Patient’s Problems • Pain (80%) • Fatigue (90%) • Weight Loss (80%) • Lack of Appetite (80%) • Nausea, Vomiting (90%) • Anxiety (25%) • Shortness of Breath (50%) • Confusion-Agitation (80%)

Tumor Edema

Suzuki, et al in (Bruera, Portenoy – Cancer Pain

Suzuki, et al in (Bruera, Portenoy – Cancer Pain

Inhibitory Modulators of Nociception 1. [Opioids peripheral and central]. 2. Adrenergic – Serotonergic [Tricyclics,

SSRIs, Tramadol]. 3. GABA pathway [analogs too toxic]. 4. Adenosyn [decreased plasma and CSF

adenosyn levels in neuropathic pain].

Excitatory Modulation of Nociception • NMDA receptors [glutamate, excitatory AAs]. • Effective in neuropathic pain in animals. • Prevent and reverse morph intolerance.

Hyperalgesia – exaggerated response to noxious stimulus

Hyperesthesia – exaggerated response to touch

Allodynia – perceiving a non-nociceptive stimulus as painful

Intensity assessment

0- 10 numerical scales Visual analogue scales Verbal scales Face scales Color scales Finger scales

Dr. Bruera

ESAS (Edmonton Symptom Assessment System)

2 minutes by patient in the waiting room

Well validated

Most common tool in cancer and palliative care

FREE!!!. Download it today and start using it!

Dr. Bruera

Symptom Assessment Edmonton Symptom Assessment Scale (ESAS)

Average intensity of 10 symptoms over past 24 hours

Numeric rating scale Physical (N=7) Emotional (N=2) Well being (N=1)

Bruera et al. J Palliat Care 1991

Dr. Bruera

©Permission to reuse given by Dr. Bruera

SYMPTOM ASSESSMENT – DAY 1

SYMPTOM ASSESSMENT – DAY 8

Schema of Symptom Construct

1. PRODUCTION/CONSTRUCT

2. PERCEPTION

3. EXPRESSION

MODULATION

COGNITIVE STATUS

MOOD

BELIEFS

CULTURAL

BIOGRAPHY TREATMENT

Dr. Bruera

PC Assessment

Pain is a Multidimensional Construct

Dr. Bruera

What’s in a name?

What’s in a number?

PAIN

0-10

What Impacts Pain Intensity 0-10?

Afferent Nociception Meaning (Cancer, Osteoporosis?) Personality (Stoic, Histrionic?) Experience/Memory (Father died in pain) Alcoholism/Drugs (Chemical coping) Intelligence/Education (Understands pain & treatment) Culture (Pain expression OK?) Spirituality (Pain Good? Punishment?) Secondary Gain (Attention from family) Depression/Anxiety (Somatization) Delirium (Disinhibition) Trust In Doctors (Adherence, Placebo!)

Dr. Bruera

Pain Intensity 8/10

Dr. Bruera

Patient #1 Patient #2 Nociception 85% 30% Somatization 5% 20% Coping Chemically 5% 30%

Tolerance 5% 0% Incidental Pain 0% 20%

100% 100%

PC Assessment

Fatigue 8/10 Patient 1 Patient 2

Depression 60% 10%

Cachexia 10% 50%

Anemia 10% 30%

Opioids 20% 0%

Autonomic 0% 10%

PC Assessment

NCCN guidelines: Pain>7: Pain emergency! Median intensity of pain reported by chronic non malignant pain patients attending outpatient clinics: 7.2 What’s in a name? What’s in a number?

Personalized Pain Goal

445 cancer patients at Supportive Care Center Median follow-up 14 days

Dalal et al. Cancer 2012

Dr. Bruera

Cancer by AMERICAN CANCER SOCIETY Reproduced with permission of JOHN WILEY & SONS - JOURNALS in the format Post in a course management system via Copyright Clearance Center.

Personalized Pain Goal A Tale of Two Patients

Dalal et al. Cancer 2012

At what level of pain would YOU feel comfortable?

