Pain in advanced illness

Transcription

1 Methadone: Safe and Effective Use for Hospice Pain Management for Adult and Pediatric Patients Nathaniel Hedrick, PharmD ProCare HospiceCare Clinical Pharmacist Jeremy L. Brown, MD Medical Director, Hospice of Lubbock Pain in advanced illness Two attitudes can disservice patients Avoidance Careless Use Critical balance between do no harm and reduction of suffering Under treatment is common Many patients and caregivers worry about addiction and stigma 1

2 Objectives Identify appropriate patients to consider for methadone use. Discuss the risks and benefits of Methadone use for pain management Provide dosing and monitoring strategies for safe and effective use of methadone Test Your Knowledge True or False Treatment with methadone is generally expensive Methadone can safely be used in opioid naïve patients Methadone is a naturally occurring opioid Methadone is only effective for neuropathic (nerve) pain Patients will not get pain relief from the first dose of methadone Methadone is safe to use in patients with kidney disease False True False False False True 2

3 History Methadone was developed in 1937 by German scientists Brought to market officially in 1943 and was widely used by the German army during WWII under the name Polamidon After the war, Eli Lily introduced methadone to the U.S. as Dolophine Marketed as a safer alternative to morphine because it does not cause as much sedation or nausea 3

4 History Dr. Vincent Dole & Dr. Marie Nyswander, sought to change the perceptions and treatment options for heroin addicts 1964: 6 patients 1967: 300 patients 1971: 25,000 patients Looked at as replacing one addiction with another By 1973, methadone saw limited use History 1990 s shed light on the positive effects it was having on neuropathic pain control Started to see a resurgence of use for chronic pain and cancer patients 2006 FDA Public Health Advisory warning of increasing reports of death and life threating side effects 4

5 Ask the Audience Methadone Perceptions What are some concerns you have experienced in your practice regarding methadone? How do patients respond when methadone is first brought up as a treatment option? What strategies do you currently employ when changing a patient s pain regimen? Nociceptive vs. Neuropathic Pain 5

6 Nociceptive vs. Neuropathic Pain Nociceptive: Inflammatory Muscle, tissue, or organ pain Often pain with movement Dull, aching, or throbbing Includes bone and arthritic pain Nociceptive vs. Neuropathic Pain Neuropathic: Shooting, stabbing, radiating, burning, tingling, numb, electrical Allodynia pain from a stimulus that normally does not provoke pain Hyperalgesia increased sensitivity to a stimulus that is normally painful Damage to peripheral nerves Lack of opioid rotation 6

7 Methadone and Neuropathic Pain Most effective opioid for neuropathic pain Active N methyl D aspartate (NMDA) receptor antagonist Reduces CNS sensitization to pain/hyperalgesia Reduces CNS amplification of pain sensation Few other known NMDA receptor antagonists: Dextromethorphan Ketamine Memantine Pharmacokinetics Patients can feel analgesia with the very 1 st dose 7

8 Pharmacokinetics Half life Long, but variable (4 130 hours) Increases with repeat dosing Duration of action 3 6 hrs with INITIATION of dosing Increased to 8 24 hours with REPEATED dosing Takes 5 7 days to reach steady state Routes of Administration Multiple dosage forms Tablet (5 mg, 10 mg, 40 mg) Liquid Concentration (10 mg/ml) Injection (10 mg/ml) Well absorbed from multiple routes of administration Oral, Rectal, Subcutaneous, IV, Sublingual, Vaginal PO Methadone to IV Methadone IV Methadone to PO Methadone PO:IV 2:1 IV:PO 0.7:1 8

9 Management of Side Effects Common side effect Opioid induced constipation (stasis) First line medication(s) Senna S Reglan Comments Induces motility Avoid all mush, no push! Less severe/frequent with methadone Opioid induced nausea/vomiting Haldol Compazine Reglan Dopamine mediated Less severe/frequent with methadone Sedation Opioid induced itching/rash Oral steroid Ritalin Oral diphenhydramine *Hydroxyzine Reduces with continued use Less severe/frequent with methadone Uncomplicated itching/rash is a common side effect, not an allergy. Switching opioids may or may not be effective Case Study 80 y/o man with End Stage COPD. At time of admission, RN assessed pain to feet and skin. Methadone started at 2.5mg daily 4 days later increased to BID Continued to titrate up to 2.5mg /2.5 mg / 5mg 4 days later developed severe hypotension. Pt s neuropathic pain was much improved and pt did NOT want to stop Methadone Dose reduced back to 2.5mg TID 2 weeks later, pt requested dose be increased back to previous 2.5mg / 2.5mg / 5mg Midodrine started to help counteract hypotension 9

