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Consideration of Cancer Related Symptoms

Expert Witness: Wayne H. Grant, PharmD, MBA - Grant Clinical Consulting LLC
With the rise of diagnoses such as heart failure, chronic obstructive pulmonary disease and various neurological degenerative disorders, the number of cancer related admissions to hospice organizations have fallen. However the symptom burden these patients experience remain high.

Interdisciplinary teams are charged with addressing these concerns as part of patients care plans. Pain, dyspnea, nausea/vomiting and cancer related fatigue (CRF) frequently present, demanding drug and non-drug intervention.

Perhaps not the most feared; pain remains at the top of patient’s physical concerns. In 1986, the World Health Organization (WHO) established a guideline to aid clinicians treating cancer pain. This treatment approach has now been accepted not only for cancer related pain, but also for all pain types. Visually developed to look like steps/ladder, the climb up is organized as such:
bottom step (mild pain): non opioid +/- adjuvant; middle (moderate pain): weak opioid +/- non opioid +/- adjuvant; highest step (severe pain): strong opioid +/- non opioid +/- adjuvant.

Currently a vast number of opioid choices exist however the most utilized opioids are discussed here. Opioids interact differently on the receptors, mu, kappa and delta. Agonists at the mu/kappa receptor can lead to analgesia, although miosis, respiratory depression, euphoria, and sedation may occur. Agonists at the delta receptor can lead to analgesia and the negative adverse effect of motor dysfunction associated with dopamine inhibition.

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Methadone has command much attention in the last decade as a drug which can address both somatic and neuropathic pain. Patient descriptors such as shooting, stabbing, burning and tingling are representative of neuropathic pain. This pain type can present centrally in spinal cord injury or peripherally such as; post herpetic neuralgia (PHN), trigeminal neuralgia (TN), polyneuropathy (diabetic, HIV), phantom limb pain.

Understand the pathophysiology becomes important when considering the treatment options. For example, diabetic peripheral neuropathy (DPN) is thought to be caused by a triad of glucose pathology including; sorbitol formation, non-enzymatic glycation of proteins, and hexosamine formation. Once damage is done, increase signaling from the peripheral and central pathways lead to what is termed, central sensitization. This neuronal discharge significantly increases in the dorsal horn resulting in multiple changes on the neurotransmitters (serotonin/norepinephrine), hypothalamic-pituitary-adrenal (HPA) axis and many other neuro-hormones thus creating a difficult environment to manage.

Methadone which is an agonist of mu and delta, and an antagonist at the NMDA (N-methyl-D-aspartate) receptor offers a unique treatment option. Pain negatively effects of the NMDA receptor through what is postulated as an interaction on the excitatory transmitters (glutamate and aspartate) resulting in central sensitization. The use of a NMDA blocking agent is thought to reduce or interfere with the discharge threshold making it not as sensitive and able to restrain transmittal of pain signals.
Methadone has extensive tissue penetration due to high lipophilic properties, which becomes important pharmacokinetically as there is associated biphasic elimination. The alpha phase (8-12 hours) shows rapid redistribution (analgesia) while the beta phase (24-120hrs.) is sufficient to prevent withdrawal. However this extended half-life could lead to both cumulative positive and negative effects.

Of these negative outcomes, methadone may cause QT prolongation resulting in Torsades de Pointes. This can occur with or without the presence of other medications. An extensive drug interaction analysis is required prior to the initiation of methadone therapy in order to minimize potential arrhythmias.

Other drug choices are reflected in the WHO ladder as the adjuvants. Tricyclic antidepressants, anticonvulsants, and additional NMDA-blockers can provide benefit through decreasing the central sensitization by ultimately disrupting the pain signaling. This would include the serotonin and norepinephrine reuptake inhibitors (SNRI) such as duloxetine, the alpha-2-delta ligands such as pregabalin and the GABA analog, gabapentin.

Pain control demands an extensive patient interview with the understanding and differentiation of somatic, visceral and neuropathic types. Although complicated, multiple choices of medication exist to address the various pain concerns our patients present with.

The pathology of dyspnea bifurcates as a supply or demand problem. For example, in heart failure the demand due to the dysfunctional distribution of oxygen leads to dyspnea. Unlike in chronic obstructive lung disease (COPD), availability of oxygen is restricted due to the reduced ability of inhaled air (oxygen) to exchange from the pulmonary system to the circulatory system. Under these two examples, treatment guidance is offered through the ACC/AHA guidelines and Gold initiative respectfully.

