Safe, Rational, and Legal Use of Opioid Analgesics American Drug Utilization Review Symposium - 2003 Kenneth C. Jackson, II, Pharm.D. Assistant Professor of Pharmacy Practice – Pain Management Clinical Pharmacy Specialist - International Pain Institute We are appalled by the needless pain that plagues the people of the world in rich and poor nations alike. By any reasonable code, freedom from pain should be a basic human right limited only by our ability to achieve it. Liebeskind J, Melzack R. Pain 1987;30:1 Pharmaceutical Care • Pain is the single most common reason that patients visit physicians, clinical facilities, and pharmacies Lipman AG. J Pharm Care Pain Sympt Control 1993;1:1-3 • The responsible provision of drug therapy for the purpose of achieving definite outcomes that improve a patient’s quality of life. Hepler CD, Strand LM. Am J Hosp Pharm 1990;47:533-43 Pain Defined Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. International Association for the Study of Pain, 1979 Rational Therapy The potential benefit to the patient must outweigh the potential risk Adverse Physiological Sequelae of Pain increased catabolic demands increased risk of thromboembolic event sodium and water retention inhibited GI motility tachypnea (acutely) hypertension tachycardia Adverse Psychological Sequelae of Pain anxiety depression sleep deprivation existential suffering Adverse Immunological Sequelae of Pain impaired immune response - decreased natural killer (NK) cell count Opioid Concerns physical dependence psychological dependence addiction tolerance CNS depression – respiration – sedation – cognition legal sanction risks Myth: Opioids Cause Addiction, Dependence and Tolerance These effects can occur They are rare in patients who have pain due to physiological causes They are seriously overestimated in American society and most of the world The should not be impediments to good analgesic therapy Addiction compulsive use of a substance resulting in – physical – psychological, or – social harm to the user and continued use despite of that harm Rinaldi R et al. JAMA 1988;259:555-7. Opioid Addiction Addiction in the context of pain treatment with opioids is characterized by a consistent pattern of dysfunctional opioid use that may involve: adverse consequences associated with the use of opioids – loss of control over the use of opioids – preoccupation with obtaining opioids despite the presence of adequate analgesia American Society of Addiction Medicine Public Policy Statement, April, 1997 American Society of Addiction Medicine Public Policy Statement “...Individuals who have severe, unrelieved pain may become intensely focused on finding relief for their pain. Sometimes, such patients may appear to observers to be preoccupied with obtaining opioids, but the preoccupation is with finding relief of pain, rather than using opioids, per se. This phenomenon has been termed ‘pseudoaddiction’…” April, 1997 Pseudoaddiction appropriate drug seeking behavior – demanding doses before they are scheduled – viscous cycle of anger, isolation, and avoidance leading to complete distrust Weissman DE, Haddox DJ. Pain 1989;36:363-6 increase the opioid dose by 50% – assure that breakthrough doses are available complaints resolve when analgesia is established Prevalence of Iatrogenic Addiction Porter J, Jick H. Addiction rare in patients treated with narcotics. NEJM (letter) 1980;302:123. 4 of 11,882 0.03% Perry S, Heidrich G. Management of pain during debridement: a survey of U.S. pain units. Pain 1982;13:267-80. 0 of >10,000 0% Medina JL, Diamond S. Drug-dependency in patients with chronic headache. Headache 1977;17:12-14. 3 of 2,369 0.12% Pharmacological/Physiological Dependence A physiological phenomenon characterized by: abstinence syndrome upon – abrupt discontinuation – substantial dose reduction – administration of an antagonist Rinaldi R et al. JAMA 1988;259:555-7 occurs with steroids and many other drugs – nearly universal with regularly scheduled opioids Physical Dependence to an Opioid A physiological state in which abrupt cessation of an opioid or administration of an opioid antagonist result sin a withdrawal syndrome. Physical dependency on opioids is an expected occurrence in all individuals in the presence of continuous use of opioids. It does not, in and of itself, imply