Opioids: Helpful or Harmful? Emerging knowledge and clinical experience

Conflict of Interest None to declare

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

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

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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

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

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

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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 45-60 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 2017 Annual Assembly of Hospice and Palliative Care

Agonist/antagonist Agents Nalbuphine Butorphanol Source: Mellar P Davis MD FCCP FAAHPM Paul Sloan MD Opioids: What is New and Potentially Good 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care

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 2017 Annual Assembly of Hospice and Palliative Care