Treating End of Life Pain

Transcription

1 Page 1 Mary Lynn McPherson, Pharm.D., BCPS, CDE Professor, University of Maryland School of Pharmacy mmcphers@rx.umaryland.edu PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This webcast has been supported by an educational grant from Purdue Pharma L.P. Objectives 1. Describe communication strategies to better counsel and treat patients who seek palliative pain relief. 2. Differentiate between acute and chronic pain, including presentation and patient management. 3. Describe the pathogenesis of pain in patients with advanced illness, and the drug therapy selection process to manage pain in these patients. 4. Explain the regulations and guidelines for the disposal of controlled substances at the time of death. Definition of Pain Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. (IASP) Pain is always subjective. Pain is what the patient says hurts. (McCaffery) Passion of the soul. (Aristotle) How do you get your arms around a complaint of pain? Goal of pain management is to relieve and PREVENT the pain from recurring. May involve use of nonpharmacologic interventions. Pharmacologic interventions are a significant part of pain management. Medications should be used judiciously in appropriate combinations.

2 Page 2 Symptom Analysis P (palliative/precipitating/previous therapy) Q (quality) R (region/radiating) S (site/severity) T (temporal) U (YOU - associated symptoms) Palliative / Precipitating What helps relieve pain? Non-drug interventions heat, cold, position change, walking, standing, lying What brings it on? Position changes, weight bearing, personal care, light touch, activities, bowel movement, change in weather Previous Therapy What methods have you used to manage the pain? (past and present): Medications OTC Prescription Herbal and natural products Coping strategies (e.g., prayer, distraction) How well did it work? Did you experience any adverse effects? Quality What does the pain feel like? aching, deep, dull, throbbing, sharp, well localized diffuse, gnawing, cramping, squeezing, pressure, distant sites burning, numb, radiating, shooting, stabbing, tingling IMPORTANT Use the patients own words!

3 Page 3 Region/Radiating Where does it hurt? Can the patient point to an area? Is it localized or referred? Superficial or deep? Does it spread or radiate to other areas or stay in one place? Severity Most commonly defined on a scale Important to use same scale each time How much does it hurt? Pain right now? Pain at its worst? Pain at its best? Pain on average? What level is acceptable? How does it change with activity or rest? Before and after medication? Pain severity scales Should be reliable, valid, and individualized Choice of scale depends on age, ability to communicate and other factors Unidimensional scales preferred in palliative care settings Numerical (1-10) Categorical (none, mild, moderate, severe) Visual Analog Wong Baker Faces Temporal Onset Duration Variation (course/daily) Frequency Patterns (constant or intermittent?) Acute, current or chronic?

4 Page 4 (U You) Associated Symptoms How does the pain affect: Mood/emotional state Work Activities of daily living (e.g., chores, hobbies) Personal relationships Sleep Appetite 1-10 Pain Impact Scale Relate Walk Walk Sleep Sleep Sleep Sleep Active Active Active Active Mood Mood Mood Mood Work Work Work Work Work Enjoy Enjoy Enjoy Enjoy Enjoy Enjoy Increasing Pain Classifying Pain Temporal Acute vs. chronic (what do we mean by chronic pain?) Pain that lasts greater than 3 months Pain that persists beyond the expected healing period Persistent vs. episodic Persistent plus breakthrough pain Malignant vs. nonmalignant Chronic malignant (cancer) Nonmalignant (non-cancer) Pathophysiologic Nociceptive (visceral, somatic), vs. neuropathic Acute vs. Chronic Characteristic Acute Pain Chronic Pain Experience An event Situation, state of existence Source External agent or internal disease May be unknown; if known treatment may be ineffective Onset Usually sudden May be sudden or insidious Duration Transient Prolonged Painful areas Well distinguished Less easily distinguished Clinical signs Typical response Response patterns vary Significance Significant (problem) No significance frequently Pattern Self-limiting or correctable Continuous/intermittent Course over time Usually decreases Usually increases Actions Actions relieve pain Actions modify pain Prognosis Likelihood of eventual complete relief Complete relief usually not possible

