Managing chronic and breakthrough pain with opioid analgesics

1. Managing chronic and breakthrough pain with opioid analgesics Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and Anesthesiology Director, Center for Pain Medicine, Research and Policy University of Pennsylvania School of Medicine Director of Pain Management Philadelphia Veteran Affairs Medical Center rgallagh@mail.med.upenn.edu

2. PRINCIPLES OF TREATMENT:Summary Primary prevention: - avoid injuries and diseases Secondary prevention: - when injuries or diseases occur, prevent or minimize nociception or neural activation of pain pathways with specific, targeted interventions and restore and maintain function Tertiary prevention - manage perpetuating factors, control pain and restore function and quality of life

3. Challenges of Providing Chronic Pain Care Changing societal laws, customs, values, economies

4. Over 30 years a major shift occurred in opinion about the use of opioids for chronic pain 1) Emphasis on evidence, not opinion, in clinical medicine 2) Emphasis on cost-containment in managed systems: short-term solutions and cost-shifting 3) Documented clinical experience over several decades: - Cancer pain management - Rehabilitation of disabling back pain - Treatment of severe neuropathic pain (often failed back surgery)

5. Over 30 years a major shift occurred in opinion about the use of opioids for chronic pain • 4) Recognition that: • poorly controlled pain damages the nervous system and must be controlled • pain as a chronic disease • societal health burden of uncontrolled pain exceeds, many fold, the burden of prescription drug abuse • 5) Recognition that opioids are: • * well-tolerated by many • * generally safe (e.g., motor function, driving,etc), • compared to other medications for daily use for pain (e.g., in elderly)

6. Over 30 years a major shift occurred in opinion about the use of opioids for chronic pain • The demonstration that NSAIDs and acetomenophen, and now Cox-IIs, are potentially dangerous • The recognition opioids are effective for pain diseases (e.g., neuropathic pain) • The recognitionthat use of opioids after painful injury may prevent chronic pain. (Secondary prevention) • The recognitionthat opioids for common chronically painful conditions in elderly may improve health outcomes

7. Opioid protective effectCastillo et al Pain 124(2006),321-326 “Patients treated with narcotic medication for pain at three months post-discharge were protected against chronic pain, despite the fact that these patients had higher pain intensity levels and were thus at higher risk.” “The results presented here appear to lend support to the theory that… ..early aggressive pain treatment may protect patients from central sensitization and chronic pain.” DID ANY PATIENTS DEVELOP: HYPERALGESIA? TOLERANCE? ADDICTION?

8. Opioid protective effect: Tertiary Prevention • Study of 10,372 nursing home residents • patients appear to function better and more safely when taking opioids for pain • presumably because with better pain control, they are more ambulatory, stronger and less likely to fall Therefore, under clinical conditions where dosing and use is monitored, such as in the Won et al. J Gerontology. 2006; 61A(2):165-69.

9. EFFECTS OF THESE CHANGE IN PERSPECTIVE AND PRACTICE MODELS • More opioids prescribed • More patients obtaining pain relief • More opioids in circulation • The Opium Wars, circa 2006

10. Changes Opioid Prescribing1997-2001 • Morphine 143% • Hydrocodone 173% • Fentanyl 240% • Methadone 350% • Oxycodone 430% • Meperidine -10% DEA ARCOS data

11. Percentage of U.S. Unintentional Drug Poisoning Deaths† from Opioid Analgesics, Cocaine, and Heroin, 1999 to 2002* • 30% • 20% • 10%

12. OUR CONUNDRUM Growing societal awareness of: 1. the prevalence of inadequately treated chronic pain 2. its impact on society 3. the need for access to effective pain treatment VS Growing societal awareness of: 1. The rapidly increasing rate of use of opioid prescriptions 2. The increasing rate of prescription drug abuse 3. The increasing rate of prescription drug abuse deaths

13. New York Times MagazineJune 17, 2007, COVER STORY When Is a Pain Doctor a Drug Pusher? By TINA ROSENBERG

14. QUESTIONS • When should I consider treating chronic pain with opioid analgesics? • What should guide selection of a long-acting opioid in the treatment of chronic pain? • How do I titrate opioid medications and evaluate effectiveness?

15. QUESTIONS 4) When and how should methadone be used in the treatment of chronic pain? 5) Should use opioids to treat patients with chronic pain who also have a substance abuse history? 6) How should I use treatment agreements? • When should I consider stopping opioid therapy in a patient who has been on opioids chronically? How should this be done?

