Pharmacological Management of Severe Pain

1. Pharmacological Management of Severe Pain Donato G. Dumlao, MD, FACP Medical Director for Palliative Care, Providence Hospital Supportive Cancer Care Specialist, Southern Cancer Center

2. Excruciating pain “Worse than torture”

3. Torture instruments

4. Barriers to effective pain management

5. The screaming lady 88 y/o with dementia FAST 7-C who is a nursing home resident under hospice. Consult was made because of uncontrolled agitation despite being on lorazepam and haldol. When I arrived I heard the patient screaming from the end of the hallway. Inside the room was the wound care nurse standing in front of a scared, screaming patient who looked like somebody who saw evil. She had a 4 cm by 8 cm non-healing vascular ulcer on the dorsum of her left foot. Prior to dressing changes, she receives lorazepam +/- haldol. She is also on Lortab 5/500 mg q 4 hours prn for pain. She received 1 tablet the past 24 hours.

6. Pain syndromes in geriatrics • 25-50 % have chronic pain syndromes • 30 % of Nursing home patients did not receive analgesics despite daily complaints of pain and another 16 % only received acetaminophen • Age and female sex were predictors of under-treatment for pain

7. The under treatment of pain is still a major issue in hospice palliative medicine

8. Recent American Academy of Hospice and Palliative Medicine Survey The 2 greatest obstacles to pain management are failure to recognize the importance of pain (40%) and a lack of systemic approach (38%)

9. Indifference to pain Only a few healthcare professionals will ever experience and understand chronic excruciating pain D. Dumlao

10. Barriers to effective pain management • Not recognizing the importance of pain • Prejudices about pain • Fears of abuse and addiction • Unpleasant experiences with pain therapy (intolerable side effects: nausea, drowsiness, fatigue, constipation) • Regulatory restrictions • Insufficient knowledge of pharmacological therapy

11. Barriers involving healthcare systems have been reduced since the standards of the JCAHO---Which asserts that pain management is a patient right However, barriers, such as failure to adhere to standards and guidelines, still exist

12. Addiction • Chronic neurobiological disorder • Genetic, psychological and social components • Characterized by an impaired ability to control drug use and continued use despite recurrent problems related to self administration.

13. Pseudoaddiction • Arises when pain is inadequately managed, and the response of the medical staff is to use this as evidence for the diagnosis of drug addiction • May result from as needed dosing schedules with inadequate potency, and longer than appropriate dosing intervals • Adequate pain control results to resolution of aberrant behavior and improved functioning

14. Risk of addiction from commonly abused substances Recrational use • Tobacco – 35% • Cocaine – 23% • Alcohol – 17% • Marijuana – < 10% • Opioids – less than 1% Use in cancer pain

15. Formulating the regimen

16. The grouchy guy 46 year old male with recurrent, progressive head and neck cancer with excruciating neoplasm related pain on the right ear, jaw, and mouth. Pain is between 8/10 to 10/10. Breakthrough pain is spontaneous. Never had relief for a year The local interventional pain physician placed him on Fentanyl 100 mcg 72 hours and oxymorphone 10 mg q 4 hours. He uses 6 to 8 doses of Subsys1600 mcg gives him relief for 3 to 4 hours. He uses 6 doses per day. He gets significant pain relief when he gets IV morphine in the oncology clinic. He is depressed, anxious, grouchy, and sleep deprived. Weight continues to drop despite a PEG. There are no curative or life prolonging treatments available for his cancer. PPS=40 %. He is hospice appropriate but wife is still in denial.

17. The dying cancer patient • 75% of dying patients will require strong opioids • 13% will require dose reduction, 44% require dose escalation, 44% unchanged • 60% will be able to swallow and 40 % will require another route of administration • More than 50% will have new pain • 10% to 20% will die with excruciating pain

18. Predictors of survival • Physical functioning • Appetite loss • Pain EORTC Clinical Groups. Lancet Oncology. September 2009

19. An understanding of basic approaches to assessing and treating pain is essential to adequate pain control Only 20% of cases requires attention of a clinician with advanced pain management

