PAIN MANAGEMENT IN PATIENTS WITH CANCER, PART II

Learning Objectives PAIN MANAGEMENT IN PATIENTS WITH CANCER, PART II MINA LEE UNIVERSITY OF WASHINGTON MEDICAL CENTER/ SEATTLE CANCER CARE ALLIANCE CLINICAL PHARMACIST, GENERAL ONCOLOGY Understand the general treatment approach to cancer pain management, including use of opioids and adjunct pain medications Compare and contrast opioid analgesics for cancer pain, including relative potency and equianalgesia dosing Develop a plan for monitoring and treating side effects related to opioid and adjunct pain medications Describe interventional and non-pharmacologic options for treating cancer-associated pain Patient Case: LW LW is a 74 y/o female who was recently diagnosed with metastatic endometrial cancer presenting with pain in her abdomen and left lower extremity. How will you manage her pain? Analgesics Adjuncts Neuraxial analgesia (not appropriate for all cancer pain) Patient Case: LW LW is a 74 y/o female who was recently diagnosed with metastatic endometrial cancer, presenting with pain in her abdomen and left lower extremity for the past few weeks. Pain diagnosis (Identify Source): Exam shows palpable lymph nodes in left groin area and left leg swelling with erythema Abdomen is tender to palpation and feels full and slightly firm Analgesics Adjuncts Neuraxial analgesia (not appropriate for all cancer pain) Image from: http://mednhealth.com/medical-condition-library 1

Patient Case: LW LW is a 74 y/o female who was recently diagnosed with metastatic endometrial cancer, presenting with pain in her abdomen and left lower extremity for the past few weeks. Modify the source/treat the cancer: Chemotherapy Radiation: palliative to sites of bone or nodal disease Surgery: debulking, relief of hydronephrosis, removal of ascites Antibiotics, etc Analgesics Adjuncts Neuraxial analgesia (not appropriate for all cancer pain) Image from: http://mednhealth.com/medical-condition-library World Health Organization (WHO) Principles of Pharmacologic Management By the mouth By the clock By the ladder For the individual With attention to detail Non-Opioids: Acetaminophen For non-inflammatory pain and fever Mechanism of action (MOA): unknown, inhibits synthesis of prostaglandins in CNS Liver toxicity with high doses max 3,000 mg per day (OTC) Tablets, capsules, oral solution, rectal suppositories, IV Caution: polypharmacy in OTC setting World Health Organization 1996; 2 nd Edition Non-Opioids: NSAIDs For mild to moderate pain, inflammation, fever MOA: reduce synthesis of prostaglandins by inhibiting cyclooxygenase (COX) enzymes Synergistic with opioids, different toxicities Ceiling effect with cancer pain Tablets, oral solution, topical, parenteral Adverse effects renal dysfunction gastric irritation, peptic ulceration bleeding avoid giving with corticosteroids caution when giving w/certain chemotherapy regimens Patient Case: Opioid Initiation LW comes to clinic and rates her pain as 8/10 almost constantly for the past 2 weeks. She has been taking acetaminophen alternating with ibuprofen without much benefit. She is nervous to start opioids because of what she has read about the side effects, but agrees that she needs better pain relief. What opioid(s) would you start for her cancer associated pain? Are all opioids the same? What dosing would you use? 2

