Topics in Palliative Care Medical Oncology Residents December 8, 2008 Jeff Myers MD, CCFP, MSEd...

Topics in Palliative CareMedical Oncology Residents

December 8, 2008Jeff Myers MD, CCFP, MSEdProgram Head – Supportive Care, Palliative Care and Psychosocial Oncology

Odette Cancer CentreAsst Professor, Faculty of Medicine, University of Toronto

HospiceHospicePalliative carePalliative care

Curative / remissive therapyCurative / remissive therapy

PresentationPresentation Death

Palliative Care Consult Team at Sunnybrook

Inpatient consult service Outpatient Palliative Care Clinic (OCC) Bone Mets Clinic CHF clinic Kidney Care Clinic ALS Clinic *PCU MDs – Wynnychuk, Chakraborty, Sirianni, Selby, Kim,

Tamber

Ed

63 yo male – HR prostate CA, several areas of bony mets (including L2, 3, 4 but not ischium, ilium, sacrum or right hip area)

C/o increasing right buttock pain, 8/10, deep, dull, achy in character, radiates down back of right leg, 10/10 (“more of a shooting feeling”)

Ed

Current analgesic regimen:– Fentanyl 50 mcg/hr patch – change q72h– Tyl #3 – 1-2 po q6h prn (uses on average

5/day when pain “severe”, unsure of benefit)

– Colace 100mg BID– wife reluctant to support increasing patch

as her nephew is a heroin addict

Objectives

Improve management of nociceptive pain

Address neuropathic pain

Address fears about opioids

Fentanyl Patch

Oral BT form not available Onset of action, time to reach steady state

and absorption highly variable Does not allow for rapid titration In setting of malignant pain, fentanyl only

appropriate when:– pain is well controlled and unlikely to vary

considerably– oral route not available**

Ed – Opioid Options

Opioid Rotation – Correct for Cross Tolerance?- If yes, decrease by 30%- If no, leave dose the same

Calculation of Breakthrough Dose:– 10% of total 24 hour dose OR– 50% of q4h dose How frequent?

Opioid Conversion TableCodeine Morphine Oxycodone Hydromorph

PO 100mg 10mg 5mg* 2mg

SC/IV 5mg 1mg

* Disagreement as to appropriate equivalency

Fentanyl patch 25micrograms q72hours = 50mg po morphine q24hours

Methadone = complex conversion, requires license

1 Percocet (5mg PO oxycodone) =

10mg PO morphine = 2 mg PO hydromorphone

Cost Comparison

Ed

Fentanyl 50mcg/hr = Morphine 100mg q24h = Hydromorphone 20mg q24h

Ed


Hydromorph Contin 9mg BID

Ed


Hydromorph Contin 9mg BID

Hydromorphone 2mg q1h prn

What was wrong with original breakthrough?

Tylenol #3 – 1-2 po q6h prn 5/day

Opioid Conversion TableCodeine Morphine Oxycodone Hydromorph

PO 100mg 10mg 5mg* 2mg

SC/IV 5mg 1mg

* Disagreement as to appropriate equivalency

Fentanyl patch 25micrograms q72hours = 50mg po morphine q24hours

Methadone = complex conversion, requires license

What was wrong with original breakthrough?

Tylenol #3 – 1-2 po q6h prn 5/day

Tyl #3 = Codeine 30mg = Morphine 3mg =

Hydromorphone 0.6 mg (1/4 of reqd)

What was wrong with original plan for constipation?

