Opioid Induced Neurotoxicity: We Didn t Start the Fire. Joel S Policzer, MD, FACP, FAAHPM joel.policzer @vitas.com Rebecca G. Smith, MD, MS, FAAPMR rebecca.smith@vitas.com.or did we?? 1
Objectives Objectives Understand the neuroanatomic and neurophysiologic basis of pain Review the pharmacokinetics of opioids and potential etiologies of OIN and OIH Recognize the clinical manifestations of these syndromes Develop a treatment plan for prevention and an intervention plan once recognized Case 1 22 yooman with mitochondrial disease 22 yo woman with mitochondrial disease probably mitochondrial neurogastrointestinal encephalopathy syndrome Diagnosed at age 14 Now terminally ill with advanced protein calorie malnutrition due to malabsorption, with nausea and with severe abdominal pain. Admitted to hospice unit for pain management. mitochondrial neurogastrointestinalencephalopathy syndrome Diagnosed at age 14 Now terminally ill with advanced protein calorie malnutrition due to 2
Case 1 Regrettably, admitting physician and patient s mother clashed repeatedly over management. Patient s mother had always made all medical decisions Patient and her spouse had capacity but deferred to mother; physician wanted patient to make her own decisions and mother felt marginalized. Case 1 Patient s symptoms continued to be prominent. She indicated she was in severe pain and appeared agitated. Over period of 72 hrs, dose of HM had been increased from 2 mg IV every 3 hrs, to 15 mg IV every 3 hrs. In addition, in attempt to control increasing agitation, lorazepam had increased from 1 mg per dose to 5 mg per dose. 3
Case 1 My first day on rounds I found the patient screaming, thrashing in bed, with incoherent speech; her mother was sitting at the bedside crying and begging us to do something. After I reviewed the chart, my initial reaction was: $%&@)*!! Patient s mother agreed to treatment for possible OIN Case 1 Interventions started: HM was stopped and equianalgesic dose of IV methadone was calculated for HM 4 mg q 3 hr Haloperidol 1 mg q 4 6 hr prn Hydration at 75 cc/hr Patient calmed within 4 hrs. Pain remained controlled with minor titration of methadone dosing. Became alert and interactive within 24 hrs. Haloperidol not required after 2 3 doses 4
Pain and etiology of OIN Nociceptive pathways Nociceptors are present throughout skin, soft tissue, bone and capsules of internal organs. Mechanical receptors, chemo receptors, thermal receptors, etc. A receptor exists to signal any type of injury to the body s integrity Two peripheral nerve fibers transmit stimulus from nociceptor A δ: myelinated fibers, rapid transmission. Localizes pain C: unmyelinated fibers, slower transmission. Chronicity of pain Both fibers (1 st order neurons) synapse in the dorsal horn of the appropriate cord level 5
At dorsal horn, signals in 2 nd order neurons decusate and ascend spinothalamic tract to thalamus. Localizes pain 3 rd order neurons continue to ascend from thalamus to terminate in somatosensory cortex and periaqueductal gray area Other signals synapse with 2 nd order neurons in spinoreticular tract Adds emotional aspects of pain Ascend to brainstem reticular formation, then on to thalamus and hypothalamus, and then cortex 6
Inhibitory pathway Decreases pain transmission in dorsal horn Originates in brainstem and descends down to dorsal horn Modulates synapse between 1 st and 2 nd order neurons 7
Neurologic system is plastic and responds to environment Pain is an emergency Need to decrease pain experience Pain receptors recruit pain receptors The more pain you have, the more pain you have 8
Neurotransmitters 1 st order neurons Depolarization caused by nociceptor opens Na + channel which transmits to presynapse. Opens Ca ++ channel which allows glutamate into synapse Glutamate binds to NMDA receptor on post synapse and continues stimulatory impulse C fibers release Substance P 2 nd order neurons Opioid receptors present post synapse. Decrease stimulatory impulses and inhibit ascending pain impulses Opioids also decrease release of Substance P Neurotransmitters From brainstem down to dorsal horn, pathway is modulated via serotonin and norepinephrine At synapse between 1 st and 2 nd order neurons in dorsal horn, inhibitory pathway releases GABA 9
