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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
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