Recent evidence suggesting no efficacy with stool softeners (docusate)

Must have laxative – maximize Senna and, if necessary, add Lactulose

Objectives




Neuropathic Pain Disordered function of the nervous system

anywhere from the periphery to the cerebral cortex; VERY common component of “malignant pain”, poorly managed

Pain may be described as sharp, burning, “pins and needles”, shooting

Treat with opioids, TCAs, anticonvulsants Specifically – gabapentin, nortriptyline,

desipramine

Ed

If neuropathic component of pain syndrome not fully relieved with opiate then add adjuvant

If ODB, begin with nortriptyline (25mg – 100mg) fewer anticholinergic SE than amitriptyline

Apply through Section 16 for gabapentin PCFA = only Palliative Care MDs

Ed

Titrate gabapentin dose: 300mg HS for two days, 300mg BID for two days, 300mg TID, continue to titrate dose (up to 3600mg/day well tolerated; renally cleared; correct for creat clearance)

Lyrica (pregabalin) – only indications are diabetic neuropathy and post-herpetic neuralgia (dosage up to 300mg/day in 2 or 3 divided doses)

Pregabalin “Lyrica” Developed specifically to maintain biologic

activity of gabapentin while improving pharmacokinetic properties

Approved in 2004 for:– Adjunct AED– Diabetic peripheral neuropathy, postherpetic neuralgia– GAD– Neuropathic pain

Pregabalin-pharmacodynamics

Lipophilic analogue of gabapentin Designed to improve diffusion across

BBB lipophylic antagonist at voltage gated

Ca channels (6× more potent than gabapentin)

Pregabalin - Dosing

Initiate 150 mg/day (divided BID or TID) Titrate to 300 mg/day (divided TID) over 1

week Maximum 600 mg/day Reduce if CrCl<60 mL/min Taper over 1 week to discontinue Abrupt discontinuation associated with

withdrawal (nausea, H/A, diarrhea)

Proposed Benefits of Pregabalin

Onset of action as early as 1 week Rapid dose titration Similar efficacy observed with BID and

TID dosing At dose > 75mg BID, more cost

effective than gaba No head to head efficacy data

Ed

Phone follow up in 3 days, deep buttock pain somewhat improved (using 8 BTs per day), radiating pain unchanged

Ed

Phone follow up in 3 days, deep buttock pain somewhat improved (using 8 BTs per day), radiating pain unchanged

Titrate Hydromorph Contin based on BT use and add neuropathic adjuvant

CIPN

Taxanes – 50-70% pts experience mild to moderate numbness, tingling, burning/stabbing in hands and feet

Vinca Alkaloids – 25%; high doses associated with absent Achilles reflex, weak distal muscles, foot drop

Platinum (Oxaliplatin) – Sx can occur after prolonged therapy and may develop 3-8 weeks after last dose

CIPN - Tx

Cancer, 2007: One placebo controlled RCT – gabapentin (max dose 2700mg) for six weeks – no benefit

JCO, 2004: Case series, gabapentin used as secondary prophylaxis with 90% reduction in taxane-induced arthralgias/myalgias (300mg TID; 2 days prior to start to 5 days following completion of chemo)

Opioid Resistant Pain

Neuropathic Pain

Bony metastases

Incident Pain

Visceral Pain

Other options for management of complex pain

Steroids Methadone Bisphosphonates Radiotherapy Interventions

Interventional Pain Management Techniques

Nerve blocks Vertebroplasty/cementoplasty Intraspinal analgesia

epidural intrathecal

Objectives




Which of the following is the strongest opioid?

A) fentanyl

B) hydromorphone

C) morphine

D) oxycodone

E) none of the above

Opioid “Strength”

Patients/caregivers ask “Is this too strong?” How do we respond?

Opioid “Strength”

Patients/caregivers ask “Is this too strong?” How do we respond? Potency (opiate receptor affinity; accounts for

“difference” in # of mg) Equianalgesic dosing Titrate to effectiveness “All opioids are in the same category in terms of

strength. Its about figuring out which one and what dose works the best for you and your pain.”