Opioids: Overview Indications: moderate to severe pain Opioid receptors Mu (µ), Kappa (κ), Delta (δ) Located in the dorsal root ganglion & on afferent neurons in the dorsal horn as well as peripheral tissues Categorized as pure µ-agonists, partial agonists or agonistantagonist Mechanism of Action µ-receptor agonists Result in inhibition of ascending pain pathways Block the release of neurotransmitters involved with processing pain Moderate Pain Hydrocodone/APAP* Oxycodone/APAP* *Combo products limited by dose of non-opioid Opioids: What to Use Severe Pain Morphine Oxycodone Hydromorphone Fentanyl Methadone Hydrocodone Buprenorphine, codeine, tapentadol, tramadol, oxymorphone not commonly used due to reduced potency/efficacy, side effects, cost Relative Potency of Opioids Least potent IV Potency Codeine Meperidine 10X less potent than morphine Hydrocodone Morphine GOLD STANDARD Oxycodone Hydromorphone 5X more potent than morphine Fentanyl 100X more potent than morphine Most potent Forms Dose freq Dose adjust ments Morphine (gold std, natural) PO soln (also concentrated), IR, ER tabs, 24h caps, injection, suppository IR = Q 4-6 hours tab sizes 15, 30 mg ER = Q8-12 hours tab sizes 15, 30, 60, 100, 200 mg Clearance impaired in patients with cirrhosis -increase interval +/- decrease dose -6-glucuronide accumulation in renal dysfunction reduce dose Commonly Used Opioids Oxycodone (semi-synthetic) PO soln (also concentrated), IR and ER tabs ER formulation has biphasic absorption pattern IR = Q4-6 hours tab sizes 5, 10, 15, 20, 30 mg ER = Q8-12 hours tab sizes 10, 15, 20, 30, 40, 60, 80 mg -metabolized primarily by CYP3A4, partial metabolism by CYP2D6 to oxymorphone (active metabolite), subject to genetic variability -Use caution in renal and hepatic impairment Hydromorphone (semi-synthetic) Hydrocodone (semi-synthetic) PO soln, IR, ER tabs, PO soln w/apap, IR tabs injection, suppository w/apap, ER tabs IR=Q4-6 hours tab sizes 2, 4, 8 mg ER= Q24h tab sizes 8, 12, 16, 32 mg Consider dose reduction in renal and hepatic dysfunction IR combo tabs= Q4-6h Hydrocodone/APAP sizes: 5/325, 7.5/325, 10/325 mg Zohydro ER : q12h 10, 15, 20, 30, 40, 50 mg Hysingla ER : q24h 20, 30, 40, 60, 80, 100, 200 mg Max 4,000 mg/day APAP if using combo product Morphine The gold standard IV, suppository, or orally as solution, IR and ER forms Organ function considerations Clearance impaired in patients with cirrhosis Increase interval +/- decrease dose 6-glucuronide accumulation in renal dysfunction Decrease dose Typical dosing frequency IR = Q 4-6 hours; ER = Q 8-12 hours Oxycodone A semi-synthetic opioid Oral solution, IR/combo products and ER forms Metabolized by CYP2D6 to oxymorphone Active metabolite, subject to genetic variability Use caution in renal and hepatic impairment ER formulation has biphasic absorption pattern Typical dosing frequency IR = Q4-6 hours; ER = Q8-12 hours 3

Methadone Synthetic opioid Formulations: oral solution, tablet, injection Unique MOA mu agonist and N-methyl-D-aspartic acid (NMDA) receptor antagonist Advantages Good oral bioavailability No neuroactive metabolite Lack of accumulation in renal impairment High potency Low cost Disadvantages Methadone Duration of analgesia (4 to 8 hours) and elimination halflife (15-30 hours) very different Rapid dose titration is not possible Risk of QTc prolongation & torsade de pointes Potential for drug-drug interactions (particularly CYP 3A4) Other medications that prolong QTc interval Equianalgesic dosing is challenging Significant safety risks in non-compliant patients Fentanyl Synthetic opioid Formulations: transdermal patch, injection, and multiple transmucosal IR formulations 80 to 100 times more potent than morphine Fentanyl products cannot be substituted mcg for mcg Good choice in renal dysfunction Fentanyl Transdermal (Duragesic ) Chronic, stable conditions in opioid tolerant patient Useful for patient s with difficulty swallowing Limited absorption if severe cachexia Slow on and off Onset = 12-24h, Steady state = 48 h Effects last up to 18 hours after removal Caution with heat (eg. hot tubs, heating pads, fever) Sizes: 12, 25, 50, 75, and 100 mcg/hr Issues with adhesive backing Transmucosal Immediate-Release Fentanyl (TIRF) Risk-Evaluation and Mitigation Strategy (REMS) Program Requires enrollment of prescribers, patients, and pharmacies for outpatient use TIRF medications only indicated in: Patients 18 years of age (Actiq 16 yrs) Breakthrough cancer pain Opioid tolerant Taking for one week or longer: Morphine 60 mg/day or equivalent Dosing specific for each specific product Start w/lowest dose regardless, max 4 doses/day Fentanyl Transmucosal Oralet- Actiq Rapid onset = 5-15 min Peak concentration = 30 min Roughly 25% of drug absorbed rapidly from buccal mucosa Duration = 2hrs Size: 200, 400, 600, 800, 1200, 1600 mcg Dose is not predicted from around-the-clock opioid dose www.tirfremsaccess.com 4