16. Medication selection in pain is based upon more than just pain severity * • Diagnosis • Efficacy • Clinical trial data • Mechanisms of pain (s) • Co morbidities: medical and psychiatric • Prior treatment responses • Side effect burden, toxicity risk, and the need to maintain function • Gallagher RM, Verma S. Sem Neurosurg 2004; 15(1):31-46. • Sindrup SH, Troels TS. Pain. 1999;83:389-400. • Galer BS. Neurology. 1995;45(suppl 9):S17-S25.

17. Gabapentin (Rowbotham et al, 1998) Drug or Therapeutic Class Efficacy Comparison, Neuropathic Pain: Numbers Needed to Treat Analyses Lidocaine Patch 5% (Meier et al, 2003) 4.4 2.7 Opioids (Raja et al, 2002) Tricyclic Antidepressants (Raja et al, 2002) 4.0 3.2 5.0 Gabapentin (Rice and Maton, 2001) Capsaicin (Sindrup and Jensen, 1999) 5.3 ∞ 15 20 10 0 5 Number-needed-to-treat (NNT) Mean ±95% Cl Meier et al. Pain. 2003;106:151–158

18. Medication selection in pain is based upon more than just pain severity * • Ease of use • dosing • titration • drug-drug interactions • patient acceptability • Pain’s psychosocial context and the doctor-patient relationship: - stigma - cost - illness behavior - risk of treatment non-adherence - risk of medication misuse • Gallagher RM, Verma S. Sem Neurosurg 2004; 15(1):31-46. • Sindrup SH, Troels TS. Pain. 1999;83:389-400. • Galer BS. Neurology. 1995;45(suppl 9):S17-S25.

19. Opioid Analgesics • Opioids have important advantages in the treatment of pain: • Opioids relieve the subjective suffering component of pain, without interfering with basic sensation, such as light touch, pinprick, temperature, position. • No ceiling effect • Actions reversible with antagonists • Patients often report: • “The pain is still there, but it doesn’t bother me”

20. What should guide selection of a long-acting opioid in the treatment of chronic pain? Identify the kind of pain: • Nociceptive pain • Neuropathic pain • Visceral pain • Myofascial pain Identify the pattern of the pain

21. What should guide selection of a long-acting opioid in the treatment of chronic pain?THE PATTERN Over Medication Around-the-ClockMedication Breakthrough Pain Persistent Pain Time

22. CHOOSING MEDICATION Expect partial effects Use multiple agents with different mechanisms: - from different classes - from the same class

23. Algorithm for Medication Selection in Chronic Pain with and without Co-Morbid Depression Pain condition Neuropathicpain Nociceptivepain Secondary depression Primary Depression Secondary sleepdisturbance Evaluate risks Persists afteradequateanalgesia Evaluate risks Persists afteradequateanalgesia Short-termNSAIDs,Cox-II (?),opioids SSRI trial Evaluate risks Evaluate risks Lidocaine patch;gabapentin & other AED (Ca+ & Na+ channels); alpha 2 agonists (tizanidine, clonidine);opioids SNRIs: venlafaxine, duloxetine Antihistamine,zolpidem,low-dosebenzodiazepine Trazodone Low-doseTCA Titrate TCAs (Na+ channels and SNRI) : desipramine, nortriptyline, Gallagher RM, Verma S. Semin Clin Neurosurgery. 2004 This information concerns uses that have not been approved by the US FDA.

24. What should guide selection of a long-acting opioid in the treatment of chronic pain? Establish the goals of treatment: • Pain relief and reduced suffering • Improved functional capacity & QOL: • Physical functioning • Cognitive functioning • Social functioning • Role functioning To do what? To think about what? To be with and enjoy whom? To accomplish what?