Ed’s Wife: Fears About Opioids

Often education and dispelling myths is all that is required to address adherence

Opioid Myths

MYTH 1 – opioids cause addiction Physical dependence is an expected result of long-term

opioid treatment but SHOULD NOT BE CONFUSED WITH ADDICTION

Physical dependence = withdrawal syndrome Addiction is a chronic neurobiologic disease with

genetic, psychosocial and environmental factors Helpful to patients to differentiate reason for use ie

relieving physical pain versus escaping psychological “pain”

Opioid Myths

MYTH 2 – opioids cause euphoria In terminally ill patients +/- those with pain,

opioids do NOT cause euphoria Mood may improve because their pain is

relieved

Opioid Myths

MYTH 3 – opioids = rapid tolerance Tolerance = state of adaptation,

diminished effect of drug over time Clinically significant tolerance is

unusual however in patients with progressive disease, increased levels of opioids are needed to control increased levels of pain

Opioid Myths MYTH 4 opioids = respiratory depression Respiratory depression is extremely rare Downregulation of mu2 receptor within 48 hours of

routine dosing Opioids are a crucial part of the treatment plan for

patients with end stage COPD, end stage CHF, advanced lung cancer

Naloxone (Narcan) is rarely indicated Differentiate between opioid side effects and

normal dying process

Nausea

Jack

58 yo male; advanced colorectal; colectomy followed by FOLFOX

Further abdominal progression; current on FOLFIRI

In ER with 6 days prog increasing abdo distension and generalized abdo pain; 2 days n/v; no BM x 2 days

prn Percocet worsened nausea

Jack

Proximal partial SBO diagnosed, NG inserted, IV fluids started, Gravol 25-50mg IV q4h prn for nausea and morphine 5mg sc q4h prn for pain

24 hour f/u - pt still c/o severe nausea, abdo pain somewhat improved (morphine BT x 4 given), pt has used Gravol routinely

Nausea/Vomiting

Vomiting centre in reticular formation of medulla

Activated by stimuli from:– Chemoreceptor Trigger Zone (CTZ)– Upper GI tract & pharynx– Vestibular apparatus– Higher cortical centres

CortexCortex

CTZCTZ

VestibularVestibular

GIGI

VOMITING VOMITING CENTRECENTRE

Chemoreceptor Trigger Zone

Vestibular Cortical Gastro-Intestinal

meds• opioids• chemoTx• etc...

biochemical• Ca++

• renal failure• liver failure

sepsis

radiotherapy

tumor

opioids

anxiety

association

ICP

inflammationobstructionparesiscompression

Stimulus Area Receptors

Drugs,

MetabolicChemoreceptor

trigger zone

Motion,

PositionVestibular

Visceral Organs

? Non-specific

CNS

↑ ICP Cerebral cortex

DD22 5HT

MM HH11

DD22 5HT

HH11

VOMITING VOMITING CENTRECENTRE

5HTMM

HH11

5HT5HT MMHH1122

EffectorEffectorOrgansOrgans

DopamineDopamineSerotoninSerotoninHistamineHistamineMuscarinicMuscarinicCB1

CannabinoidCannabinoid

CB1

DD22

DD22

1250

Relative Anti-Emetic Receptor Affinities

Summary of Anti-Emetics

Dopamine Antagonists – haloperidol > prochlorperazine > CPZ > metoclopramide

Muscarinic Antagonists – scopolamine Histamine Antagonists – dimenhydrinate

> promethazine > meclizine Serotonin Antagonists – ondansetron Misc – cannabinoids, steroids, benzos

Jack

Proximal partial SBO diagnosed, NG inserted, IV fluids started, Gravol 25-50mg IV q4h prn for nausea and morphine 5mg sc q4h prn for pain

24 hour f/u - pt still c/o severe nausea, abdo pain somewhat improved (morphine BT x 4 given), pt has used Gravol routinely

Jack

Optimal medical management of both nausea and the MBO would include:– Octreotide 500 micrograms sc tid– Dexamethasone 4mg sc/iv q8h – Opioids for pain– Consider Buscopan– Consider motility agents

Haloperidol 0.5 mg anti-emetic of choice for opioid induced nausea

Nausea

Think about underlying mechanism, associated receptor and use appropriate category of medication

Haldol – safe

Dyspnea

Epidemiology 70% of patients experience dyspnea in the

final six weeks of life1

55% of patients with advanced cancer experience at least moderate dyspnea2

Of those with symptom, 60-80% rate it as clinically important3

1National Hospice Study2Bruera et.al.3Donnelly and Walsh. The symptoms of advanced cancer. Sem Oncol 22(2):67-72