5 Page 5 Breakthrough Pain Volitional in response to something the patient does Preventable volitional moving, dressing change, rolling over, walking Not preventable volitional bladder spasm, coughing End of dose deterioration Idiopathic breakthrough pain Malignant vs. Nonmalignant Pain Malignant Cancer Advanced, progressive pain Non-malignant pain Low back pain Diabetic neuropathy Osteoarthritis Admitting diagnoses into Hospice Prevalence of Pain at End of Life Advanced cancer 40-90% patients have pain Cardiovascular disease (CHF) 75% patients HIV/AIDS 50-93% Due to virus or treatment Neurologic diseases Multiple sclerosis, Parkinson s disease, cerebral vascular disease or spinal cord injury patients Dementia patients difficult to assess Skin breakdown, contractures

6 Page 6 Nociceptive Pain Neuropathic Pain Pharmacotherapeutic Options Somatic Visceral Dull, aching, well-localized. Skin, bone, joint, soft tissues. Mets to bone, fractures. Diffuse, deep, aching, gnawing. Poorly localized. Bladder distension/cramping, intestinal distension, constipation, angina Peripheral Or Central Burning, shooting, pricking, paresthesias, dysesthesias. Phantom limb pain, SCI pain, stroke, diabetic neuropathy, post-herpetic neuralgia Nociceptive Pain Antineoplastic treatment Conventional analgesics Opioids, non-opioids, co-analgesics Metastatic bone pain NSAIDs Neuropathic pain Opioids Nondrug Interventions Co-analgesics (anticonvulsants, antidepressants) What is the GOAL in Pain Management? Comfort-Function Goals What would you like to do that you can t do now because of your pain? I d like to be able to to my needlework. I d like to walk to the bathroom alone. I want to get a good night s sleep so I m not tired all day long I want to go back to work I want to be able to play with my children

7 Page 7 Treatment Modalities Non-pharmacologic Heat, cold, massage, TENS units, physical and occupational therapy, guided imagery, aromatherapy, comfort food Pharmacologic Non-opioid Opioid Adjuvant analgesics Acetaminophen Mechanism of action COX-3 inhibitor Analgesic and anti-pyretic Lacks anti-inflammatory activity Ceiling effect Acute and chronic toxicity Acute liver failure increased from 28% in 1998 to 51% in 2003 May cause liver or renal toxicity Common in multi-ingredient products consider OTC products Maximum daily dosage is 4 grams per day Or is it? Aminotransferase Elevation in Healthy Adults Receiving 4 Grams of Acetaminophen Daily Objective to characterize the incidence and magnitude of ALT elevations in health participants receiving 4 g acetaminophen per day Methods participants received either: Placebo 1 of 3 acetaminophen-opioid combinations Acetaminophen alone JAMA 2006;296:87-93 Aminotransferase / Acetaminophen Outcomes serum liver chemistries and trough acetaminophen concentrations Results maximum ALT more than 3 x ULN incidence 31-44% in 4 treatment groups Acetaminophen levels never exceeded therapeutic limits; were often undetectable before ALT levels resolved JAMA 2006;296:87-93

8 Page 8 American Liver Foundation Issues Warning on Dangers of Excess Acetaminophen ALF recommends that people not exceed three grams of acetaminophen per day for any prolonged period of time Equivalent to six extra-strength Tylenol per day for several weeks Regular short-term use is not an issue In the beginning there was salicylate, and that begat acetylsalicylic acid (ASA; aspirin), and that begat nonsalicylate NSAIDs, and more NSAIDs and more until there 100, and that begat selective cyclo-oxygenase (COX)-2 NSAIDs: and then here was celebrating in the land. Roth SH. Drugs 2005:65(14): NSAIDs Effective in the treatment of bone metastasis, soft tissue infiltration, arthritis, serositis. Mechanism - inhibits prostaglandin-mediated irritation of nociceptive receptors. Toxicities dyspepsia, gastritis, gastric bleeding, fluid retention, hypertension, CHF, renal failure, platelet dysfunction, salicylism, confusion. Pick your poison- gastrointestinal or cardiotoxicity?? ALL TISSUES Normal Physiologic Stimulus COX-1 Prostaglandins stomach, kidney, endothelium, brain Cyclooxygenase Pathways GI protection Platelet Aggregation Regulation of blood flow Kidney function Sensory processing ARACHIDONIC ACID NSAIDS COX-2 Specific Inhibitors INFLAMED TISSUES Inflammatory Stimulus COX-2 Prostaglandins found in synovial fluid, vascular SM, endothelium, macrophages, monocytes, tumor cells, brain Inflammation Pain Fever Kidney function