10 Hepatic and Renal Considerations Renal Function Renal Function CrCl > 40 CrCl = CrCl = CrCl < 10 Preferred Agents Morphine Oxycodone Hydromorphone Methadone Oxycodone Hydromorphone Methadone Oxycodone Methadone Oxycodone Methadone Safe in renal failure No active metabolites Dose should still be reduced in severe impairment Does undergo hepatic metabolism so should be avoided in severe liver disease. Pharmacokinetic Concepts Liver Metabolism Normal Process CYP enzyme (mainly CYP3A4, CYP2B6) Active methadone 100% inactive methadone NO ACTIVE METABOLITES 10

11 Pharmacokinetic Concepts Liver Metabolism CYP inhibitors and Liver Failure Active Methadone CYP enzyme (mainly CYP3A4, CYP2B6) CYP inhibitors CYP3A4 and/or 2B6 INHIBITORS CYP3A4 and CYP CYP inhibitors 2B6 (Think: Methadone TOXICITY) verapamil desipramine* sertraline* clotrimazole nicardipine erythromycin metronidazole clarithromycin haloperidol amiodarone fluconazole caffeine doxycycline diltiazem paroxetine Case Study 43 y/o woman with Cervical Cancer with metastasis to the Liver, Small Intestines, Omentum, and Peritoneum. Pt s methadone doubled from 12.5mg daily to 25mg daily On the same day, Diflucan 200mg daily for 14 days started A month later, pt presented to office and complained of increased somnolence 11

12 Pharmacokinetic Concepts Liver Metabolism CYP Inducers CYP CYP enzymecyp enzyme enzyme (CYP Inducers) CYP3A4 and/or 2B6 INDUCERS (Think: methadone REDUCTION/WITHDRAWAL) Active Methadone carbamazepine (Tegretol ) dexamethasone oxcarbazepine (Trileptal ) phenytoin* phenobarbital* nevirapine* primidone* Opioid Cost Comparison Opioid Avg cost: Per dose Per 15 days supply Continuous infusion Varied $ 250+ OxyContin $ 5.39 $ 226 OxyFast $ 3 6 $ 180 Hydromorphone Injectable $ 2.83 $ 170 Morphine Injectable $ 2.63 $ 158 Morphine Sulfate ER $ 2.13 $ 85 Fentanyl Patch $ 16/patch $ 80 Methadone $ 0.13 $ 5. 12

13 QT Prolongation QT prolongation Torsades de Pointes (TdP) Ventricular tachycardia (FATAL) QT Prolongation Risk Factors Impaired liver function Arrhythmias, CAD/MI, CHF QT prolonging medications (amiodarone, quetiapine, haloperidol, chlorpromazine, citalopram, paroxetine, fluoxetine, sotalol, trazodone, Ranexa, ondansetron) Electrolyte imbalances (hypokalemia, hypomagnesemia), also caused by diuretics, laxatives, vomiting and diarrhea Doses greater than 200 mg of methadone per day 13

14 QT Prolongation Avoid in multiple risk factors; reduce controllable risk factors (dehydration, nausea/vomiting/diarrhea, QT drugs) Arrhythmia alone is not a contraindication Risk vs benefit discussion with patient and caregivers Monitor for new/increased tachycardia, syncope, palpitations, diaphoresis (indicating new arrhythmia) Consider baseline/periodic EKG in patients with longer prognoses When to Use Methadone Patients with rapidly escalating drug requirements (greater than 200 mg of morphine equivalents a day) Full Conversion Adjunct Dosing Patients with dose limiting side effects from other opioids Nausea, constipation, hallucinations, myoclonus Patients having trouble swallowing pills who need long acting pain control Patients or caregivers with a history of drug addiction or diversion 14