Opioids: Important Considerations Previous opioid exposure and preferences Medication allergies/intolerances Age Extent of cancer, particularly hepatic and renal involvement altering pharmacokinetics Concurrent disease states Route of administration, formulations, cost IV to PO is not 1:1 conversion Opioid risk Opioids: Important Considerations Inter-patient variability in responsiveness Use of IR versus ER or both depends on severity and nature of disease, clinical course Around-the-clock administration is most effective for chronic pain No ceiling effect The correct dose is that which controls pain but does not cause unacceptable side effects! Breakthrough Pain A fluctuation in pain intensity that interrupts a tolerable background pain Idiopathic, incidental, or end-of-dose failure Characterized by: Moderate to severe intensity Rapid onset (<3 minutes) Relatively short duration (< 1 hour) BTP Medication Option 1 Option 2 scheduled dose in 24h = prn dose in 24h Total scheduled dose Total prn dose OR 10-20% of daily dose q3h prn Morphine ER 90 mg q12h =180 mg morphine Morphine 30 mg po q4h prn =180 mg morphine max 15-30 mg po q3h prn Patient Case: Oral Opioids LW responded well to oxycodone in the hospital so you start Oxycodone 5 mg tabs, 5-15 mg PO Q4-6 hrs PRN pain to gauge her use. LW comes back in one week and has used oxycodone 10 mg PO Q3-4 hours and states she uses about 10 tablets/day (~50 mg/day oxycodone) You start her on a long acting opioid given her opioid use and choose Oxycontin 20 mg PO Q12 hr with oxycodone 5-10 mg PO every 4-6 hours for BTP She is still concerned about opioid side effects and has been struggling with constipation. How should she manage these side effects? Neuro Opioid Adverse Effects Symptom Management Develop tolerance? Sedation, drugged, medicated feeling Confusion, cognitive impairment Hallucinations Decrease dose or extend interval Decrease dose, antipsychotics GI Nausea/Vomiting Anti-emetics, take with food/meals Opioid rotation Pulm Other Constipation Respiratory depression (rare, but serious) Myoclonus Mild to moderate muscle jerks seen at higher doses Pruritus Urinary retention More common w/intraspinal Prophylaxis with bowel medications (senna QHS w/docusate), miralax, lactulose, exercise, fiber, fluid intake, methylnaltrexone SQ or naloxegol PO for refractory opioid induced constipation Decrease opioid dose, hold opioids Administer naloxone if sedation sore =3, RR <8 Assess for central sleep apnea/osa, limit sedatives Decrease to lowest effective dose Opioid rotation Prn ativan if intolerable Antihistamines, topical creams, cool compress Limit IV opioid use, bladder scan PVRs, I/O catheterization, indwelling foley Yes sometimes Yes No Yes Usually transient Patient Case: Oral Opioids LW calls in to clinic after 1 week with worsening pain. She has taken an extra 40 mg of breakthrough oxycodone each day. She has not yet been able to start chemotherapy or radiation and feels her leg swelling is worse. You escalate her Oxycontin to 40 mg Q12 hrs with oxycodone 10-15 mg PO q4-6 hrs PRN pain. She calls back the next week with confusion and feels foggy. Her husband tells you he is concerned about her change in mental status. She has a brain MRI that is negative for metastasis. You check her labs and note that her SCr has been increasing and her renal function is declining. An abdominal scan shows left hydronephrosis. Her pain is still 7/10. How can we better manage her pain and opioid side effects? 5