20. Goal of opioid therapy • The best pain medication is one that will control pain without any adverse effects • There is considerable inter-individual variability in response to each opioid • Opioids have a very wide effective dose range • Dose titration until adequate pain control is achieved or intolerable adverse effects manifest • Is there a maximum dose

21. Factors that influence choice of opioids • Trajectory of the disease process and pain syndrome • Co-morbid condition • Socio-economic factors • Knowledge and experience in using specific opioids • Genetic factors • Life expectancy

22. Trajectory of the disease process and pain syndrome

23. Dosing an opioid tolerant patient • Always continue or convert chronic stable dose of home opioid analgesic. Be creative. May combine po with iv or transdermal with iv • There is incomplete cross tolerance among opioids. Because of this when converting stable doses use 75% of conversion dose if pain is fairly controlled • If pain is uncontrolled you may use 100% of conversion dose

24. Breakthrough dosing of the opioid tolerant patient • Patient should be given a breakthrough or rescue dose for incidental or acute on chronic pain • Breakthrough dose is 10 to 15 % of 24 hour stable dose • Or 30% to 50% of q 4 hour dose • Find that dose that will control excruciating pain

25. Conversion table

26. Conversion table • Fentanyl 25 mcg patch=45 mg oral morphine • 100 mcg IV fentanyl=10 mg IV morphine

27. Convert to the standard drug morphine • Fentanyl 100 mcg q 72 hours = 180 mg oral morphine per 24 hours • Opana 10 mg = 30 mg oral morphine x 6 doses = 180 mg oral morphine • Subsys 1600 mcg x 6 doses = no available conversion data = 1,440 to 2,880 mg oral morphine

28. The choice • Methadone 10 mg/ml, 20 mg q 6 hours sublingual • Roxanol 20 mg/ml 4 to 8 ml q 1 hour prn per peg for breakthrough pain. Instruction was given to try 4, 5, 6, 7, 8 ml and take note what dose will control breakthrough pain • Subsys 1600 mcg q 4 hours prn for breakthrough pain • Gabapentin 300 mg tid • Dexamethasone 4 mg bid

29. Genetic factors • 20% to 40% of variable drug efficacy caused by phenotypic variations • Genetics is involved in drug metabolism. It causes differences to drug response • Extensive or normal metabolizers • Poor metabolizers • Ultra rapid metabolizers • Intermediate metabolizers

30. Opioid metabolism • Phase 1 metabolism by the cytochrome P450 pathway (oxidation or hydrolysis) • CYP 3A4=metabolizes 90% of all drugs • Methadone, Fentanyl, Buprenorphine, Oxycodone, Tramadol • CYP 2D6=Codeine, Hydrocodone • Phase 2 metabolism by conjugation (glucurodination) • Morphine, Hydromorphone, Oxymorphone • Little or no pharmacokinetic drug-drug interaction • Pharmacodynamic drug-drug interactions are possible (additive effect with benzodiazepine

31. Opioid metabolism • CYP 3A4 • Tramadol→M1 (Q-desmethytramadol) • Fentanyl→Norfentanyl • Oxycodone→Noroxycodone • CYP 2D6 • Codeine→Morphine • Oxycodone→Oxymorphone • Hydrocodone→Hydromorphone (90%) and Norhydrocodone(via CYP 3A4)

32. Opioids that produce active metabolites • Codeine • Morphine • Hydromorphone • Tramadol • Oxycodone

33. Opioids with inactive metabolites • Fentanyl • Oxymorphone • Methadone

34. Opioids less affected by renal or liver impairment • Methadone • Fentanyl

35. Follow up • Saw the patient weekly • 2nd visit, patient was smiling and said he has not had relief for 1 year until he saw me • His dose was titrated to • Methadone 20 mg q 4 hours sublingually • Roxanol 5 ml q 1 hour prn averaging 4 doses per day • Subsys 1600 mcg was not stopped. He averaged 0 to 2 doses per day • He survived for 5 months with good pain control until the last 4 days of life

36. Adverse effects of opioids • Related to initial use and intolerance - the opioid naïve patient • Delirium, drowsiness, respiratory depression etc. • Related to chronic high dose opioid use • Other adverse effect different from the first two • Persistent myoclonus, persistent drowsiness, persistent delirium (persistent neurotoxicity)