25. Choices of LA opioid All preparations are mu opioid agonists. All opioids are effective. LA morphine: provides sustained serum levels of active morphine • Q 8-12 hours (MS Contin) • Q 12-24 hours (Kadian) • Q 24 hours (Avinza) LA oxycodone (Oxycontin): Q 8-12 hours [now manufactured by two companies] Methadone Q 6-12 hours [also has NMDA effect specific for neuropathic pain] Transdermal fentanyl patch: Q 48-72 hours

26. Variability Opioid Responsiveness • Pain syndromes differ • Somatic versus neuropathic • Different patients respond differently • Responsiveness may be genetically mediated • Drugs may vary in specific activity • Evidence of sub-mu receptors emerging • Incomplete cross tolerance suggests variable sub-mu activities of different opioids

27. Genetic variability of morphine analgesia in Mouse Strains Strain Morphine (5 mg/kg) CD-1 76% Swiss Webster 40% BALB/c 90% C57/bgJ 62% C57/+ 40% HS 62% CXBK 0% Pasternak, G 2003

28. *P <.004 **P <.001 100 75 Analgesia (% of mice) Morphine Morphine, s.c. 50 Fentanyl Fentanyl (-)Methadone Heroin, s.c. Morphine, s.c. Heroin, s.c. Morphine M6G M6G (-)Methadone 6AcMor 6AcMor 25 * ** 0 CD-1 CXBK All drugs were given i.c.v., unless stated otherwise 6AcMor=6-acetylmorphine Rossi GC, et al. Neurosci Lett. 1996;216:1-4. Opioid Analgesia in CD-1 and CXBK Mice Courtesy, G Pasternak 2006

29. Who is likely to do well on LA opioids? Level 3-4 evidence suggests that the following characteristics predict lower rates of aberrant behavior: • Goal-directed, adherent to medical regimens, and functional • Takes responsibility for health and multi-modality treatment • Understands concepts in opioid use: tolerance, dependence (physical), addiction Bloodworth D, Am J Phys Med & Reh 2005(S);84(3):S64

30. Who is likely to do well on LA opioids? Level 3-4 evidence suggests that the following characteristics predict lower rates of aberrant behavior: • Understands and accepts the need for treatment agreements • Absence of severe, chronic psychopathology • Absence of personality disorder • Rarely overuses medication • No illicit drug abuse or alcohol abuse Bloodworth D, Am J Phys Med & Reh 2005(S);84(3)

31. Which characteristics might predict that a patient might require more structure? • Aberrant Behavior: The Opioid Renewal Clinic: A structured approach to managing opioids for pain in primary care (Wiedemer et al PAIN MED 2007) 2)In pain and addiction co-morbidity, managing either addiction or chronic pain alone, without managing the other, is usually futile.

32. When and how should methadone be used in the treatment of chronic pain? Advantages over other LA opioids • moderate NMDA (N-methyl-D-aspartate) receptor antagonist activity, such that in animal studies methadone attenuates the development of tolerance and hyperalgesia • theoretically methadone may reduce wind-up and sensitization that leads to tolerance and dosing escalation in neuropathic pain Advantage over morphine • lower potential for opioid-induced neurotoxicity • lower mu-opioid-receptor affinity • absence of active metabolites

33. Methadone • Not prone to conversion to a SA opioid by crushing, as are LA morphine and oxycodone preparations • Relatively graduated onset of action reduces the likelihood of a psychoactive effect.

34. Methadone’s disadvantages • Stigmatization due to long association with the treatment of heroin addiction • Inexactness of equivalency tables due to the variability of methadone metabolism: SAFETY ISSUE • Interactions with other medications due to metabolism by the type I cytochrome P450 (CYP450) group of enzymes - fluoxetine directly inhibit CYP3A4, reducing elimination of methadone - venalafaxine has the lowest probability of interaction with methadone, only marginally inhibiting CYP1A2 • May require three or four times daily dosing for pain control

35. Pharmacokinetic & Pharmacodynamic Properties • Long and variable half-life (15 to 150 hours) • Elimination half-life does not reflect duration of analgesia • Onset of action 1-2 h • Peak effect 3-4 h • Steady state 5-7 days • Analgesic effect - approx 6 to 8 hours

36. Points to consider regarding equianalgesic conversion ratios Due to inter-individual variability in hepatic metabolism of methadone and potential interactions with other meds: • Equianalgesic conversion ratios are imprecise • Contrary to logic, methadone appears to be more potent when changing from high doses of other opioids, thus there are dose dependent conversion ratios. • Equianalgesic conversion ratio is only one factor in properly dosing methadone or any other opioid. Use the conversion table to get an idea of what the end point of titration might be. It is often lower but depends on many variables.