As the standard of care through medical management fails to achieve the perceived shortness of breath, other modalities are implemented in order to improve quality of life (QOL). Hospice patients are treated with opioids +/- benzodiazepines or phenothiazines. Opioids depress neuronal activity centrally; depress tidal volume and respiratory frequency peripherally; and decrease preload and afterload. The addition of benzodiazepines (e.g., lorazepam) or phenothiazines (e.g., promethazine) are less understood for dyspnea. Clinical benefit is achieved when combining an opioid with a benzodiazepine or phenothiazine rather than just implementing the opioid.

Opioid dosing for dyspnea is initiated low and on an as needed schedule such as: morphine, 5 mg orally; every 4 hours; oxycodone, 5 mg orally; every 4 hours; hydromorphone, 1 to 2 mg orally; every 4 hours. Adjuvants such as lorazepam are initiated at 0.5mg orally; titrate dose every 8 hours; promethazine 12.5mg; titrate dose every 8 hours.

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology establish recommendations for our current care. Clinicians must know the past chemotherapy/radiotherapy treatment timeline. This will allow one to know if the patient is having breakthrough, delayed or refractory nausea/emesis.

Patients who enter into hospice often present after not tolerating most recent oncological offering. Post chemotherapy nausea/emesis demands and understanding of the pathophysiology and subsequent pharmacotherapy. The mechanism of delay-nausea (>24hours) involves stimulation of neuroreceptors other than serotonin. Dopamine mediations dominate this type of nausea. This leads to the benefit seen with phenothiazines (chlorpromazine, promethazine) and butyrophenone (haloperidol). The use of 5HT-3 antagonists, such as ondansetron is not beneficial in this phase of emesis control as it lacks dopaminergic activity. The use of other drugs such as dexamethasone, metoclopramide, droperidol and olanzapine may provide relief.

Intractable nausea and vomiting represents a substantial source of physical and psychological distress for patients and caregivers. As the oral route of administration becomes limited to non-existent, medication choices are scarce. Attempting rectal administration of various medications becomes an appropriate route for some medications; unfortunately infusion therapy may be required. The use of a subcutaneous continuous haloperidol infusion may provide the relief these patients deserve.

Understanding the pathology and associated pharmacology will aid in developing a plan of care which successfully addresses such a distressing symptom.

Cancer Related Fatigue
The overall disability of a patient escalates as fatigue insidiously introduces itself. Defined as a persistent, subjective feeling of tiredness and weakness that interferes with patient’s usual functioning that is not relieved by rest. Insomnia, depression, anemia, anorexia, and deconditioning lead a partial list of attributes. Addressing each diagnosis is recommended if possible. Unfortunately, this is often not obtainable.

Drug therapies are minimally successful. The use of methylphenidate at a starting dose of 5mg by mouth twice daily has proven to be beneficial. Additionally, the use of dexamethasone starting at a lower dose of 2mg by mouth daily has shown benefit, however the tolerability and maximum dosing has not been establish.

The concurrent use of non-pharmacological and pharmacologic interventions provides the best benefit to patients in end-of-life care. Understanding the pathology, pharmacology and pharmacotherapy all can significantly improve cancer related symptoms. However, as important to the patient’s care is addressing the psychological, social and spiritual issues necessary for providing a holistic approach to care.

The intent of this article is to discuss general principals of disease states and the management of. Discussion regarding medications may be outside of U.S. Food and Drug Administration approved labeling. This information is intended solely for continuing education and is not intended to promote off-label use of these medications. Personal patient specific cases are not the focus of this educational article and will not be discussed. All patient centered questions should be addressed to appropriate health care professional.

All drugs identified are stated with their generic and associated trade (brand, proprietary) name and although a corresponding trademark symbol (®, ™) may not be noted, all names are property of their respective pharmaceutical companies.

ABOUT THE AUTHOR: Dr. Wayne H. Grant, PharmD
Dr. Wayne H. Grant has been a registered pharmacist, in good standing, in the State of Ohio, since 1990. Dr. Grant received his Bachelor of Pharmacy degree from Ohio Northern University, Ada, Ohio in 1990 and his Doctor of Pharmacy degree from the University of Florida, Gainesville, Florida in 2007. Dr. Grant is employed by a hospice in Cleveland, Ohio. Current clinical practice is in hospice and palliative care targeting disease state management in multiple areas including but not limited to; cardiology, gastrointestinal, geriatrics, nephrology, oncology, psychiatry, and pulmonology.

Copyright Wayne H. Grant, PharmD, MBA - Grant Clinical Consulting LLC

Disclaimer: While every effort has been made to ensure the accuracy of this publication, it is not intended to provide legal advice as individual situations will differ and should be discussed with an expert and/or lawyer.For specific technical or legal advice on the information provided and related topics, please contact the author.

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