9 Page 9 Step 2-3 Agents - Opioids Variables Effecting Therapy Codeine Propoxyphene Hydrocodone Dihydrocodeine Oxymorphone Meperidine Heroin Morphine Hydromorphone Oxycodone Levorphanol Methadone Fentanyl Agonist/Antagonist or partial agonists Agent Variables Things about the drugs that effect response Patient Variables Things about the patient that alter therapeutic response How do these variables affect your selection of an opioid? Agent Related Variables Mechanism of action and efficacy Available dosage formulations Pharmacokinetics (distribution, onset, peak and duration of action, t 1/2, method of elimination from body, presence of active metabolites) Side effects and toxicities Cost (Total cost impact) Agent Related Variables Mechanism of action and efficacy Opioids have similar MOA Mu opioid agonist Methadone NMDA receptor antagonist Generally speaking - weak vs. strong terminology not applicable, with some exceptions Propoxyphene Codeine Tramadol??

10 Page 10 Agent Related Variables Available dosage formulations Long-acting oral pharmaceutical preparations (morphine, oxycodone, oxymorphone) Long acting tramadol (opioid?) Inherently longer-acting (methadone) Long-acting transdermal (fentanyl) Immediate-acting (morphine and oxycodone elixir, transmucosal fentanyl [Actiq, Fentora]) Only available in combination (hydrocodone) Dosing Breakthrough Analgesics Oral long acting opioid is basal therapy Rapid/quick onset, short acting analgesic used for episodic pain, incident pain and breakthrough pain. End of dose deterioration increase dose/change dosing interval Dosed as 10-15% total daily dose MS Contin 90 mg po q12h TDD 180 mg morphine MSIR 20 mg po q2h prn Dosing Opioids Evaluate average pain intensity rating < 5/10 increase by 25-50% > 6/10 increase by % Evaluate use of breakthrough analgesic. Agent Related Variables Pharmacokinetics Onset and duration of action Most opioids are short-acting Can alter with oral long-acting dosage formulations Methadone - longer half-life in body than half-life of analgesic effect Metabolic fate Propoxyphene, meperidine, morphine have active metabolites Oxycodone, hydromorphone less active metabolites Fentanyl, methadone inactive metabolites

11 Page 11 Agent Related Variables Side effects and toxicities many opioid adverse effects are class-wide constipation, nausea, sedation codeine causes dose-limiting adverse effects opioids with active metabolites contribute to toxicity Cost Opioid Adverse Effects Common Adverse Effects constipation nausea/vomiting sedation Uncommon Adverse Effects respiratory depression pruritus Specific Pain Syndromes Treatment of Neuropathic Pain Bone pain due to malignancy NSAIDs, corticosteroids, osteoclast inhibitors CCS pain, nausea, anorexia Refractory pain Parenteral lidocaine Ketamine (NMDA inhibitor) Interventional strategies (neural blockade)

12 Page 12 General Considerations Reduction of 30% on a severity rating scale Clinical important Considered to be moderate relief or much improved Statistical vs. clinically significant improvement General Considerations Drug-induced adverse effects are common in treating neuropathic pain Nature of the medications used Patients older, taking other medications, more comorbid illnesses Agents for Neuropathic Pain First-Line Medications Co-analgesic Carbamazepine (Tegretol) Gabapentin (Neurontin) Transdermal Lidocaine (LidoDerm) Duloxetine (Cymbalta) Trigeminal Neuralgia X Diabetic neuropathy X Post herpetic neuralgia X X Gabapentin (Neurontin) [Pregabalin (Lyrica)] 5% Lidocaine patch (LidoDerm) Opioid analgesics Tramadol hydrochloride (Ultram) Tricyclic antidepressants (TCAs) [Duloxetine (Cymbalta)] Pregabalin (Lyrica) X X Pregabalin recently approved for fibromyalgia Dworkin RH, et al. Advanced in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:

13 Page 13 Gabapentin (Neurontin) Approved for the treatment of post-herpetic neuralgia Also used to treat: peripheral diabetic neuropathy mixed neuropathic pain syndromes phantom limb pain Guillain-Barre syndrome acute and chronic pain from spinal cord injuries Gabapentin (Neurontin) Adverse effects: Somnolence, dizziness Cause or exacerbate gait or balance problems OR cognitive impairment in elderly Gastrointestinal symptoms Peripheral edema In general, fairly tolerable, safe, and relatively free of drug interactions Gabapentin (Neurontin) Titrate dosage against adverse effects 100 or 300 mg qhs 100 or 300 mg tid Increase very one to seven days by 100 to 300 mg as tolerated Three times daily is the target dose Gabapentin (Neurontin) Titrate dose to pain relief If partial relief achieved at 1800 mg/day, titrate up to 3600 mg/day (1200 mg tid) Final dose determined by pain relief or intolerable side effects Adequate trial is 3-8 weeks for titration, plus 1-2 weeks at maximum tolerated dose

14 Page 14 Gabapentin and Renal Impairment Pregabalin (Lyrica) CLcr (ml/min) TDD (mg/d) > < Dosage Regimens Based on Renal Function (mg) 300 tid 400 tid 600 tid 800 tid 1200 tid 200 bid 300 bid 400 bid 500 bid 700 bid 200 qd 300 qd 400 qd 500 qd 700 qd 100 qd 125 qd 150 qd 200 qd 300 qd Administer in 3 divided doses per day Begin dosing at 150 mg/day Increase to 300 mg/day within 1 week Maximum daily dose mg/day Common AE: dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, difficulty concentration/attention Lexi-Comp s Drug Information Handbook, 11 th Edition Pregabalin in Renal Dysfunction 5% Lidocaine Patch (Lidoderm)

15 Page 15 5% Lidocaine Patch Indicated for treatment of post-herpetic neuralgia Topical preparation In patients with normal hepatic function, blood levels of the drug are minimal On 12 hours, off 12 hours (max 3 patches) Adequate trial is 2 weeks Only adverse effect is mild skin reactions (erythema or rash) Patches should be applied only to intact skin with no blisters. Use no more than three patches at one time. Patches should be worn for no more than 12 hours within any 24-hour period (ie, 12 hours with patches on and 12 hours with patches off). Opioid Analgesics If irritation or burning sensation occurs, remove the patches and do not reapply until the irritation subsides. The potential exists for a small child or pet to suffer serious adverse effects from chewing or ingesting a new or used Lidoderm patch. Patients should store and dispose of Lidoderm patch(es) out of the reach of children and pets. Several clinical trials have demonstrated the effectiveness of opioids (e.g., oxycodone) in the management of PHN and PDM. OxyContin mg qd significantly relieved pain, disability, and allodynia compared with placebo. Also improved functional status.

16 Page 16 Opioid Analgesics Controlled-release morphine vs. TCA vs. placebo for PHN CR MS up to 240 mg/day provided better pain relief and sleep quality, but not physical function or mood Patients preferred CR MS over TCA Levorphanol useful in peripheral and central neuropathic pain Opioid Analgesic Selection Short-acting vs. longacting Role of methadone? NMDA receptor antagonist Conversion from other opioids TDD Oral Morphine EPERC Conversion (morphine:meth) Then reduce 50% % of morphine dose (Pkg insert) < 100 mg 3: % mg 5: % mg 10:1 8-12% mg 12:1 5-10% mg 15:1 Tramadol A norepinephrine and serotonin reuptake inhibitor with a major metabolite that is a mu opioid agonist. Evaluated in PHN and polyneuropathy from various causes (including PDM) Effective when titrated to 400 mg/day Effective vs. allodynia and improves QOL > 1000 mg 20:1 < 5% Gazelle G and Fine PG. Fast Facts and Concepts #75: Methadone for the treatment of pain, 2nd Edition. July End-of-Life Physician Education Resource Center.

