10/11/2018

DISCLOSURE

CANCER : • I am not making a ton of money (or any money, actually) through a relationship with a pharmaceutical or device PRINCIPLES AND PRACTICE company.

Kerstin Lappen, MS, ACNS, ACHPN Allina Health, Abbott Northwestern Hospital

October 11, 2018

OBJECTIVES Supportive Care in the Oncology Patient

• List pharmacologic and nonpharmacologic interventions for pain management in patients with cancer.

• Identify different types of pain commonly seen in cancer and appropriate Spiritual interventions. Journeying Maslow’s Hierarchy • Identify criteria for eligibility for medical cannabis for patients with cancer. Psychological Modified by Laurel Herbst, MD & Social Issues

Information

Physical symptoms

Why is pain undertreated? The Meaning of Pain to the Patient Clinician Factors • Current climate—opioid epidemic, overdoses, diversion, fear of • Worsening disease being sued or board complaints • Fear—may have witnessed others in unrelieved, agonizing pain. • Decreasing functional status • Lack of training beyond the basics • Fear of loss of control and loss of independence • Lack of time it takes to do a full assessment • Punishment • Provider and patient discrepancy in judging the severity of the pain • Unrelieved pain can lead to hopelessness, depression and increased risk of • Fear of causing respiratory depression suicide in uncontrolled pain • Fear of causing addiction • Relief of pain often “cures” perceived behavioral disorders: • “It took 18 years and a terminal illness for me to finally get good pain control.” • Patients may not be fully honest about their pain because it might • --Melissa, a patient I cared for. impact the decision to keep treating the cancer.

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Causes of Treatment Related Pain

• INFLAMMATION! Release of chemicals by tumors • and myopathies due to chemo and (prostaglandins, endothelins, cytokines,TNF) sensitize hormone therapy peripheral nerves and cause painful inflammation •Mucositis/esophagitis from immunosuppression and • Ischemia and necrosis, tumor erodes in to tissues, vessels tissue damage from chemo, radiation • Rapid weight loss => cancer cachexia, immobilization, •Chemo-induced (CIPN) increased muscle tension and spasms causing muscular pain •Surgical interventions that give rise to nerve damage • Cancer treatment…. and chronic post-op pain

Types of Pain in Cancer: Nociceptive Pain Types of Pain in Cancer:

• Primary activation of somatic or visceral nerves by the tumor, typically • Pain caused by damage/injury to nerves directly from the tumor or impinging on adjacent tissues or obstructing blood vessels. Think—normal by enzymes made by the tumor, or by toxic effect of cancer body response to painful stimuli treatment on the nerves. Also, malignant involvement of the CNS • Somatic pain: Referring to skin, deep tissue, muscle. Pain is localized. such as leptomeningeal carcinomatosis. Patients can point to it. Often described as sharp, achy, intermittent, related to activity. • Described as burning, numbness, tingling, “pins and needles”, • Visceral Pain: Mechanical invasion or stretching of hollow organs or sharp, shooting, stabbing, “like a spear going through me”, distortion of the capsule of solid organs (i.e. ). Pain is generalized (all electrical shock, throbbing, pulsating, “like walking on marbles”. over) or referred. Usually described as dull, aching, squeezing, cramping. Can cause a physical reaction of pallor, sweating, nausea and vomiting.

Types of Pain in Cancer: Bone Pain Opioids as the Mainstay of Cancer Pain Management • Considered a subset of nociceptive somatic pain. Can also often • Morphine—gold standard. SR and IR oral forms cause neuropathic pain, particularly with spinal involvement. • Codeine—used rarely • The membrane covering the surfaces of bones (periosteum) has many nerve endings that are injured by malignant cells. • Hydrocodone (only available in combination with ibuprofen or acetaminophen—Norco//Vicodin) • Loss of mechanical strength of bone leading to pathological fractures • Oxycodone: SR and IR. ONLY oral. $$$ • Hydromorphone: SR ($$$) and IR. Short acting. Good in • Usually described as continuous, achy with sharp impaired renal function—no metabolites. exacerbations—incident pain typically with movement: “It doesn’t hurt unless I move.” • Fentanyl: TD primarily. Good in impaired renal function and impaired gut function. Not good in cachectic patients. • Bony mets can also cause painful muscle spasms • Methadone

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Adjuvant Analgesics Neuropathic Pain Treatment:

• Anticonvulsants: Bind to the calcium channels on nociceptive neurons. • Adjuvants refer to drugs that are marketed for indications other • Gabapentinoids, compared to other AEDs, tend to not have as many drug interactions or than pain, but are potentially useful as analgesics when added to adverse effects. • Renal excretion so careful dosing in patients with renal dysfunction. opioid therapy in patients with cancer and chronic pain syndromes. • 2 OPTIONS: • AEDs: Pregabalin, Gabapentin • Gabapentin: • Initiate at 100 mg q 8 hrs, increase q 2-3 day • Antidepressants: Duloxetine • Titrate upward to effective dose, usually 900-3600 mg per day • Main SE is drowsiness, fluid retention • Steroids • Has not been found to be effective in CIPN in studies • Anti-spasmodics: flexeril, baclofen, robaxin • Pregabalin: • Similar to gabapentin in action but typically better side effect profile and quicker titration • In more recent years, some of these drugs have acquired • Initial dose: 50-75 mg BID. Titrate up to max of 300 mg per day after one week • More expensive. Often have to demonstrate failure with gabapentin 1st approved indications for pain. • Carbamazepine: trigeminal neuralgia • Valproic Acid

Neuropathic Pain Treatment Neuropathic Pain Treatments: Antidepressants

• Anti-depressants: Although very few studies have included cancer patients, • Tricyclics: old drugs, anticholinergic side effects make them difficult to use in the utility of these drugs for treatment of cancer pain has been extrapolated many patients from data in other conditions. • Amitriptyline • Analgesic effects are related to inhibition of norepinephrine reuptake, but • Nortriptyline and Desipramine--better side effect profile than amitriptyline serotonergic and dopaminergic effects also may play a role, exerting their • Serotonin-norepinephrine reuptake inhibitors (SNRIs) effects particularly along the descending spinal pain pathways. • Duloxetine, venlafaxine have analgesic effects. Evidence of analgesic efficacy is best • Antidepressants have been predominantly used for neuropathic pain. described with duloxetine but the literature lacks trials in patients with cancer pain, and However, given the range of their potential analgesic efficacy, they could be there are no comparative trials within the SNRI class. considered for other types of cancer/chronic pain as well. • there is minimal evidence of analgesic efficacy with SSRIs • Analgesia from an antidepressant is not dependent on mood elevation and • Dopamine/Norepi reuptake inhibitor pain can be improved in non-depressed patients. • Bupropion: (contraindicated for current or past history of seizures or eating disorder, also may be excessively activating)

Neuropathic Pain: Nonpharmacologic Treatment Adjuvant Therapy for Bone Pain • NSAIDS: ibuprofen, naproxen • COX-2 selective NSAIDs for pts on anticoagulation or have impaired clotting: Celecoxib •Radiation therapy: for spinal cord compression • Ketoralac: IV or po in limited prognosis • Steroids, emergent 1st line treatment for spinal cord compression. Dexamethasone drug of •Surgical decompression: spinal cord compromise choice due to less mineralcorticoid side effects (less salt and water retention, edema, hypertension, hypokalemia). Has a long T1/2: 36-54 hours, allowing for daily administration. Adrenal suppression unlikely if an acute course is discontinued within 2 wks. Not good long •Acupuncture term due to side effects: hyperglycemia, weight gain, immune suppression, bone density, muscle weakness, moon face. • Radiation therapy • Bisphosphonates--usually infused monthly to prevent or slow down bone destruction • Radionuclide therapy-indicated for longer prognosis (> 6 mo), multiple and scattered bone mets, commonly used in patients with . Targets areas of increased bone turnover: • •strontium-89 • •samarium-153 • •radium-223 dichloride

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Chemo-induced Peripheral Neuropathy Why does it matter?

• Many of the best agents for solid tumor treatment have • Development of CIPN can be dose-limiting, thus promoting neurotoxicity as dose-limiting side effects: evolution of drug resistance • Vinca alkaloids (, , vinorelbine, and etoposide) • CIPN is a frequent cause of chemo dose reduction or • Platinum-complex agents (, , and ) termination of otherwise successful treatment • Proteosome-inhibitors ( and carfilzomib) • 20% of patients develop a neuropathic pain syndrome that • Less common: 5-FUPlatinum drugs like (, , and cabazitaxel is difficult to treat, can be chronic, and range from • , such as annoying to debilitating in it’s effects. • Plant alkaloids, such as , lenalidomide and pomalidomide • Eribulin

Mechanism of CIPN CIPN

• Research has found atypical mitochondria (swollen) in the sensory • Typically dose-dependent and cumulative. axons—not motor—making them unable to manufacture ATP (the energy currency every cell in our body uses) • Predominantly consists of sensory rather than motor symptoms, and motor nerve function usually remains • What happens if axonal mitochondria don’t make enough energy (ATP)? Damage occurs in the peripheral nerves, especially in areas of high unchanged during treatment (exception is thalidomide, which metabolic demand (hands and feet). is associated with weakness and tremor in 30-40%) • Peripheral nerve damage leads to sensitization and spontaneous • Typically simultaneous and bilateral onset in hands and feet: activity of pain fibers which lead to hyperexcitability in the dorsal column stocking/glove presentation. Described as numbness, tingling, of the spinal cord. This process involves increased release of substance mechanical , cold allodynia and on-going burning pain P and of pain-propagating glutamate, which acts at N-methyl-D- aspartate receptors. • Can continue to worsen after treatment is stopped. Eventually • Knowing the mechanism opens the door to developing potential improves in most patients, although this depends on the drug treatments to prevent and manage neuropathy. and recovery is often incomplete