addiction. American Society of Addiction Medicine Public Policy Statement, April, 1997 Myth: Tolerance to Opioids Occurs Predictably Clinicians and patients commonly believe that ever increasing doses of opioid are needed to maintain analgesia It may take several days to titrate a patients to the opioid dose needed to provide comfort Once an effective dose is found, dose increases are rarely needed unless pathology increases or another variable occurs Tolerance to an Opioid Tolerance is a form of neuroadaptation to the effects of chronically administered opioids (or other medications) which is indicated by the need for increasing or more frequent doses of the medication to achieve the initial effects of the drug…Tolerance is variable in occurrence, but is does not, in and of itself, imply addiction. American Society of Addiction Medicine Public Policy Statement, April, 1997 Pseudotolerance progressive disease new pathology excessive activity noncompliance drug interaction drug diversion addiction Pappagallo M. J Pharm Care Pain Sympt Control 1998; 6(2):95-98 Distinct Types of Opioid Tolerance Tolerance to Analgesia may occur in first days to weeks of therapy; rare after pain relief achieved with consistent dosing without increasing or new pathology. Tolerance to Respiratory Depression and Sedation occurs predictably after 5-7 days of consistent opioid administration Tolerance to Constipation does not occur; scheduled stimulating laxatives are indicated with regularly scheduled opioids Lipman AG, Jackson KC, Opioids. in Warfield, editor, Principles and Practice of Pain Management, 2nd edition, Williams and Wilkins, 2003 Myth: Patients Who Demand Increasing Opioid Doses are Tolerant or Addicted Drug seeking behavior may be an indication of undertreatment This may be “pseudoaddiction” – such patients are often angry and hostile – increase the dose by 50% to determine effect This may be “pseudotolerance” Myth: Dependence and Tolerance Indicate Risk of Addiction Tolerance to analgesia is uncommon and totally independent of addiction Dependence is universal after 5-7 days of regularly scheduled opioid – true also for prednisone and many other drugs – patients can be tapered off opioids in 5-10 days Myth: Patients Who Complain of Other Pains After the Initial Pain is Controlled are Abusers Multiple pains are common in advanced disease – 80% of 100 patients had 2 or more different pains – 34% of 100 patients had 4 or more different pains Twycross, RG, Fairfield S. Pain 1982 Most patients perceive primarily their most severe pain Expect > 1 pain and patiently address each as it presents Myth: If Used Early in Progressive Disease, Opioids May Not Work Later There is no ceiling effect for mu opioids Doses can be increased over a large range Tolerance to analgesia is rare Failure to treat pain may result in adverse sequelae of undertreated pain Treat pain whenever it occurs in the course of the disease Myth: All Pain is Opioid-Responsive Most nociceptive pain is opioid-responsive Some chronic pain is not opioid responsive – – – – – neuropathic pain myofascial pain pain due largely to stressors pain in somatization disorder learned pain behavior Opioid-responsive constipation pain should not be treated with opioids Myth: Parenteral Opioids are More Effective than Oral Opioids The level of drug at the receptor determines effect, not the route of administration IV may be useful for more rapid onset with the first dose or dose finding (PCA) Oral opioids are as effective as parenteral – parenteral routes reinforce the sick role – IM hurts, use SC or IV (if there already is access) – IV dosing may increase morphine tolerance Myth: Morphine is the Most Potent Opioid Equivalent doses of mu opioids are equianalgesic duration of action may vary among opioids time to onset of activity may vary among opioids Tolerance is not the same as activity Patients’ beliefs about drugs can affect efficacy problematic with methadone and morphine avoid a drug to which a patient is resistant Drug Approximate Approximate Approximate Equianalgesic Equianalgesic Equianalgesic Onset Dosing Oral Dose IM Dose PO - IM Interval (mg) morphine 30 a.t.c. 60 p.r.n. oxycodone 15-30 hydromorphone4-6 methadone 20 levorphanol 4 meperidine 150-250 (mg) (minutes) (hours) 10 10 n.a. 1.5-2 10 2 75-100 20 15 4- 6 20 n.a. 20 15 30 20 30 20 