Patient 1

Patient 2

Dr. Bruera

ASK Personal Pain Goal! (≈ 3/10 for Assessment)

Number is only part of the assessment

Function more important

Refer patients who continue to express high levels of pain intensity to Supportive Care/Palliative Care team

Dr. Bruera

PC Assessment

↑ Pain Intensity

Chemical Coping

Ischemia

Tumor Growth Infection

Opioid Tolerance Delirium

Fracture

Mood Change

Cancer Related

Patient Related Dr. Bruera

Pain Intensity

Prognostic Features

Some bedside clinical findings are associated with worse response to pain management

Dr. Bruera

The Five Poor Pain Prognostic Features

Neuropathic

Incidental ( BTP)

Delirium

Somatization

Chemical coping

Dr. Bruera

Pathophysiology

Neuropathic

Incident

Dr. Bruera

Neuropathic

Brachial plexopathy (breast, lung)

Lumbosacral plexopathy (retroperitoneal or pre- sacral tumor)

Lower response rate to opioids

Opioids remain first line to therapy!

Dr. Bruera

PC Assessment

Incident Pain

Nociceptive input is variable

Analgesic modulation is slower

Movement, swallowing, cough, bowel movement

Few to several hundred episodes/day

Rapid onset and termination

Dr. Bruera

Increased Expression

Delirium disinhibition

Chemical coping

Somatization (“total pain”)

Dr. Bruera

Delirium

Sepsis

Chemo

OPIOIDS and other drugs (psych!!)

Tumor byproducts and host cytokines

Metabolic Na, Ca, Creat

CNS Involvement

Dehydration

Dr. Bruera

Delirium

PC Assessment

Delirium

85% cancer patients before death

Multi-causal

80% of brain is GABA

Disinhibition: expression of symptoms and emotions

Dr. Bruera

Delirium

Opioids can cause- dose escalation!!

Increased pain: hyperalgesia /delirium

Screening!! Mini-Mental State Examination, hallucinations, agitation

Dr. Bruera

Delirium and Symptom Expression (Delgado- Guay)

A 60 year old man with advanced small cell prostate cancer, lumbar adenophathies and bone metastases.

Dr. Bruera

Chemotherapy + lumbar radiotherapy Referred STAT due to severe pain

Admission: calcium 12.44, creatinine 1.6 Pain 9, MDAS 14

Bedridden

ESAS Findings at Admission

Delgado-Guay MO, et al. JPSM 2008; 36(4):442-449

Dr. Bruera

Somatization

“total pain”, “total suffering”

Diagnostic criterion for affective disorders

Meaning of pain for the patient

Aggravated by stressors

High intensity expression (10/10)

Multiple symptoms (“all black graph”)

Dr. Bruera

Somatization

Intensity – 10 PPG - 0

Reason for Concern

Dr. Bruera

Chemical Coping

Using the opioid (and other psychoactive drugs) to cope with distress rather than pain

Approximately 1/ 5 cancer patients

The vast majority underdiagnosed until aberrant opioid use detected

Dr. Bruera

Opioid

MOR Nociceptive Pathway

Nociceptive Input

Excitatory Amino Acids Fast ! Slow !

PAIN + −

Dr. Bruera

Opioid

MOR limbic System

Distresss

Fast !

Non Opioid

Pathways

+

−

Fast !

Dr. Bruera

Methods

• 432 outpatients seen at SCC • 13 PM specialists assessed for cc all pts

they had seen for the last 40 days • Review of documentation in chart

Results

• 76/432 pts (18%) diagnosis of Chemical coping by pall med specialist

• Only 15/432 (4%) documented CC in the chart !!

CAGE (AID) Questionnaire

• Have you ever felt that you should cut down on your drinking (or drugs)?

• Have you ever been annoyed by people criticizing your drinking (or drugs)?

• Have you ever felt bad or guilty about your drinking ( or drugs)?

• Have you ever had a drink first thing in the morning or a drink ( or drugs) to get rid of a hangover (eye-opener)?

