Pharmacological Management of Severe Pain

1. Pharmacological Management of Severe Pain Donato G. Dumlao, MD, FACP SMC Palliative Care Services Houston, Texas Tammy L. Groher, NP Palliative Care Nurse Practitioner, Saint Joseph’s Hospital, Atlanta

2. “The alleviation of suffering is universally acknowledged as a cardinal goal of medical care”Doyle et al

3. Goals of Palliative Medicine • Improve or maintain the quality of life • Alleviate suffering • Maintain functionality, if possible • Near the end of life, functionality can be sacrificed as long as suffering is alleviated

4. Significance of Severe Pain “Worse than torture”

5. Torture Instruments

6. Most common reason to seek medical attention 60-90% with advance cancer have pain 50 to 75%% report inadequately relieved pain 25 % die with unrelieved excruciating pain 80-90% can be managed relatively simple with oral analgesics ECOG Study of 15 Cancer Centers 61% percent of the sample had pain 40% of those with pain rated it as significant (i.e., greater than 5 on a 0 to 10 scale) No patient in this sample was reported to be receiving morphine or a morphine-like opioid Cancer Pain

7. HIV/AIDS Pain Syndromes • 25 % in asymptomatic phase • 40-50 % of ambulatory patients with AIDS • 80 % hospitalized patients with advance disease • Pain in HIV/AIDS is dramatically under treated • Only 6% of AIDS patient with severe pain are on opioid analgesics(Oxford Textbook of Palliative Medicine)

8. Pain Among Those With Neurological Disorders • CVA • Loss of muscular ensheathment to bones and joint, contractures, frozen joints • Skin pressure pain • 18 to 32 % post-stroke headache • 20 to 30% hand shoulder syndrome • MS • 50 to 60 % have several pain syndromes • Trigeminal neuralgia, Lhermitte’s sign, central dysaesthetic pain, headache, optic neuritis, and painful tonic spasm • Parkinson’s: • Stiffness, rigidity causes dystonic spasms • Spinal cord injuries: • About one-quarter to one-third of patients have severe chronic pain that significantly affects quality of life

9. The undertreatment of pain is still a major issue in both oncology and palliative medicine

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

11. 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

12. Addiction Chronic neurobiological disorder Genetic, psychological and social components Characterized by impaired ability to control drug use and continue use despite recurrent problems related to self administration Pseudoaddiction Arises when pain is inadequately managed May result from prn dosing schedules with inadequate potency and/or frequency Staff responds by using this as evidence of drug addiction Adequate pain control resolves aberrant behavior and improves function Addiction vs. Pseudoaddiction

13. Risk of Addiction and Substance Use Disordersamong Patients Receiving Opioid Medications • Actual risk is low • The risk is over estimated • Physical dependence is not addiction • These concerns results in physician reluctance to write opioids and patient reluctance to use them

14. 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

15. “The doctor who leaves a patient to suffer intolerably is more morally reprehensible than the doctor who opts for death assistance” Robert Twycross

16. Pharmacological Therapy: Opioid Analgesics • Major class of drugs used in pain management • There is considerable inter-individual variability in response to each opioid • Agonists have no relevant ceiling effect to analgesia • Adverse effect limits useful dose

17. Goal of Pain Management Titrate dose until adequate pain control is achieved or intolerable adverse or toxic effects manifest

18. Pharmacokinetics of Opioids • Renal Excretion • Metabolized in the liver • Concern is with toxic metabolites which can cause neurotoxicity • 6 morphine glucuronide • Normeperdine • Norpropoxyphene • 6 hydromorphone • Norfentanyl • Onset of action ranges from 0 to 15 minutes (IV) or 15 to 30 minutes (po) (depends on lipid solubility) • Duration of action

19. Pharmacokinetics of Commonly Used Opioids • Dilaudid: • Half life: 1 to 3 hours • Morphine: • Duration of analgesia: 2 to 6 hours • Half life: 2 to 4 hours •  Fentanyl: • Duration of analgesia: 0.5 – 1 hour • I.V half life: 2 - 4 hours • Transdermal patch half life: 17 hours (13-22 hours, half-life is influenced by absorption rate) • Transmucosal half life: Lozenge: 7 hours • Buccal film: 14 hours • Buccal tablet half life: 100-200 mcg: 3-4 hours, 400-800 mcg: 11-12 hours • Methadone • Duration of analgesia: Oral: 4-8 hours, increases to 22-48 hours with repeated doses • Half-life elimination: 8-150 hours