Mechanism of opioid action Opiates naturally occurring alkaloids found in opium poppy Morphine Codeine Opioids semi synthetic substances derived from opiates Hydromorphone Oxymorphone Oxycodone Hydrocodone 10
Mechanism of Opioid Action All bind to various opioid receptors (µ, δ, κ) in various concentrations Interdrug variability Interpersonal variability Behind the fact that different opioids have differing effectiveness in different people Explains benefit of opioid rotation Mechanism of opioid action At dorsal horn: Pre synaptic decrease release of neurotransmitters from C fibers Post synaptic inhibit evoked activity Supraspinal: Modulate descending inhibition There is a facilitatory pathway with on cells Pain increases firing of on cells There is an inhibitory pathway with off cells Opioids induce off cells to turn on, and oncells to turn off 11
Opioid metabolism All opioids metabolized in liver by Cytochrome P450 enzymes Phase 1 metabolism oxidative; metabolites clinically inactive Phase 2 metabolism glucuronidation; to make lipophilic molecule highly hydrophilic for renal excretion 3 glucuronides actively bind to opioid receptors (less that native molecule); highly neuroexcitatory 6 glucuronides actively bind to opioid receptors (less than native molecule); responsible for sedation, respiratory depression Opioid metabolism M3G and H3G easily cross blood brain barrier Felt to be reason for behavioral excitability Codones (oxycodone, hydrocodone) Primarily Phase 1 metabolism (oxidation) Very few clinically active metabolites produced Little role in OIN/OIH 12
Mechanism of hyperalgesia Full mechanism unknown Pre clinical studies: Role of NMDA NMDA decreases transport glutamate out of neurons increased intracellular glutamate increased sensitization of neurons When NMDA antagonist (ketamine) is given before painful stimulus, there is attenuation of hyperalgesia Anecdotal observation: methadone attenuates OIH/OIN 60% of activity of methadone is as NMDAantagonist Mechanism of hyperalgesia Gabapentin/pregabalin when given before painful stimulus, attenuate hyperalgesic effect GABA effect is inhibitory at level of cerebral cortex, cerebellum, hippocampus and limbic system Clonidine (α2 agonist) decreases sympathetic outflow from CNS Sympathetic system mobilizes fight or flight Increased alertness, heart rate, peristalsis, adrenaline secretion Can cause signs/symptoms of agitation, anxiety, delirium 13
Mechanism of hyperalgesia Naloxone no effect whatsoever on OIH/OIN therefore not opioid receptor mediated Support thesis that syndrome due to neuroadaptive changes in pain circuits Clinical Manifestations 14
Clinical Manifestations Think: rev d up sympathetic nervous system Progression of symptoms from less severe to more severe Myoclonus Allodynia Hyperalgesia Delirium: confusion, disorientation Hallucinations: visual Seizures Clinical setting Patient often elderly (diminished hepatic and renal function) Pain is out of control Well intentioned treatment is to regain control quickly Opioid doses are escalated progressively and pain does not get better or gets worse Think: gasoline on a fire Patient is dehydrated 15
Clinical setting Often occurs when caregiving is fragmented Volunteer or professional caregivers are not consistent No one person is assessing patient from shift to shift or day to day No consistency in observers Each person gets a snapshot of situation: wow, this pain is terrible. We need to increase the pain meds No one person has the whole video : wow, the dose of morphine has been increased 3 times in 2 days and everything is getting worse! Hmmm Management 16
Management Based on etiology of syndrome: Active metabolites of morphones Increased production of metabolites Decreased excretion of metabolites Rotate analgesic away from phenanthrene ring opioids that are glucuronidated Management Stop morphine and hydromorphone Start NMDA antagonists: ketamine, methadone Can be problematic in home setting where parenteral administration is difficult Start codone whose non active metabolite comes from oxidation Can be problematic in situation where patient cannot take oral dosing and needs parenteral 17