Why should you care about CAGE ? • Marker for chemical coping, NOT just

ETOH!! • ETOH shares reward with opioids • MDs do not diagnose chemical coping- dose

escalation and OIN • Counseling helps reduce conflict and dose

Opioid management

• Document chemical coping/ aberrant opioid use ( sensitive notes)

Smoking is a risk factor (Kim, Dev, et al JPSM 2016

• 300 consecutive cancer pts comprehensive smoking assessement:

• 119 (40%) never smokers, 148 (49%) former smokers and 33 (11%) current smokers

• CAGE +: 3%, 12%, 42% • Hx drugs +: 3%, 16%, 33%

2. Assess Pain Characteristics Location Medical treatments Number of episodes Onset Position Quality Radiation Severity Triggers Identification of pain mechanism

3. Assess Pain Modulators Somatization ( psychological/ spiritual) Chemical coping Delirium

5. Formulate Personalized Pain Treatment Plan Analgesia—based on pain mechanism, individual preference, past treatment history Psychological distress—counseling Spiritual distress—pastoral care Chemical coping—education, focus on function, close monitoring Cognitive impairment—treat underlying cause (e.g. opioid rotation), neuroleptics

6. Regular Reassessment Duration of follow-up is individualized based on complexity, generally 1-4 weeks Personalized pain goal achieved? Medication side effects, adherence and aberrant behaviors

Hui and Bruera. J Clin Oncol 2014 (in press)

Personalized Pain Management

Dr. Bruera

1. Routine Pain Screening From 0 to 10, what is your level of pain over the last 24 hours?

4. Assess Personalized Pain Goal From 0 to 10, at what level do you feel comfortable?

PC Assessment

Patient Understanding

Addiction

Pain escalation in the future

Opioids as the cause of death

Fear of side effects

Regular vs. PRN

Dr. Bruera

Opioid Titration/Rotation

Opioid naïve patient → EASY!!

Always starting dose

Intensity of pain expression is not important consideration – Safety is the main reason for always using standard dose: – ≡ 30 mg morphine/day orally – 20 oxycodone (hydrocodone, etc.)

Dr. Bruera

Which Opioid?

Good kidney, good liver, no other drugs → all good

Dr. Bruera

Opioid

Phase I: Oxydation Hydrolysis 3A4 – 2D6

Phase II: Conjugation UGD

Renal Elimination

Dr. Bruera

Opioid metabolism

Phase I (* = Active) Morphine * Hydromorphone * Oxymorphone * Tapentadol * Codeine Hydrocodone* Oxycodone* Tramadol Fentanyl* Methadone*

0 0 0 0 ? 2D6 Morphine* 3A4 Norcodeine 2D6 Hydromorphone* 3A4 Norhydrocodone 3A4 Noroxycodone 2D6 Oxymorphone* 2D6 O-demethyl-T* 3A4 N-demethyl-T* 3A4 Norfentanyl 3A4 M1 – M2

Dr. Bruera

3A4

Macrolides

Fluroquinolones

Azoles

Antiretrovirals

Grapefruit

Imatinib – Irinotecan

New targeted agents

Dr. Bruera

2D6

SSRIs

Genetic Poor Metabolizers

Neuroleptics (Haloperidol – Chlorpromazine)

Dr. Bruera

Clinical Implications

Sedation New Drugs 3A4? (Methadone, Fentanyl, Oxycodone, Hydrocodone, Tramadol, Codeine)

No Response to codeine, tramadol: Slow 2D6, SSRI, Neuroleptic

Sedation Renal Failure? (Morphine, Hydromorphone, Oxymorphone, Oxycodone)

Sedation Liver Failure? (Methadone, Fentanyl)

Dr. Bruera

Cleaner opioids (No major 2DG – 3A4 metabolism)

Morphine

Hydromorphone

Oxymorphone

Dr. Bruera

Potential toxicity in patients with Fluconazole, macrolides, quinolones, anti retrovirals, etc.

Methadone

Fentanyl

Oxycodone

Hydrocodone

Dr. Bruera

3A4 METABOLISM

Less effects in patients on SSRIs, haloperidol, genetically poor metabolizers

Codeine

Dr. Bruera

2D6 Activation

Methadone

Probably fentanyl

Hydromorphone

Dr. Bruera

Renal Failure

Clean ones

Morphine

Hydromorphone

Oxymorphone

Dr. Bruera

Liver Failure

Extended Release or Immediate Release?