15 10 4- 6 4 6- 8 6- 8 2.5-3.5 Do not usefor >1-2 days dueto long acting toxic metabolite fentanyl,transdermal 50 g/h patch ~30mg s.a. morphine q12h ~10 mg p.o. morphineq4h Myth: Opioid Dose Increases Should be Conservative Ineffective doses provide risk without benefit Opioid doses should be increased by a full 50% in opioid-tolerant patients Smaller increments may support false beliefs that opioids are not effective Continue to increase the dose until analgesia or unacceptable side effects occur there is a large interpatient variation in response Myth: Opioids Always Depress Respiration Acutely, opioids can be profound respiratory depressants opioid-naïve patients After 5-7 days of continuous opioids, patients predictably become tolerant to respiratory effects opioid-tolerant patients pain is a powerful analeptic in awake patients Myth: Only Use Regularly Scheduled Opioid Doses in Patients with Continuous Pain Use regularly scheduled doses to maintain analgesia Also use 1/2 of the q4h dose (1/6 of the q12h dose) q2h prn breakthrough pain When > 2-3 breakthrough doses are needed for > 2-3 days, increase the regularly scheduled dose Myth: Ranges of Opioid Doses and Intervals Should be Ordered Nurses often are more aware of their patients’ pain than are the doctors Nurses commonly use the lowest dose at the least frequent interval ordered Prescribers should order what they believe is needed on a regular schedule Probable effective doses should be the minimum ordered with provision to increase Myth: Patients in Pain Don’t Skip Analgesic Doses Once pain is controlled for a few days, patients often try to skip doses of short acting opioids – fear of adverse drug effects – family and friends who fear drug effects Long term compliance is greatly aided with less frequent dosing WA 134:.? Gamma-alum Tm Pin Com PoorOrNo Coma 4 81210 20 a4 Physiological Responses to Repetitive Nociceptive Input Windup highly augmented response to repetitive afferent (C-fiber) input Neuronal plasticity changes in the CNS in response to repetitive afferent nociceptive input WHO Principles for Opioid Use 1) use the oral (or other noninvasive) routes when possible, 2) titrate doses to individual response, 3) utilize analgesics as described on the analgesic ladder, 4) maintain effective drug concentrations while noxious stimulus is present, and 5) use adjuvant medications when indicated. Rationale As long as a noxious nociceptive stimulus responds to pharmacotherapy, medication should be used on a regular schedule or time-contingent basis. Time-Contingent Dosing   Utilized for Acute and Chronic pain Minimizes centrally mediated pain processes  Neuronal plasticity  Physiologic Windup  Around the clock dosing schedule  Regular schedule versus “PRN” only dosing Oral Long Acting Opioid Dosage Forms Pharmacologically Long Acting methadone levorphanol Pharmaceutically Long Acting morphine – MS Contin, Oramorph SR, Kadian, Morphine ER, Avinza oxycodone – OxyContin hydromorphone (?soon) – Palladone XL Myth: Patients Taking Opioids Cannot Drive Safely Opioids impair cognition and psychomotor coordination initially – patients should not drive for 5-7 days after starting opioids or a dose increase After 5-7 days of continuous opioids, tolerance to these effects develops – studies show no increase in MVA in patients taking chronic opioids Vainio A et al. Lancet 1995;346:667-70 Galski T et al. J Pain Symptom Manage. 2000;3:200-8. Myth: Opioids Cause End Organ Toxicity Respiratory and CNS toxicity have occurred with high opioid doses in opioid-naïve patients Long term opioid therapy does not produce reported end-organ toxicity in patients who are titrated to response and monitored correctly – Long term NSAIDs may cause GI and renal toxicity – High acetaminophen doses can cause hepatotoxicity Refute Myths About Opioids Addiction is exquisitely rare 0/~10,000 burn patients receiving opioids < 4/12,000 exposures caused iatrogenic addiction Dependence in nearly universal Not a problem, drugs can be tapered over ~7 days End organ damage very rare with chronic use Tolerance to analgesia is not common Opioids do not produce functional deterioration Barriers to Pain Management Health professionals – Fear of addiction, tolerance and respiratory depression – fear of regulatory sanctions Patients – fear of addiction and adverse