine 15 mg SQ q 4hr straight + Morphine 10mg sq q 1hr prn. 5)Treat cause of pain ( Prohphylactic Pin femur + XRT.) 6)After 48hrs, delirium resolved, pain control improved, rotated to oral Morphine 30mg po q 4hr,, and finally to Mesilon 90 mg b.i.d + 20 mg po q 2hr prn.

77. Setting the Scene: YOU!! are called @ 01:00hrs to the ER 76 yo lady (AB) is screaming in pain.....writhing on stretcher “nothing is working, you have got to do something” Family upset++ “she is a cancer patient and no one cares” Phx: Breast cancer x years, known bone mets, Off rx. “Do something !!!”

78. Mrs AB contd Hx: Sudden onset Mid dorsal spine pain. Hx x 4 hrs T3 x 6 po..no effect Dhx: Metoprolol/ Lipitor AHx: Prior Opioids with surgery..nausea++ Demerol 50mg im no analgesic effect…..vomiting++ Localized pain, no weakness or sensory deficit. Phx: breast cancer.. OFF Rx………active+++ Cannot image …..cannot lie still Exam: Distressed+, nutrition/hydration /color-normal No obvious delirium, Moving all 4 limbs+ Remains Distressed ++++ Assessment: Acute Pain Crisis ( 10+)mainly Somatic ? Osp #

79. Mrs AB: A Pain In the ER contd….. Management: Morphine 2mg iv + Maxeran 10mg iv stat Reassess after 30 minutes: Pain 8/10 : Increase (double) Morphine 4mg iv Reassess after 30 minutes: Pain 5/10: repeat Morphine 4mg IV …..can be repeated q 30minutes prn. COMPLETE INVESTIGATIONS. Including lab/Xray-MRI MRI: Pathological fracture of T8 bony metastases. NO SCC……….but major metastatic bone disease progression Rx: CADD Morphine, Dexamethasone, vertebroplasty.+/- XRT Neil A. Hagen, Tom Elwood & Scott Ernst Journal of Pain & Symptom management Vol. 14 No. 1 July 1997.

80. DMD: 46yo F, with 3/12hx escalating back pain, now using walker……..pain 10/10+ ( + = “don’t ask anymore!) Exam: pale frail “small” lady….distress++, Multiple tender points on spine, ribs + pelvis. PPS 50%. Pain: somatic with ++++ incident pain, minor NP Labs; Hgb 70g/l, Creatinine 250umol/l Meds: Dex 8mg/d, HDM Contin 12mg b.i.d+ 4mg q 2hr, TCA Intolerant opioids…nauseating, drowsy, hallucinations+ CADD Fentanyl 60ucg/hr…........helps but cannot move due to pain!...increasing dose ….drowsy+ hallucinations. Dx: Multiple myeloma/ renal failure/ low opioid threshold……………….MRI --

82. Xena “ Warrior Princess” PCA Ketamine 2mg /hr …no bolus Day3..Combined Fentanyl (40) + Ketamine (2) per ml Rate 1.5 mls /hr, 1 ml q 20mins prn. Pain controlled at rest -- Start chemo + physio + TLSO brace. Day 80: PCA a nuisance. …..cant go to rehab with it. Feeling better……….mobilising well……how about the PCA? Start Methadone 2.5mg q 8hr……titrate PCA Day 8..stop PCA, Methadone 10mg q 8hr + 5 mg q 3hrs prn HOME.

83. Successful Treatment of Pain Depends On ………… Determining that pain is present! Focused History and Physical Exam Identifying + Charting Pain mechanisms involved WHO analgesic ladder. Clear Treatment plan Predominance of neuropathic or incident pain Presence or absence of Delirium Patient’s + family’s expectations and beliefs Goals of Care clear. Attitudes + Knowledge of Health Care Professionals Leave your egos at the door!