20. What Opioid Analgesic to Use? • Pharmacokinetics • Patient co-morbidities ( Kidney and liver Disease: Methadone or Fentanyl) • Intensity of pain • Previous experience with opioid analgesics • Considerable inter-individual variability in response to each opioid • Adverse events • True allergy to opioids (Drugs of choice: Methadone or Fentanyl) • Etiology of pain • Nociceptive • Neuropathic • Opioid Induced Hyperalgesia • Total daily dose of pain medications

21. When To Start IV Opioid Analgesics • Loss of gut function • Sublingual morphine will not control breakthrough pain of patients on mega doses • Requires rapid onset of analgesia • Requires very high doses • Cost

22. Determine the dose that will control excruciating pain The best pain medication is the drug that will control pain without adverse effects

23. What Dose to Give an Opioid Naïve Patient? • For opioid naïve start at a morphine equivalent of 2 to 5 mg IV or 10 mg PO • Dose escalation should be more than 30 to 50% of base dose to observe a meaningful change. • Frequency of parenteral dosing can be as often as every 15 to 30 minutes until adequate analgesia is achieved

24. Opiod Analgesic Usual Starting Dose

25. Once Analgesia is Achieved • A regular dosing schedule of every four hours can be started • Rescue or breakthrough dosing • 30% to 50% of every 4 hour dosing • 10 to 15 percent of total 24 hour dose • Best time to give rescue dose is time of peak onset • Convert to PO or transdermal if possible

26. The Opioid Tolerant Patient • Etiology of pain • Nociceptive • Neuropathic • Opioid Induced Hyperalgesia • Has there been progression of pain due to progression of disease or some other factors • Some cases might require opioid rotation not a dose increase • Previous response to opioids.

27. 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 • Be sure breakthrough or rescue regimen is ordered

28. Conversion Table

29. Circumvents repetitive injections Prevents delays in analgesic administration Provides continuous level of pain control Decreased side effects Less breakthrough pains Prompt delivery Patients administer analgesic based on pain level Economical Not nurse dependent Lower Overall narcotic use High degree of safety Advantages of Patient Controlled Analgesia

30. Disadvantages of Basal Dosing with PCA • May increase adverse effects like • Sedation • Nausea • Respiratory depression

31. Dosing Consideration for PCA • Basal dose depends on chronic stable home dose. • Demand dose can range from 25 to 200% of hourly basal or background dose. As to interval or lockout, q 5 to q 15 minutes is acceptable. • Upward titration is dependent on dose patient can tolerate. Check hourly delivered doses and 24 hour total doses. • Monitor number of attempts and correlate to the number of doses delivered

32. Upward Titration of Basal PCA Dose • Increase by at least 25 to 50% of hourly dose • Increase by getting hourly average of demand doses during a given time period and adding the average to the hourly basal dose • Increase basal dose by adding 1 demand dose to the basal dose • Monitor closely during the first 3 to 4 hours of initiating a new dose. It is important to note if patient can tolerate the dose

33. Three Complications of Chronic High Dose Opioid Therapy • Neurotoxicity • Tolerance • Opioid Induced Hyperalgesia

34. Opioid-induced Neurotoxicity • Mediated through non-opioidergic mechanisms • Due to neuro-excitatory metabolites of opioids (morphine-6-glucuronide, oxymorphone-3-glucuronide) • Causes spectrum of symptoms ranging from mild confusion or drowsiness to hallucinations, delirium and seizures • Typically develops on initiation to a week of initiating an opioid or reaching a dose that causes metabolite buildup.

35. Opioid-induced Neurotoxicity • Dehydration, infection, or adding drugs that depress the central nervous system can tip a frail older adult into opioid toxicity. • A patient who has been receiving a stable dose of an opioid for more than 2 weeks is unlikely to develop OIN unless precipitated by dehydration, infection, or a drug interaction. • OIN is managed by opiod rotation, dose or frequency reduction and rehydration. • Opioids should not be discontinued if they are needed for pain or dyspnea.