Treatment of CIPN Methadone • No clear evidence-based recommendations for neuroprotective • Mechanism of action: stimulates opiate receptors (opiod effects. AGONIST) and inhibits NMDA receptors (ANTAGONIST) • Steroids for a short time until a long-term treatment plan is in place • Methadone is effective for neuropathic pain due to NMDA receptor • Topicals: Lidocaine patches or creams, Capsaicin cream, Neuropathic Pain gel (ketamine, ketoprofen and gabapentin, with antagonist activity or without lidocaine) • Available in many formulations: oral, SL, (pills, liquids, • Antidepressants: Duloxetine concentrated solutions) and IV • Anti-seizure medicines, which are used to help many types of • Inexpensive nerve pain, but have not been shown in (few) studies to be effective for CIPN. • Opioids when pain is severe: Methadone

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Monthly Cost Comparison Pharmacokinetics of Methadone (Average Wholesale Price 2005 cost per month) • Lipophilic. (Other opioids are hydrophilic) MS Fentanyl Oxycontin Dilaudid Methadone • Unique effect on neurotransmitters: inhibits re-uptake of serotonin and Contin patch norepinephrine • Rapid distribution: fast acting 100 mg po 80 mg po 200 mcg/hr top 12 mg po 10 - 20 mg po • Good GI absorption, including oral mucosa q8h q8h q72h q4h q8h • Initial duration of action for pain relief 6-12 hours • Long and variable elimination half-life: 8-59 hours, resulting in drug accumulation during initial titration period of 3-5 days • Biphasic elimination: due to lipophilic nature $440 $890 $1060 $330 $12 - $25 • Phase 1: 8-12 hours corresponds to analgesic duration of action • Phase 2: 30-60 hours—sufficient to prevent withdrawal

Drawbacks to Methadone Interventional Pain Management: think earlier than later

• Liquid/tablets taste bitter • Epidurals, Intrathecals: • Association and stigma with heroin addiction/treatment • Delivery directly to CNS • Physicians, nurses, pharmacists are unfamiliar with methadone • Use opioids, local anesthetics, clonidine, baclofen, etc • Reduces or can eliminate opioid requirements • Needs close follow up with a knowledgeable provider, takes time. The patient MUST be reliable and completely compliant with med instructions. • More rapid control of symptoms • Risk for QTc Prolongation and Torsade de Pointes (form of VT in patients with • Implanted pain pumps: think prognosis in relation to cost ($30,000+) a long QT interval) • Vertebroplasty: tumor-related compression fractures • Primarily in doses > 200 mg per day and IV • Neurolytic blocks • Do not use in QTc > 500, avoid in patients with bradycardia, ventricular arrhythmias, other meds that affect the QT • Celiac plexus: for upper abdominal visceral pain (pancreatic, liver) • Get baseline EKG, and serial EKGs with dose increases. • Hypogastric plexus: pelvic visceral pain: bladder, cervical/ovarian, rectal, prostate

Indications for Medical Cannabis and Cancer Pain REFERENCES

Up To Date: Prevention and treatment of chemotherapy-induced peripheral neuropathy. Author:Charles L • Cancer associated with severe/chronic pain, nausea or severe vomiting, or Loprinzi. Literature review current through: Aug 2017; last updated: Aug 22, 2017 cachexia or severe wasting. • Terminal illness: “To qualify for the program, you must suffer from cancer or a Up To Date: Cancer pain management: Adjuvant analgesics (coanalgesics). Authors:Russell K Portenoy, terminal illness with a probable life expectancy of under one year, if your MD, Ebtesam Ahmed, PharmD, MS, Yair Y Keilson, MD. Literature review current through: Aug 2017; last updated: Mar 06, 2017. illness or its treatment produces one or more of the following: severe or chronic pain; nausea or severe vomiting; or Cachexia or severe wasting.” Pain: Volume 122, Issue 3, June 2006, Pages 245-257. Studies of peripheral sensory nerves in paclitaxel- • Intractable pain: “a pain state in which the cause of the pain cannot be induced painful peripheral neuropathy: Evidence for mitochondrial dysfunction. Sarah J.L. Flatters a, Gary removed or otherwise treated with the consent of the patient and in which, in J. Bennet

the generally accepted course of medical practice, no relief or cure of the Minnesota Medical Cannabis Program: http://www.health.state.mn.us/topics/cannabis/index.html cause of the pain is possible, or none has been found after reasonable efforts.”

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Contact Information

• Kerstin Lappen, ACNS-BS • Palliative Care, Abbott Northwestern Hospital • (W) 612-863-3055 • [email protected]

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