Pathophysiology

Initiation of breathing and its ongoing control is one of the main functions of the medulla (and to a lesser extent the pons)

Medulla receives afferent neural input from:– chemoreceptors in carotid and aortic bodies

– receptors in the muscles/tendons that participate in breathing

– receptors in the upper and lower airways

– receptors in the medulla itself that respond to changes in pH (which is largely regulated by pCO2)

Pathophysiology

Efferent instructions to the muscles involved in breathing comes through two spinal cord pathways:– from the medulla through the ventral portion– from the cortex through the dorsal

corticospinal tract

Pathophysiology

The Management of Dyspnea in a Palliative Care Setting: A Symptom-Based Approach. Mckee, University of Saskatchewan

Symptom Management

Non-pharmacologic Pharmacologic:

– opioids– benzodiazepines– phenothiazines– systemic corticosteroids

Opioids

Exact mechanism is not well understood

Benefit does not result from inhibition of respiratory drive– significant relief has been demonstrated

with no change in ventilation or pCO2

Opioids Few opioids have been studied and data is

surprisingly sparse Majority of evidence – morphine Conclusions of a systematic review:

significant overall benefit of systemic opioids on breathlessness and exercise tolerance1

Nebulized morphine compared to placebo is not beneficial for relieving dyspnea or exercise tolerance

1Jennings et. al. A systematic review of the use of opioids in the management of dyspnea. Thorax. 57:939-944

Benzodiazepines

Only one trial published involving cancer patients1

– compared morphine alone, midazolam alone and the combination

– when combined, dyspnea significantly improved

No trials examining benzos alone have demonstrated significant improvement in dyspnea or exercise tolerance

1Navigante et. al. Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage 31:38-47

Phenothiazines No studies in cancer patients One placebo controlled trial detected a

significant benefit with promethazine on dyspnea and exercise tolerance1

1Woodcock et. al. Drug treatment of breathlessness. Br Med J 283:343-346

Corticosteroids

No comparative trials have been published

Dyspnea - Conclusions

Existing evidence supports the use of systemic opioids for treating dyspnea

Oral promethazine could be used as an alternative if opioids not an option

No evidence to support the use of benzodiazepines to treat dyspnea (although known to significantly improve anxiety)

Future research: hydromorphone, oxycodone, fentanyl corticosteroids

End of Life Discussion

Prognosis


JAMA. 2008 Oct 8;300(14):1665-73

Wright AA, Zhang B, Ray A, Mack JW, Trice E, Balboni T, Mitchell SL, Jackson VA, Block SD, Maciejewski PK, Prigerson HG.

Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment.

End of Life Discussion To determine whether end-of-life discussions with

physicians are associated with fewer aggressive interventions

Multisite, prospective, longitudinal cohort study of patients with advanced cancer and their informal caregivers (n = 332 dyads)

Median f/u (enrollment to death) = 4.4 months Bereaved caregivers' psychiatric illness and quality

of life was assessed a median of 6.5 months later


Primary outcome measures: aggressive medical care (eg, ventilation, resuscitation) and hospice in the final week of life

Secondary outcomes included patients' mental health and caregivers' bereavement adjustment

123 of 332 (37.0%) patients reported having end-of-life discussions before baseline


Discussions were not associated with higher rates of major depressive disorder or worry

After propensity-score weighted adjustment, end-of-life discussions were associated with lower rates of ventilation, resuscitation and ICU admissions

More aggressive medical care was associated with worse patient QoL and higher risk of major depressive disorder in bereaved caregivers

Advance Care Planning

Advocate for ACP and Goals of Care Discussions to be an iterative routine element of cancer care for patients with incurable disease

“The role of chemotherapy at the End of Life: When is Enough, Enough?”

JAMA June 11, 2008 – Vol 299(22): 2667-2678.

[email protected]

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