37. The confused patient 52 y/o male with metastatic lung cancer. Severe back, bilateral hip, and chest wall pain due to multiple bone metastasis. Had palliative XRT. Morphine controlled release titrated to 400 mg TID. On Morphine IR 30 mg, 2 to 3 tabs q 2 hours prn for breakthrough. Pain was controlled until he had his first chemotherapy. Had nausea and vomiting that led to dehydration. He developed confusion, generalized pain and some myoclonus. Discussed case with Oncologist. Syndrome can be due to terminal phasebut………

38. Terminal delirium vs opioid induced hyperalgesia Morphine was stopped. Had aggressive hydration therapy. Methadone 5 mg q 6 hours was given (20% of conversion) and Dilaudid 4 mg po q 2 hours prn for breakthrough. Mental status improved, pain was perfectly controlled, and myoclonus resolved. He completed his palliative chemotherapy and survived for 8 months with good quality of life. He signed up with hospice 2 months before he passed away due to progressive weakness and onset of terminal delirium.

39. Delirium • Disturbance of consciousness and defects in attention, orientation, and memory. • The patient is disoriented and cannot focus, sustain, or shift attention. He or she is unable to remember well or cannot use language without disorganization. • This disability fluctuates over hours and days. • The key finding of fluctuating consciousness sets delirium apart from dementia, and disorientation sets it apart from functional psychiatric disorders. • In dementia, cognition is impaired despite the patient's alert state and ability to pay attention. In functional psychiatric disorders, patients may have delusions and hallucinations, but their orientation to time and place are not typically impaired.

40. Antinociceptive Tolerance • Due to prolonged use of opiates • It occurs when there is a progressive lack of response to a drug requiring increased dosing • Higher doses of opiates are required to elicit same amount of analgesia or anti-nociception • Can occur with other drugs including opioids

41. Opioid induced hyperalgesia • Hyperalgesia and allodynia • Myoclonus • Confusion (delirium) • Related to but different from tolerance • Has been observed and documented in literature since 19th century (Observed by Albutt in 1870)

42. Etiology of OIH • Results from prolonged opiate exposure • Occur at a certain critical opioid dose • NMDA plays central role in it’s development • Causes sustained neuroplastic changes in the spinal cord • Results into up-regulation of spinal dynorphin and CGRP (proposed mechanism)

43. Increasing opioid dose will reduce pain in undertreated pain and tolerance Conversely Opioid Induced Hyperalgesia would be worsened by increasing opioid dose

44. Opioids with unique properties that may mitigate OIH • Methadone • Mu agonist and NMDA antagonist • A racemic mixture in which the d-isomer is the NMDA antagonist • Displays incomplete cross tolerance properties • Anecdotal reports show improvement or control of OIH when reducing opioid dose and adding low dose methadone

45. Methadone • Can be used to treat OIH • Methadone can relieve opioid withdrawal • Due to long half life there are fewer variations in plasma levels • Standard of treatment for opioid dependence for over 40 years • Methadone can also cause OIH?

46. Bibliography • Chu L.F. Analgesic tolerance without demonstrable opioi-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. Pain 2012;153(8): 1583-1592 • Crews, K.R. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for codeine therapy in the context of Cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharm & Therapeutics 2012; 91(2): 321-326 • DuPen, A. et al. Mechanisms of opioid induced tolerance and hyperalgesia. Pain Man Nurs 2007; 8(3): 113-121 • Greenberg, D.B. Preventing Delirium at the End of Life: Lessons From Recent Research. Prim Care Companion J Clin Psychiatry 2003; 5(2): 62–67 • Ferrari A. et al. Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res 2004; 50(6): 551-559 • Hanks, G. et al. Oxford Textbook of Palliative Medicine. Oxford University Press Inc., New York, 2010 • Hutchinson, R.M. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J ClinPharmacol 2003; 57(3): 287-297 • Lee, M. A comprehensive review of opioid –induced hyperalgesia. Pain Physician 2011; 14: 145-161 • Smith, H.S. Opioid Metabolism. Mayo Clin Proc. 2009; 84(7):613-624