36. Antinociceptive Tolerance • Is a pharmacologic concept • 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 antinociception

37. The mechanism by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear Opioid Induced Hyperalgesia

38. Opioid Induced Hyperalgesia • Hyperalgesia and allodynia • Myoclonus • Confusion • Related to but different from tolerance • Different from opioid neurotoxicity • Has been observed and documented in literature since 19th century (Observed by Albutt in 1870)

39. Tolerance vs Opioid Induced Hyperalgesia • OIH cannot be overcome by increasing dosage • OIH is a form of pain sensitization induced by opiates which occurs in the CNS • Pain is worsened with increased opioid dosing • Pain is improved by reducing/eliminating opioid • OIH occurs at a certain critical opioid dose (may be lower in patients with renal dysfunction) • OIH is often overlooked as a potential complication of opioid therapy

40. Opioid Induced Hyperalgesia • Results from prolonged opiate exposure • Causes sustained neuroplastic changes in the spinal cord • Results into upregulation of spinal dynorphin and CGRP (proposed mechanism) • Activity of opiates at the mu receptor results to activation of NMDA receptors resulting into this state of hyperalgesia

41. Challenge patient with an increased opioid dose and evaluate for increased efficacy (tolerance) Increased opioid dose will lead to increased pain while a reduction or elimination of opioid dose may improve pain in OIH Utilize opioids with unique properties that may mitigate OIH Utilize NMDA antagonists Respite sedation with propofol? Interventional pain techniques or neurosurgical procedures OIH Treatment Strategies

42. 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

43. 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?

44. Case #1 74 y/o with pancreatic cancer • Started on Duragesic patch progressively titrated to 150 mcg • Had worsening myoclonus, no confusion, no hallucinations • Progressively worsening pain • Shifted to Dilaudid PCA. Dose titrated to 2 mg per hour basal and 1 mg q 10 minutes demand. Pain was controlled, myoclonus resolved.

45. Case # 2 74 y/o with progressive malignant lumbosacral plexopathy • On morphine ER 200 mg TID which was progressively titrated to 1000 mg q QID • Had progressive pain then developed delirium and myoclonus • Hospitalized and started on Dilaudid PCA that controlled pain for a few days. Upward titration to 25 mg per hour and 10 mg q 10 minutes • Had progressive delirium, myoclonus and pain • Dilaudid basal dose was stopped, demand dose was decreased to 5 mg q 10 minutes. Methadone 10 mg QID was started

46. Bibliography • Gardell LR, King T, Osipov MH, et al. Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. www.sciencedirect.com • Silverman SM. Opioid induced hyperalgesia: Clinical Implications for the pain practitioner. Pain Physician 2009; 12;679-684 • Cleary JF. The Pharmacologic management of cancer pain. J of Palli Med 2007;10:1369-1394 • Thomas J , M.D., Ph.D. Optimizing Opioid Management in Palliative Care. J Palli Med; Volume 10, Supplement 1, 2007 • Doyle, Hanks, Cherny, Calman. Oxford Textbook of Palliative Medicine 3rd Edition. New York: Oxford University Press; 2005 • Geller A, O’Connor K. The Sickle Cell Crisis:A Dilemma in Pain Relief. www.mayoclinicproceedings.com/content/83/3/320.full • Allard P, Maunsell P, Labbe’ J, Dorval M. Educational Interventions to Improve Cancer Pain Control. A Systematic Review. J Palli Med 2001;4:2 • Martell BA, O’Connor PG, Kerns RD, et al. Systematic Review: Opioid Treatment for Chronic Back Pain: Prevalence, Efficacy, and Association with Addiction: Ann Intern Med. 2007;146:116-127. www.annals.org • Allard P, Maunsell E, Labbe’ J, MICHEL Dorval M. Educational Interventions to Improve Cancer Pain Control. A Systematic Review: J Palli Med, Volume4, Number 2, 2001 • Woodall HE , Chiu A, Weissman DE. Opioid Allergic Reactions #175. J Palli Med, Volume 11, Number 5, 2008 • Tennant F. Opioid Serum Concentrations in Patients with Chronic Pain. J Palli Med, Volume 10, Number 6, 2007 • Chang VT, Janjan N, Jain S, Chau C. Update in Cancer Pain Syndromes. J Palli Med, Volume 9, Number 6, 2006 • Opioids for Chronic Cancer and Non-Cancer Pain: A Survey of State Medical Board Members. DAVID E. JORANSON, MSSW; CHARLES S. CLEELAND, PhD; DAVID E. WEISSMAN, MD; AARON M. GILSON, MS. PPSG Website • Hatfield, A.K; C.S. Cleeland; R. Gonin; K.S. Wagler, and K.J. Pandya. 1991. Results of an outpatient pain survey in outpatient cancer centers: An ECOG pilot study. Presented at ASCO meeting in Houston, TX, May 19-21.