Opioids: Equianalgesia Incomplete cross tolerance between opioids Wide inter-individual variability Several different equianalgesia charts available Derived from single dose studies Does not reflect long-term opioid exposure or changes made due to ineffective analgesia or toxicity Opioids: Equianalgesia OPIOID ORAL DOSE PARENTERAL DOSE Codeine 100mg 50mg Hydrocodone 15mg N/A Oxycodone 7.5-10mg N/A Morphine 15mg 5mg Hydromorphone 4mg 0.75-1.5mg Levorphanol 2mg 1mg Methadone* 10mg 5mg Fentanyl** N/A 50mcg Oxymorphone 5mg 0.5mg *Ratio may range from 1:1 at low doses of oral morphine up to 20:1 for patients receiving high doses or oral morphine (~300mg/day) **Fentanyl transdermal 25mcg/hr 60mg PO morphine Stepwise Approach to Opioid Conversion 1. Pain assessment and total daily opioid use 2. Use conversion table to convert to new opioid 3. Individualize dose More aggressive conversion for uncontrolled pain 75-100% of dose Less aggressive conversion for well controlled pain 50-75% of dose 4. Follow-up and continual reassessment Patient Case: Opioid Conversion LW is on 40 mg Oxycontin Q12 hr and uses 60 mg of oxycodone/day for breakthrough pain. Given her renal dysfunction you are concerned she is not clearing the oxycodone as well and you choose to convert her to a fentanyl patch. Calculations: Oxycodone 140mg/day =? Fentanyl mcg patch First convert to morphine equivalent (oxy 1 = morph 1.5/2) Oxycodone 140 mg = morphine 210 mg/day Then convert morphine equivalent to fentanyl Fentanyl transdermal 25mcg/hr 60mg PO morphine Morphine 210 mg = fentanyl ~87.5 mcg, round down to patch size = 75mcg patch every 72 hours Continue PRN oxycodone 10-15 mg PO every 4-6 hours and titrate patch up every 3-9 days OR if renal function continues to decline, start Actiq 200 mcg up to 4 times/day Patient Case: Tumor Progression LW has done well with the fentanyl patch and her dose has been titrated over the last month to 125 mcg Q72 hours. She is using Actiq 200 mcg three times/day for BTP. Unfortunately, 3 months later, the patient s tumor markers begin to rise and she notes new pain in her left hip and low back. CT scan shows new lytic lesions in T9-10 with a new soft tissue mass in the left pelvis. She also has new lung lesions and her pain is no longer controlled on her regimen. Her pain is now 9/10 and she feels she is in a pain crisis. How can we treat the patient s escalating pain due to tumor progression? IV Patient-Controlled Analgesia (PCA) Convenient for patients to determine opioid requirements with severe, uncontrolled pain Available medications Morphine Hydromorphone Fentanyl Settings for inpatient use Incremental dose: mg/mcg per button push Lockout: how often dose can be given q min Continuous Infusion: mg or mcg/hr 4-hr limit: maximum cumulative dose over this time period Clinician boluses Image from https://www.ottawahospital.on.ca 6