15 Case Study 83 y/o man with Cutaneous T Cell Lymphoma and Mycosis Fungoides. Upon admission to hospice, pt c/o a head to toe rash that was pruritic at all times and making the patient uncomfortable. Methadone was started at 2.5mg qhs 7 days later increased to 2.5mg BID Titrated up over several weeks to 5mg BID In the last 5 days of life, Methadone was changed to oral concentrate (10mg/ml) and given q8hrs Methadone Dosing 1. Add up total oral morphine equivalents (OME) 2. Use morphine : methadone conversion factor 3. Consider cross tolerance dose reduction 4. Divide daily dose into 2 3 doses per day Use breakthrough medication during titration Monitor daily for pain levels and new/worsening adverse effects Increase total daily dose no more frequently than every 5 days Patients on greater than 200 mg of morphine/day may need to cross taper 15

16 Methadone Dosing Story P, et al. Methadone is dosed using a non linear conversion The higher the dose of oral morphine equivalents a patient is taking, the greater you divide to get your methadone dose Methadone (NMDA blockade) reverses tolerance/increases sensitivity to opioids Increased opioid sensitivity = lower methadone dose required Methadone Dosing During initial titration Utilize other immediate release opioid, dosed q2 4hr prn Morphine IR, oxycodone IR, hydromorphone IR IF methadone must be used for breakthrough pain, start low and limit to 3 prn doses/day Calculate breakthrough dosing One breakthrough dose = 5% 15% of total daily dose of oral morphine equivalents (OME) Good rule of thumb: 10% of the total daily dose of OME 16

17 Methadone Dosing Current medications: MS Contin 30mg PO q8h Morphine IR 10mg PO q2h prn BTP (using 5 doses/day) Total Oral Morphine/day: 140mg Methadone equianalgesic dosing ratio: 8:1 140 divided by 8 = 17.5mg per day Dose reduce by 25% = mg When switching between opioids Round up to 15 mg (severe pain) or down to 10 mg (pt is not in pain) Case Study AR, 6 y/o girl with Cerebral Palsy, Spontaneous and Chronic Dislocation of the Left Hip. Pt also has worsening scoliosis Patient was using morphine 15mg every 3 hours around the clock with worsening pain Methadone 5mg q8 selected as starting dose Dose not reduced based on Morphine usage Dose reduction accounted for in oral morphine equivalents to methadone ratios But what about Cross Tolerance? 17

18 Case Study 6 y/o girl with a Pilocytic Astrocytoma, multiple resections and treatment. 2 years after diagnosis she developed bilateral subdural hygromas and a hemorrhagic tumor to the left basal ganglia Pt admitted to hospice Methadone started after 10 days of morphine Summary Two attitudes that can disservice patients in pain management Avoidance Careless Use 18

19 Questions?? References 1. Vincent P. Dole and Marie Nyswander, "A Medical Treatment for Diacetylmorphine (Heroin) Addiction: A Clinical Trial With Methadone Hydrochloride" Journal of the American Medical Association, August 23, 1965, Story P. Primer of Palliative Care, 3 rd Ed. AANPM Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol Jun 1;19(11): Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14): Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA receptor. J Pain Symptom Manage. 2000;19(suppl 1):S2 S6. 6. Davis AM, Inturrisi CE: d Methadone blocks morphine tolerance and N methyl D aspartate(nmda) induced hyperalgesia. J Pharmacol Exp Ther 1999;289: Zichterman, A. Opioid Pharmacology and Considerations in Pain Management [Online]. Continuing Education webpage. US Pharmacist website. Available at: Accessed 12/28/ Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003;8: Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol Sep Oct;1(3): Morley JS, Bridson J, Nash TP, et al. Low dose methadone has an analgesic effect in neuropathic pain: a double blind randomized controlled crossover trial. Palliat Med. 2003;17: Stephens E, Louden M (Ed.), VanDeVoort J (Ed.), Burns M (Ed.), Halamka J (Ed.), and Tarabar A (Chief Ed.). Opioid Toxicty: Pathophysiology. Medscape website. Available at: overview#a0104. Accessed 12/28/ Lexi Comp OnlineTM, Lexi Drugs OnlineTM, Hudson, Ohio: Lexi Comp, Inc.; July Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, Inturrisi C, et al. Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society. J Pain Apr;15(4): Dolophine Product Package Insert. Roxane Laboratories, Inc., Columbus, Ohio. October