Dr. Bruera

Ideal Regime

Extended release regularly

PRN orally immediate-release opioid ≈ 5%- 20% of the daily dose

Always 100% laxative

Always PRN Antiemetic (especially first 3 days, metoclopramide)

Dr. Bruera

Characteristics of patients with consult only vs. consult plus follow up visit

Median ESAS scores at baseline and first follow up visits

Percentage of patients having pain treatment response and percentage of patients with good pain control (pain ≤3/10) at first follow up visit

Follow-Up: Phone/See ≤ 1 week

Dr. Bruera

Minimal Increase/ decrease ≈ 30% of daily dose ( opioid titration always % due to large dose range!!)

Dr. Bruera

• Rapid dose escalation: hyperalgesia!! • Opioid induced neurotoxicity • Financial cost (USA) • Rarely other side effects ( nausea,

constipation)

When do we rotate?

Delirium

Sepsis

Chemo

3 Cyclics, Benzodiazepines

Opioids

Metabolic Na, Ca, Creat

CNS Involvement

Dehydration

To which opioid? → NOT IMPORTANT!! Stopping the offending opioids IS IMPORTANT

Dr. Bruera

How Do We Rotate?

A. Calculate MEDD (Morphine Equivalent Daily Dose) 260 regular + 60 mg BTP → 320 mg/day

B. Equianalgesic Ratio (from table) For hydromorphone MEDD/ 5 → ≈ 60 mg/day For oxycodone MEDD/ 1.5 → ≈ 200 mg/day For oxymorphone MEDD/ 3 → ≈ 100 mg/day

C. DOSE REDUCTION! Due to incomplete cross tolerance (30% – 50%)

D. New Opioid and Dose: ER Hydromorphone 30 mg daily orally IR Hydromorphone 2mg-4mg every hour PRN

Phone/see patient in 2-3 days to further titrate – large interpersonal variation!!

Dr. Bruera

Relationship Between Hydromorphone & Morphine

Dr. Bruera

Image provided by Dr. Bruera

Patient unable to swallow

Admit the patient and change to parenteral opioid A. All opioids except methadone need continuous

infusion! (short half life)

B. Correct dose from PO to parenteral ratio from tables (orally given has first passage elimination and intravenous [IV] avoids liver). For most opioids oral/IV ratio is 2-3:1

Dr. Bruera

Dr. Bruera

C. Rescue dose also is IV/SC approximately 10% daily dose or about two hours of infusion

D. Assess Daily → Steady state of IV opioid reached in ≤ 24 hours! – increase or decrease 30% – 50%

Patient Case Continued

When IV Route Not Possible or Comfortable

Subcutaneous intermittent injection every four hours into an indwelling butterfly needle (morphine, hydromorphone), or every 8 to 12 hours for methadone

Fentanyl (too short half life) will need a subcutaneous continuous infusion

Dr. Bruera

When Pain severe, neurotoxicity severe or patient has financial problems: METHADONE!!

Dr. Bruera

Extraordinary results but potential for severe toxicity if medical doctor unfamiliar. NMDA receptor blocker → less hyperalgesia Much more potent Much cheaper More dangerous in tolerant patients Every 12 hours and once in steady stage can be used also

for BTP Subcutaneous/IV can be used every 12 hours (long half life) QT prolongation reported & EKG good idea before starting

IV and after three to five days We do not find QT prolongation orally and do not regularly

do EKG for methadone rotation

Dr. Bruera

All Other Opioids: Toyotas or Hondas Methadone: Lamborghini

Oral Methadone in Cancer Pain

Dr. Bruera

Pain by INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN Reproduced with permission of ELSEVIER HEALTH SCIENCE JOURNALS in the format Post in a course management system via Copyright Clearance Center.