85. Questions??

86. I really think you should sue your doctor for malpractice! Two years ago he only gave you six months to live! Dilemma in Palliative Care

87. Another Case Mr. B is a 74 year old man with extensive small cell cancer of the lung. (PPS 40%) Multiple hepatic and bone metastases. Hepatic and renal function normal. Initially treated with chemotherapy and radiation to the lung and the spine. Presented to the clinic with complaints of increasing ‘excruciating’ back pain (10+/10).

88. The Case Continued…. On initial assessment Mr B described the following: Constant aching pain in his mid back with band- like pain across his chest Mild numbness and tingling from his waist down Pain rated at 6/10 that increased to 10/10 with any movement or weight bearing. Sharp stabbing component of pain on movement

89. Current medication: MS Contin 75 mg Q12H (MEDD 150mg) PO Morphine sulphate 15 mg Q2H PRN PO Dexamethasone 2 mg daily Acetaminophen 500mg q 6hr straight Laxatives Pain 10+/10

90. How do we deal with his pain? What type(s) of pain does Mr. B describe? -Somatic -Neuropathic Emergency pain management

91. Management:- IV morphine 15 mg given stat ( Prior MS Contin 150mg/d) Waited 30 minutes Pain rated at 7/10 IV morphine doubled (30 mg) Pain reassessed – 4/10 S/C Morphine 30mg ordered Q4H regularly and Q1H PRN ( Ms Contin discontinued) Complete investigations: MRI spine

92. Causes of Mr. B’s Pain MRI spine: Progression of bone mets in thoracic and lumbar spine with possible compression fractures but no SCC CT scan also shows extensive progression of lung and liver metastases

93. Additional Management Dexamethasone 16mg/d Pregabalin 25mg po stat + t.i.d. Titrated to 50mg t.i.d after 48hrs. Urgent PXRT

94. Continuation Mr. B’s baseline pain improved however incidental pain remained challenging. He required frequent breakthrough pain medication but developed some confusion and myoclonus, drowsiness +. Dry+ Morphine changed to dilaudid SC infusion via CADD (5 X stronger than morphine) IV hydration.

95. Continuation Mr. B was discharged home on Dec 23 rd to spend Christmas with his family @ home. Mr. B died on Dec 30 th peacefully at home surrounded by his family.

96. Vision for Palliative Care Every person, when faced with an incurable disease, has the opportunity to live life fully, to receive timely and appropriate symptom management, to be supported along with his/her family with dignity and respect throughout the course of their illness, and in the face of incurable disease, to have the opportunity to die in a setting of his/her choice. CCO Signature Event: Toronto March 2006

97. Copyright © 2012 American Medical Association. All rights reserved. From: Managing an Acute Pain Crisis in a Patient With Advanced Cancer: “This Is as Much of a Crisis as a Code” JAMA. 2008;299(12):1457-1467. doi:10.1001/jama.299.12.1457 :

98. Opioid Responsiveness A patient in pain should not be declared “unresponsive to opioids” until he/she has failed a titrated, sequential trial of all of the different opioid analgesics.

99. DN4 Four questions that can elicit 10 different pain sensations. Each point that is positive is given a score of 1. A score of >or=4 is positive for neuropathic pain. Sensitivity: 82.9%; Specificity:89.9%) Bouhassira, D.(2005) Pain; 114:29-36

100. Ketoralac : parenteral NSAID analgesic NSAID: non-selective reversible Cox1 +2 inhibitor. 30mg IV equianalgesic with 10-12mg Moprhine. Oral bioavailability= 100% Onset analgesia IV/IM = 30mins, Peak 2hrs, duration 8hrs. Dosing: IV/IM 30mg q hr prn ( max 120mg/d) Oral: 20mg stat, 10mg po q 4hr prn (max 40mg /d) Max duration of use ( ≤5 days). Metabolism: 68-92% excreted unchanged in urine. Toxicity: Renal: increase risk ATN, ARF, esp if dehydrated. CVS: increased risk thrombotic events (MI /CVA) GI: increased peptic ulceration/perforation *All side effects increased with prolonged use ≥5 days *