17 Page 17 Tramadol Adverse effects include: Dizziness, nausea, constipation, somnolence, orthostatic hypotension Occur more frequently with rapid dosage escalation and concurrent administration of medications with similar adverse effects Increased risk of seizures in patients with history, or drugs that lower seizure threshold Tramadol Drug interactions: Serotonin syndrome if taken with other serotonergic medications (SSRIs) and MAO inhibitors May cause or exacerbate cognitive impairment in older adults Need to adjust dose in renal and hepatic disease Tramadol Initiate at low doses: 50 mg once or twice daily Titrate every 3 to 7 days by mg/day in divided doses as tolerated Maximum dosage is 100 mg 4 times daily Patients over 75 years, 300 mg/day in divided doses Adequate trial is 4 weeks Tricyclic Antidepressants (TCA) First medication category proven effective in neuropathic pain Main problem with TCAs is adverse effect profile

18 Page 18 Tricyclic Antidepressants (TCA) Amitriptyline (Elavil) MOST anticholinergic adverse effects Blurred vision Urinary retention Dry mouth Constipation Cognitive impairment Orthostatic hypotension Sedation Nortriptyline, despiramine Tricyclic Antidepressants (TCA) Use with caution in: Cardiovascular disease Screening EKG when beginning TCA after age 40 in non-eol population Glaucoma Urinary retention Autonomic neuropathy Risk of suicide or accidental death from OD Tricyclic Antidepressants (TCA) Analgesic effect independent of antidepressant effect Start TCA dose low mg qhs Increase every 3-7 days by mg/day as tolerated Dose to mg qd as tolerated Blood level of about 100 ng/ml Adequate trial is 6-8 weeks with 1-2 weeks at maximally tolerated dosage SNRIs: Duloxetine and Venlafaxine MOA inhibit the reuptake of biogenic amines, primarily norepinephrine Duloxetine (Cymbalta) Indicated for diabetic neuropathy treatment. AE insomnia, somnolence, headache, nausea, xerostomia, constipation, anorexia, liver issues Venlafaxine (Effexor) Efficacy shown in PDN, painful polyneuropathy AE headache, somnolence, dizziness, insomnia, nervousness, nausea, xerostomia, constipation, anorexia, weakness

19 Page 19 Other Therapeutic Options Other anticonvulsant agents Lamotrigine (Lamictal) Carbamazepine (Tegretol) Levetiracetam (Keppra) Oxcarbazepine (Trileptal) Tiagabine (Gabatril) Topiramate (Topamax) Zonisamide (Zonegran) Valproic Acid (Depakote) Phenytoin (Dilantin) Corticosteroids Dexamethasone vs. prednisone Patient related variables Thrush / immunosuppressed Diabetes / glucose intolerance Peptic ulcer disease / gastrointestinal bleeding Agent related variables Dosage formulations Proper Disposal of Expired or Unwanted Drugs New federal prescription drug disposal guidelines for disposal of expired or unwanted drugs ions/pdf/prescrip_disposal.pdf Proper Disposal of Expired or Unwanted Drugs Take unused, unneeded, or expired prescription drugs out of their original containers and throw them in the trash Mix the prescription drugs with an undesirable substance Used coffee grounds or kitty litter Put them in impermeable, non-descript containers, such as empty cans or sealable bags Throw containers in the trash

20 Page 20 Proper Disposal of Expired or Unwanted Drugs The American Pharmacists Association recommends crushing solid medications or dissolving medications (solid or liquid) in water and mixing with kitty litter or another unpalatable substance before placing in a sealed plastic bag for disposal. APhA also recommends destroying all personal information (e.g., Rx label) from the container prior to disposal. Proper Disposal of Expired or Unwanted Drugs Flush prescription drugs down the toilet ONLY if the accompanying patient information specifically instructs doing so Take advantage of community pharmaceutical take-back programs that allow the public to bring unused drugs to a central location for proper disposal. FDA Advises Drugs to be Flushed Actiq (fentanyl citrate) Daytrana Transdermal Patch (methylphenidate) Duragesic Transdermal System (fentanyl) OxyContin Tablets (oxycodone) Avinza Capsules (morphine sulfate) Baraclude Tablets (entecavir) Reyatax Capsules (atazanavir sulfate) Tequin Tablets (gatifloxacin) Zerit for Oral Solution (STavudine) Meperidine HCl Tablets Percocet (oxycodone and acetaminophen) Xyrem (Sodium Oxybate) Fentora (fentanyl buccal tablet) You matter because you are you, and you matter to the end of your life. We will do all we can not only to help you die peacefully, but also to live until you die Dame Cicely Saunders