37. Dosing Strategies • Overall strategy: start low and go slow • Opioid naive or on low dose of current opioid • Stop current opioid • Start low : generally 2.5 to 5 mg • Start with one dose or BID on day one. • If tolerated increase to q 6 to 8 hours over the next 2 to 4 days, hold at this level for 5 to 7 days then start with the incremental increases as listed below. • Each 6 or 8 hourly dose may be increased by 2.5 to 5 mg increments every 5 to 7 days • If the patient becomes sedated, hold increasing dose until tolerance to sedation develops • Once adequate analgesia has been achieved, the same daily dose can be given in divided doses every 8 or 12 hours

38. Patient education highlights a. Explain that initial dose will often be inadequate for pain relief b.Reassure that the dose will be titrated to adequate analgesia c. Explain that analgesic effect of methadone will probably be felt toward the end of the first week d. Address the stigma of use in heroin addiction up front. Methadone was a pain medication before a heroin addiction medicine ! e. It is " different" than what is used for heroin addiction- it is a pill, not a liquid

39. Methadone and Torsade de Pointes • Methadone is used daily by > 180,000 Americans. • The literature reports 17 cases of torsades. • Of the 17cases, 10 patients were on other contributing drugs and most were on doses > 100 mg/day.

40. Methadone and Torsade de Pointes Recommendations: • Titrate methadone slowly; Monitor patient for dizziness, lightheadedness, palpitations. • Monitor ECG in patients with risk factors (i.e. on medications that have torsades potential) • DO NOT use in patients with: - Prolonged QT - Recent conversion from atrial fibrillation - Family history of sudden death

41. When to stop opioid in a patient • If they have adverse reactions to opioids, such as depression or respiratory depression. • If they do not achieve reasonable therapeutic goals such as improved physical or social functioning, even with effective pain relief.

42. When to stop opioid in a patient • If they do not adhere to other prescribed treatment that is necessary for a desirable treatment outcome • If they exhibit persistent aberrant behavior and are unable to responsibly manage opioids within the constraints of a treatment agreement. • If they are diagnosed with an addiction disorder and refuse referral for its treatment.

43. How to taper opioids? • Discuss with the patient and other responsible persons who may be or helpful. • Reassure patient and SO of alternative plan for pain control. • Patients with aberrant behavior or addiction may refuse to comply and leave treatment, seeking opioids elsewhere. • Document discussions and provide a written treatment plan that is given to the patient.

44. How to taper opioids? 4) The speed depends on the clinical circumstances. • A slow taper can be done by reducing the dose by 10 % every two weeks or even longer. • A more rapid taper can be accomplished but may require additional medical management of withdrawal symptoms. 5) An alpha 2 agonist such as clonidine can be used to help medically stable patients manage withdrawal symptoms. Some advocate gabapentin as well.

45. How to taper opioids? 6) Patients and their significant others need to know what to expect – discomfort, anxiety, restlessness, nausea, sweating, etc. – but that controlled withdrawal from opioids is not dangerous in and of itself. 7) If the patient is taking a sedative or benzodiazepine, these should be maintained, as their withdrawal is more difficult and dangerous.

46. SUMMARY: Using opioids in pain medicine Generate: • hypotheses about pain diagnosis and mechanisms • a biopsychosocial formulation of pain • Identify risk factors for opioid use Prioritize a problem list for each patient, identifying immediate, pivotal and background biopsychosocial problems. Use evidence-based algorithms to treat different types of pain Identify functional outcome goals for treatment

47. SUMMARY: Using opioids in pain medicine Gradually titrate short acting opioids to effects Replace with Long Acting Opioid to equivalent dose Provide limited amounts of Short Acting Opioids for breakthrough pain Train patient to use other behavioral and physical techniques to manage pain: • Ice • Stretch • TENS • Relaxation • Avoidance • Pacing

48. SUMMARY: Using opioids in pain medicine If one opioid not tolerated, or loses effectiveness, switch to another If switching to methadone, start very low and go slow, and be aware of drug interactions Be patient and don’t leave the patient short Empower and engage patient: www.nationalpainfoundation.org

49. ABOVE ALL, MAINTAIN INTELLIGENT AND INFORMED EMPATHY – BE PATIENT If I can stop one heart from breaking I shall not live in vain; If I can ease one life the aching Or cool one pain, Or help one fainting robin Unto his nest again, I shall not live in vain  Emily Dickinson

50. The Public Health Problem of Chronic Pain • Causes • lack of societal & medical knowledge about chronic pain diseases and conditions • primary prevention • secondary prevention • treatment • education and training deficits • social inequities in access to care • ineffective organizational models of care