1. Opioids: Helpful or Harmful?
Emerging knowledge and clinical experience

2. Conflict of Interest
None to declare

3. Objectives Brief overview of areas of emerging knowledge
Facilitated discussion of clinical experiences and evolution of clinical practice related to opioid therapy

4. Historical Context
The mean opioid dose at St Christopher ‘s hospice in the 1970s was 30 mg of morphine per day
Hey Doc Can We Cut Down on the Pain Pills? Current Status of Opioid Tapering Guidelines and How to Do it
Mellar Davis, MD FAAHPM Mary Lynn McPherson, Pharm D Eric Prommer, MD, FAAHPM Kathryn A. Walker, Pharm D

5. Helpful, but…
New/nuanced understanding of opioid receptors and drug effects both acutely and chronically
Palliative = Chronic Pain management (unless clear disease progression/end-of-life)?
Opioid reduction as therapeutic measure
Knowing what we don’t know
Townhall session: Timely and effective management of pain and other distressing symptoms is critical to providing seriously ill patients with high‐quality palliative care, and opioid analgesics are an important tool in that process.
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

6. Cellular Level
Opioid receptors have many subtypes, variants; receptors form heterodimers
Downstream effects (beta-arrestin, dynorphin)
Opioids from different classes produce different physiologic effects
How do we separate analgesia from analgesic tolerance and various toxicities?
1, 6, 7TM mu
Mu-delta
beta-arrestin - dysphoria - Talwyn targeted this more - nalbuphine less
also resp depression and constipation
in >60 yo, >50 mg MEDD greater risk of falls/fractures
Evidence hard to generate and put in context - diclofenac gel study looked the same - healthty individuals in studies may have systems that operate differently from chronic pain/sick patients
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

7. I don’t understand this either…
Agonist, Inverse agonist, antagonist
I don’t understand this either…
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

8. Acute pain
Opioid receptors are constitutionally activated by acute pain (independent of endorphins) -> reduces pain sensitivity and this can remain for months (or years?)
Effect can be reversed by inverse agonists and exogenous opioids can interfere with this mechanism and prolong pain
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

9. Chronic Pain Concepts Catastrophization, Depression
Central Sensitization and Chronification of pain – neuroplasticity
Opioid Syndrome: • Unresolved pain • Frequent breakthrough doses despite stable disease (escalation independent of disease course) • Withdrawal interpreted as recurrent or persistent disease • Analgesic tolerance at high doses • Hyperalgesia‐increasing unpleasantness to pain and sensitivity • Altered social and occupational interactions • Distorted insight as to risks and harms to opioid therapy
catastrophizing scale Sullivan MJL Clin J Pain 2014;30:183
Hey Doc Can We Cut Down on the Pain Pills? Current Status of Opioid Tapering Guidelines and How to Do it
Mellar Davis, MD FAAHPM Mary Lynn McPherson, Pharm D Eric Prommer, MD, FAAHPM Kathryn A. Walker, Pharm D

10. Long‐term Opioid Side Effects
• Increased infections • Increased cancer relapses? • Endocrinopathies–central hypogonadism • Osteoporosis • Sarcopenia • Falls and fractures • Delayed healing of fractures • Opioid induced depression • Wound dehiscence • Complex sleep apnea –obstructive and central • Increased cardiovascular mortality • COPD exacerbations/Pneumonia • Increase mortality in at risk populations –COPD and chronic non – cancer pain • Similar effects will be observed in patients with cancer on long‐term opioids‐there is no “opioid adverse effect immunity” with cancer
Hey Doc Can We Cut Down on the Pain Pills? Current Status of Opioid Tapering Guidelines and How to Do it
Mellar Davis, MD FAAHPM Mary Lynn McPherson, Pharm D Eric Prommer, MD, FAAHPM Kathryn A. Walker, Pharm D

11. Likely to Fail an Opioid Taper
Depression and pain together
High pain intensity prior to taper
Experience of withdrawal prior to taper
Female
Smokers
No evidence-based guidelines, but some literature to support different strategies
Hey Doc Can We Cut Down on the Pain Pills? Current Status of Opioid Tapering Guidelines and How to Do it
Mellar Davis, MD FAAHPM Mary Lynn McPherson, Pharm D Eric Prommer, MD, FAAHPM Kathryn A. Walker, Pharm D

12. Future Strategies
Combining opioids: Better analgesia? Increased side-effects, e.g. addiction?
Partial agonists? Full analgesic response without side-effects? (buprenorphine)
Drugs with agonist/antagonist effects? Full agonists can be added to relieve pain without withdrawal
Strategic use of antagonists
Use of adjuvants to mitigate harmful effects
All need more studies
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

13. Combining opioids
Some preclinical and clinical evidence for oxycodone + morphine, but not enough evidence to determine utility
Preclinical studies on fentanyl + morphine
Methadone + morphine: methadone synergy effects unrelated to NMDA, but (weak) clinical studies of coanalgesic methadone suggest benefit actually came from simply reducing the morphine
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

14. Combining Opioids Therapeutic windows can be narrow
Variables multiply: genetic variation, pain phenotype, region
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

15. Buprenorphine Seems to work differently in many ways
Possible synergy with other opioids
No RCT – need proper studies to determine utility, i.e. efficacy/adverse effects
Suboxone now general ODB benefit; patch is expensive
Can cause withdrawal if rotation attempted from greater than mg MEDD
partial agonist of 6TM mu opioid receptor, kappa opioid
Better versions in the drug pipeline
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

16. Agonist/antagonist Agents
Nalbuphine
Butorphanol
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

17. Opioid antagonists
Peripherally acting mu-opioid receptor antagonist (PAMORA) = Methylnaltrexone, Naloxegol
naloxone within Targin, Suboxone has minimal bioavailability via GI route – NB liver disease increases systemic absorption
Isomers of opioid antagonists that do not bind the opioid receptor but have good adjuvant effects
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care

18. Use of adjuvants
Haloperidol – preclinical studies – potential to mitigate adverse effects of methadone
NSAID
gabapentinoids
Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good Annual Assembly of Hospice and Palliative Care