effects – concern that drugs should be saved until needed The health care system – multiple copy prescription forms – overly zealous regulators – the “just say no” mentality Barriers to Pain Management Attitudes – no one ever died from pain – patients will tell me if they hurt Knowledge – opioid doses and pharmacokinetics – risk:benefit ratio of using analgesics appropriately Practices – discouraging opioid use – avoiding patients who seek opioids – using nonopioids in favor of opioids Report of the Institute of Medicine Committee on Care at the End of Life Field MJ, Cassel CK, Editors Division of Health Care Services Institute of Medicine National Academy of Sciences National Academy Press Washington DC 1997 Initiation of of Palliative Care Current Model of Care Palliative Care Curative interventions Diagnosis Death Optimal Model of Care Curative interventions Palliative care Diagnosis Death Lipman AG, Jackson KC, Tyler LS. (eds) Evidence Based Symptom Control in Palliative Care, Binghampton NY Haworth Press Inc, 2000 The Use of Opioids for the Treatment of Chronic Pain American Academy of Pain Medicine and American Pain Society Joint Consensus Statement New science supports use of opioids in CNMP Pain management is often inadequate Many common assumptions need modification Policy is evolving Principles of practice for opioids are needed Good medical practice should guide the prescribing of opioids October 1997 Model Guidelines for the Use of Controlled Substances for the Treatment of Pain Federation of State Medical Boards of the United States Quality medical practice dictates pain relief Inadequate care results from lack of knowledge Boards should define boundaries of practice * evaluate the patient * define treatment plan * informed consent * periodic review * consultation * medical records * complies with law & regulations May 1998 Good Documentation is Essential Accurate and complete records to include History and physical examination Evaluations and consultations Risk:benefit discussions Lab test results Treatment objectives Treatments Medications with date, type, dosage, quantity Instructions and agreements Periodic reviews Pain Guidelines: A “Historical” Perspective WHO Analgesic Ladder (1986) AHCPR Acute Pain (1992) AHCPR Cancer Pain (1994) American Pain Society Quality of Care Committee QI Guidelines (1995) “Recent” Pain Guidelines American Society of Addiction Medicine - Public Policy Statement on Opioids (1997) American Geriatrics Society - Clinical Practice Guideline on the Management of Chronic Pain in Older Persons(1998) American Medical Directors Association - Clinical Practice Guideline for Chronic Pain in the Long Term Care Setting (1999) American Academy of Pediatrics/American Pain Society Joint Statement - Assessment and Management of Acute Pain in Infants, Children, and Adolescents (2001) “Recent” Pain Guidelines American Pain Society – Principles of Analgesic Use in Acute and Cancer Pain, 4th ed. (1999) – Clinical Practice Guideline for Sickle Cell Disease Pain (1999) – Clinical Practice Guideline for Osteoarthritis and Rheumatoid Arthritis Pain (2002) – Clinical Practice Guideline for Pain Associated with Fibromyalgia (2003?) Pain Assessment & Treatment in the Managed Care Environment American Pain Society Position Statement (2000) www.ampainsoc.org/managedcare/position.htm Opioid Statements American Academy of Pain Medicine and the American Pain Society – Joint Consensus statement entitled, The Use of Opioids for the Treatment of Chronic Pain. (1997) Federation of State Medical Boards of the United Sates – Model Guidelines for the Use of Controlled Substances in the Treatment of Pain (1998) Opioid Statements - Continued American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine – A consensus document for definitions related to the use of opioids for the treatment of pain Use in the 'lreatment {If Acute Pain and Cancer Pain 17:) will Editi?n AMERICAN PAIN SOCIETY All this needless pain and suffering impoverishes the quality of life of those afflicted and their families; it may even shorten life by impairing recovery from surgery or disease. People suffering severe or unrelenting pain become depressed. They may lose their will to live and fail to take normal health preserving measures; some commit suicide. Liebeskind J, Melzack R. Pain 1987;30:1