Management If either of above are not possible Continue current opioid but reduce dose by 80% Requires great self confidence in diagnosis Often accompanied by putting on Big Boy/Big Girl pants or Depends If patient s CV status will tolerate it, hydrate as much as possible Management Treat any untoward behaviors as needed Delirium Haloperidol Atypical antipsychotics: quetiapine Benzodiazepines: lorazepam if patient needs to be calmed quickly Seizures lorazepam 18
Case 2 Hospital 59 year old man, Jehovah s Witness, who had a complicated past medical history that began in 1987 with multiple orthopedic & visceral trauma following a fall from 5 stories He also had a history of chronic pain, chronic opioid use and recurrent infections After being cleared by ID, he underwent a left THA in 2016 for pain and functional limitations due to traumatic osteoarthritis He subsequently developed a left prosthetic his infection and sepsis. He was readmitted to the hospital for treatment, however, the orthopedic surgeon could not operate due to a Hgb of 5.9 Gm and unstable condition Case 2 Hospital The patient developed Stevens Johnson Syndrome as a reaction to Vancomycin which was subsequently stopped He decided, after a number of Palliative Care visits in the hospital, that he was tired of his chronic pain and loss of function, wanted to stop all aggressive treatments and be made comfortable on hospice services. His prognosis was poor and he said that he did not want to live like this anymore. His wife was his HCS and took over decision making when her husband could no longer make decisions for himself The patient was subsequently admitted to hospice care for symptom management 19
Case 2 Hospice IPU The patient continued to have moderate to severe pain related to erythema and blisters all over his arms, trunk and legs A SQ infusion of hydromorphone was started and gradually increased to 5 mg/hr with a bolus of 2 mg q 15 min prn The hydromorphone was titrated over 6 days to a level of 17 mg/hr and a bolus of 6 mg q 15 min prn The nurses continued to report that the patient had severe pain anytime he was touched or turned. He was comfortable at rest. They were unable to provide care and the patient s wife and children were distressed Case 2 Hospice IPU Why is the patient still having severe pain despite hydromorphone SQ at 17 mg/her and 6 mg bolus q 15 min prn? What would you do? 20
Case 2 IPU After a meeting with the interdisciplinary team, discussion with our pharmacist and with the patient s wife, I discontinued the bolus dose of hydromorphone and increased the dose of phenobarbital that the patient was already receiving for agitation to insure that the patient remained asleep and comfortable until he passed Conclusions and Review 1. Neuroanatomy & physiology of PAIN PERCEPTION 2. Signs & Symptoms of OIN/OIH 1. Severe pain, myoclonus, allodynia, hyperalgesia, delirium, seizures 3. Pathophysiology of complications 1. Central sensitization 4. Management strategies 1. Rotate analgesics, stop morphine and hydromorphone, start NMDA antagonist, reduce opioid dose by 80% if other options are not available, hydrate if possible, manage other conditions (seizures, delirium) 21
References Bannister K. Opioid induced hyperalgesia: where are we now?. Curr Opin Support Palliat Care. 2015, 9:116 121 Barry J, Dave et al. Neurotoxic Emergencies. Psychiatr Clin N Am. 2013, 36:219 244 Chen L et al Clinical Interpredtation of opioid tolerance versus opioid induced hyperalgesia. J Opioid Manag. 2014, Nov Dec 10(6):383 93 Gulur P et al. Morphine versus hysdromorphone: does choice of opioid influence outsomes? Pain Research and Treatment. 2015, 1 6 Lee M et al. A comprehensive review of opioid induced hyperalgesia. Pain Physician. 2011, 14:145 161 Lotsch J. Opioid Metabolites. J Pain Symp Manag. 2005, 01.004: 510 524 Murray A et al. Hydromorphone. J Pain Symp Manag. 2005, 01.007: 557 566 References Roeckel LA et al. Opioid induced hyperalgesia: cellular and molecular mechanism. Neuroscience. 2016, Dec 3, 338: 160 182. Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician. 2009, 12:679 684. Smith T. Neuroexcitatiory effects of morphine and hydromorphone: evidence implication the 3 glucuronide metabolites. https://doi.org/10.1046/j.1440 1681.2000.03290.x Varrassi G et al. A pharmacological rationale to reduce the incidence of opioid induced tolerance and hyperalgesia: a review. Pain Ther. 2018, 7:59 75 22
Questions? 23