Home IV PCA Orders: Example Home IV PCA Home PCA is an option if: Central IV access obtained: PICC or port, double lumen ideal Failed adequate pain control on oral/patch regimen Tolerated IV PCA inpatient and appropriately use PCA button Must have 24-hr continuous infusion of opioid Adequate home infusion services, caregiver/family support Managing outpatient provider (Oncologist, Cancer Pain Clinic, Hospice Director, etc) Image taken from: http://www.wolfmed.com/infusion-supplies/pump-pouches/pump-pouch-html Medication: Fentanyl 50 mcg/ml Incremental dose: 50 mcg Lockout: 6 minutes Incremental dose range: 10-200 mcg Incremental dose titration: may increase or decrease by 10 mcg q12h for inadequate pain control or side effects Continuous Infusion: 50 mcg/hr Continuous Infusion Range: 10-200 mcg/hr Continuous infusion titration: may increase or decrease by 10 mcg/hr q12h for inadequate pain control or side effects Managing provider: Dr. Smith fax 206-XXX-XXXX Cancer Pain Clinic Definition Adjunct Medications Medications whose primary indication is for situations other than pain, but can be an effective analgesic Can be opioid dose sparing, often used in neuropathic pain Examples Corticosteroids Antidepressants Anticonvulsants Local Anesthetics (neuraxial blocks) Bisphosphonates Corticosteroids MOA: Inhibit prostaglandin synthesis and reduce edema surrounding many types of tissues May be useful in treating neuropathic, bone, or visceral pain Common adverse effects: psychosis, proximal muscle wasting, insomnia, hyperglycemia Benefits: increases energy and appetite Antidepressants Tricyclic antidepressants (i.e. amitriptyline) Indications: neuropathic pain, fibromyalgia Inhibits norepinephrine and serotonin reuptake Adverse Effects: sedation, anti-cholinergic Contraindications: patients with cardiac arrhythmias, conduction abnormalities, narrow-angle glaucoma and significant prostatic hyperplasia Atypical antidepressants (i.e. duloxetine, venlafaxine) Data for prevention of chemotherapy induced neuropathic pain (colorectal cancer), post-surgical pain (breast cancer) Inhibits serotonin and block norepinephrine reuptake Usually better tolerated than TCAs Anticonvulsants For neuropathic pain Used alone, with an antidepressant or an opioid Gabapentin and pregabalin can be rapidly titrated and are well tolerated Gabapentin: 100 mg TID up to 2700mg/day Pregabalin: 50 mg TID, up to 300 mg/day Topiramate, lamotrigine, carbamazepine and oxcarbazepine should be titrated slowly (rarely used) Dose limiting sedation 7

Local Anesthetics: Lidocaine Topical gel, cream, patch Neuropathic pain or musculoskeletal pain Challenges with cost/insurance coverage for off label use IV formulation Spinal administration for nerve block Analgesia Antidepressants/Adjuncts Neuraxial analgesia, neurolytic blocks (not appropriate for all cancer pain) Neuraxial Blocks Externalized Intrathecal System Epidural or intrathecal Bupivacaine (local anesthetic) Provides regional block Requires imaging NOT implanted or internal, different than Medtronic Synchromed pumps Surgical procedure Tunneled catheter Advantages: pain control for patients with significant tumor burden uncontrolled by oral or IV opioids Disadvantages: possible motor loss and mobility, bowel/bladder control, NO anticoagulation, hypotension Risks: infection, spinal hematoma, paralysis Image from www.riversideonline.com Requires home infusion services if for home use Bupivacaine 0.5% + morphine 200 mcg/ml for dense block Continuous infusion: usually between 0.4-1 ml/hr or higher Image from UWMC Nursing Policies & Procedures Analgesia Antidepressants/Adjuncts Miscellaneous Agents Topical THC L-Glutamine, Alpha lipoic acid, Vitamin B6 Prevention of chemo-induced neuropathy Variable regimens Can be costly for patient Neuraxial analgesia, neurolytic blocks (not appropriate for all cancer pain) 8

Conclusion Satisfactory cancer pain relief is dependent upon comprehensive assessment of disease process, symptoms, and treatment and appropriately utilizing both drug and non-drug therapies Pain management should be individualized to the patient and requires frequent re-assessment Interdisciplinary care is a must! Thank you for your attendance! Laura Alwan, PharmD, BCOP lmiars@uw.edu Office: 206-288-7455 9