Lawlor P et al. Pain 1997 72(1-2):79-85

Conclusions

Use only a few opioids so you are quite familiar with them

Titration, rotation, and route change to and from are simple if you follow a checklist

Remember interpersonal variations:

Follow-Up Frequently

Dr. Bruera

Opioid Side Effects Common • Sedation • Constipation • Nausea

Less Common • Opioid-induced neurotoxicity • Sweating • Urinary Retention • Pruritus • Adult Respiratory Distress Syndrome • Addiction • Respiratory Depression • Hypogonadism

Managing side effects

• 100% laxative and titrate to regular bowel movement

• 100% metoclopramide 10 mg po q4h prn • Phone if more than >3- 4 BTP doses per day • Stop and phone if too sleepy/ confused

Drugs For Opioid-Induced Constipation

FDA Approved: Methylnaltrexone: Periph mu Antag Lubiprostone: Chloride Channel Activator Naloxegol: Periph mu Antag Almivopan: Periph mu Antag (Not for Opioids!)

In Research: Axelopran: Periph mu Antag Sustained release Naloxone: mu Antag (periph x central)

ALTERNATE ROUTES

ESTABLISHED • Subcutaneous • Rectal • Transdermal • Transmucosal

EMERGING • Intranasal • Inhalatory • Sublingual • Transdermal -

iontophoresis

Parenteral opioids

• IV always infusion for morphine, hydromorphone, fentanyl, oxycodone (very short half life!)

• Intermittent IV: methadone q 12 h ( EKG need controversial, not in hospice or when not available

• BT dose: 10% of daily infusion • SC: intermittent injection

When IV Route Not Possible or Comfortable

Subcutaneous intermittent injection every 4 hours into an indwelling butterfly needle (morphine, hydromorphone), or every 8 to 12 hours for methadone

Fentanyl (too short half life) will need a subcutaneous continuous infusion

Abuse deterrent formulations

1. Tamper proof ( cannot be chewed/ injected). 2. Mixed with antagonist (naloxone, naltrexone) 3. Mixed with local irritants (pain upon snorting/

injection, or niacin (flushing, nausea, headache) • Will reduce street value, but will NOT prevent the

main issue with chemical coping: taking too much!

• Do not address IR rescue opioid • Very expensive

Pathophysiology poor prognostic factors • Neuropathic • Incidental

Neuropathic

• Non cancer ( periph neuropathy, post herpetic): >65% response to non opioids

• Cancer ( brachial, lumbosacral pexopathy): < 30 % response to non opioids, >60% response to opioids

Allodynia, “burning”, “pins and needles”, radiation : frequent but not necessary!!

INCIDENTAL PAIN – Clinical Aspects

• Main Pain Problem for the Patient (Intensity) • Range: 1 - 3000 times/day • Duration: Seconds - One Hour • Causing Factor: Present (movement) or Absent (Neuralgic)

PC Assessment

Incident pain

• 1. Nociceptive input is variable. • 2. Analgesic modulation is slower • 3. Movement, swallowing, cough, bowel

movement • Few to several hundred episodes/ day • Rapid onset and termination

PC Assessment

Incidental pain- Strategies

• Decrease nociceptive input- XRT, bisphosphonates, nerve block

• Psychostimulants • Adjuvants

• RCT, Double-blind, Placebo • Tolerant to 60-1000 mg/ day • Open Label Titration!! • 80/123 Responded (65%!!)

11/05/2012

• What happened to intention to treat? • Loading the dice ( placebo control) • Falls, Cognition, Addiction

11/05/2012

11/05/2012

11/05/2012

• No Cross-over, No Patient Choice • “Efficacious and Safe” • Efficacious? : 3.02 versus 2.69! • Safe? Falls, Cognitive, Addiction!!

6. The opioid access story

• Most cancer patients die without a single opioid dose

Distribution of Morphine Consumption in 2009

OPIOID COSTS MEDD 100 mg/day Cost of

Opioid,U$ Opioid Cost as % of monthly GNP/capita

Cost of Morphine

Morphine cost as % of

monthly GNP

Number of observations

Developing Developed

45 76

45 76

13 20

13 20

Mean (Standard deviation)

Developing Developed

828 (1711) 127 (189)

267 (534) 7 (12)

463 (910) 71 7(1)

148 (313) 4 (4)

Median (range) Developing Developed P value

112 (4-7542) 53 (2-103) =0.02

36 (3-2262) 3 (<1-65) <0.0001

108 (4-3240) 52 (2-305) >0.02

38 (3-1170) 3 (<1-14) =0.0003