What s New in Pain and Symptom Management Jim McGregor MD Play the 2018 Conference Post to Win Game for a chance to win different prizes each day! 1
Objectives Describe patients who are appropriate for methadone therapy List drug interactions with methadone List the possible uses for ketamine in symptom management Describe patients who may benefit from buprenorphine for pain May 22-24, 2018 CAHSAH CHAPCA Annual Conference 3 Methadone Semisynthetic opioid developed during WW 2 Used to treat opioid dependent patients Increasingly being used to treat chronic pain Has a long and variable half-life Many potential drug interactions Risk of prolongation of QTc May 10-12, 2016 CAHSAH 50th Anniversary Annual Conference 4 2
Methadone Pharmacodynamics Racemic mixture of R and S methadone R-methadone is 8 to 50 times more potent than S-methadone Mu, kappa, delta agonist NMDA receptor antagonist Inhibits reuptake of norepinephrine and serotonin May 22-24, 2018 CAHSAH CHAPCA Annual Conference 5 Methadone Pharmacokinetics Absorbed orally, rectally, IV, IM, SQ, epidural, intrathecal Oral bioavailability 70-80% Onset 15 to 45 minutes after oral Peaks at 2.5 to 4 hours Widely and quickly distributed- brain, gut, kidney, liver, muscle, lung Extensively metabolized May 22-24, 2018 CAHSAH CHAPCA Annual Conference 6 3
Methadone Pharmacokinetics Extensively metabolized in the liver and to a lesser extent the gut by N-demethylation into inactive metabolites Citochrome P450-3A4,2b6, 2C9, 2C19, 2D6 May 22-24, 2018 CAHSAH CHAPCA Annual Conference 7 Methadone Pharmacokinetics Drug Interactions Enzyme inducers increase the metabolism and decrease methadone e.g. retroviral drugs, phenytoin, carbamazepine, risperidone, long term alcohol use, phenobarbital, spironolactone Induction may take 1-2 weeks Enzyme inhibitors increase methadone levels: e.g. TCAs, ketoconazole, fluconazole, SSRIs, erythromycin, metronidazole, ciprofloxacin Inhibition happens in 1-2 days May 22-24, 2018 CAHSAH CHAPCA Annual Conference 8 4
Question A 68 yr. old man with stage IV pancreatic cancer on methadone 5 mg every 12 hours for pain develops thrush and is prescribed fluconazole 150 mg daily for 7 days How quickly will the drug interaction happen and what might be the outcome? May 22-24, 2018 CAHSAH CHAPCA Annual Conference 9 Question A: fluconazole will induce methadone metabolism decreasing methadone levels in 1 week B: fluconazole will inhibit the metabolism increasing methadone levels in 1 week C: fluconazole will induce metabolism with decreasing methadone levels in 2-4 days D: Fluconazole will inhibit metabolism increasing methadone levels in 2-4 days May 22-24, 2018 CAHSAH CHAPCA Annual Conference 10 5
Who Are Methadone Candidates? True morphine allergy Significant renal impairment Neuropathic pain Opioid induced adverse effects including OIH Pain refractory to other opioids or uncontrolled Cost Long acting opioid preferred (liquid) May 22-24, 2018 CAHSAH CHAPCA Annual Conference 11 Who Should Not Take Methadone? Very limited prognosis (< 1 week) Numerous drug interactions with methadone History of syncope or arrhythmias Lives alone, poor cognitive function, unreliable, not able to understand instructions History of nonadherence to therapy May 22-24, 2018 CAHSAH CHAPCA Annual Conference 12 6
What About That QT Thing? Chou (APS) recommends baseline ECG prior to initiation for patient with: Risk factors for QTc prolongation H/O QTc prolongation H/O prior ventricular arrhythmia Consider a baseline ECG in any patient One within 12 months ok May 22-24, 2018 CAHSAH CHAPCA Annual Conference 13 ECG Monitoring (APS) Baseline QTc >500ms methadone not recommended > 450 t0 500 ms consider alternatives to methadone and correct reversible causes of QTc prolongation May 22-24, 2018 CAHSAH CHAPCA Annual Conference 14 7
ECG Monitoring (APS) Patients with risk factors for QTc prolongation QTc > 450 mms H/O syncope Perform ECG F/U every 2-4 weeks and after significant dose increases May 22-24, 2018 CAHSAH CHAPCA Annual Conference 15 ECG Monitoring (APS) Any patient reaching TDD methadone of 30-40 mg/day or reaches 100 mg/day Repeat ECG Any patient with new risk factors for QTc prolongation or exhibit signs or symptoms suggestive of arrhythmia Repeat ECG May 22-24, 2018 CAHSAH CHAPCA Annual Conference 16 8
ECG Monitoring (APS) Methadone treated patient has QTc > 500 ms Switch to another opioid or immediately decrease dose of methadone QTc 450-500 ms Consider switching to another opioid, if can t or won t discuss risks Evaluate and correct reversible cause May 22-24, 2018 CAHSAH CHAPCA Annual Conference 17 ECG Monitoring (HPM) Level of Vigilance High: for patients receiving life prolonging treatment methadone 1 st line opioid-ecg if positive risk factors; consider if no ECG in the last year Moderate: curative treatment and methadone 2 nd line opioid- discuss risks and benefits in light of goals of care (document) Baseline ECG not necessary Consider based on risk factors May 22-24, 2018 CAHSAH CHAPCA Annual Conference 18 9
ECG Monitor (HPM) Level of Vigilance Low: comfort measures only Informed consent and no monitoring May 22-24, 2018 CAHSAH CHAPCA Annual Conference 19 Opioid Choice in Organ Failure Hepatic Failure Renal Failure Preferred Consider Avoid hydromorphone morphine methadone fentanyl methadone oxycodone oxycodone fentanyl hydromorphone hydrocodone codeine hydrocodone oxymorphone tramadol codeine morphine tramadol Hepato-renal Syndrome hydromorphone methadone fentanyl oxycodone codeine hydrocodone morphine tramadol 10
Initiating Methadone (Chou, APS) Start at low dose - opiate naïve or converting from low dose of other opioid: do not exceed 2.5 mg po q8h Increase in increments of no more than 5 mg every 5-7 days Converting from higher doses of opioid start methadone at 75-90% < calculated equianalgesic dose Not > 30-40 mg po/day May 22-24, 2018 CAHSAH CHAPCA Annual Conference 21 Starting Methadone (HPM) OME/day Recommended Methadone Starting Dose 40-60 mg 2-7.5 mg dosed (in 2-3 divided doses) 60-200 mg 10:1 (morphine to methadone) >200 mg 20:1 (morphine to methadone) May 22-24, 2018 CAHSAH CHAPCA Annual Conference 22 11
Starting Methadone Do not exceed 30 mg methadone a day as a starting dose Reduce calculated dose by 25-33% if enzyme inhibitor on board Do not adjust dose for 5-7 days May 22-24, 2018 CAHSAH CHAPCA Annual Conference 23 Ms. D S 58 year old with 8 year H/O low back pain failed back Did not improve with NSAIDs or acetaminophen Opiate naïve and doesn t want SA opioid because might interfere with her work Recommendations May 22-24, 2018 CAHSAH CHAPCA Annual Conference 24 12
Ms. D S Starting dose: 1 mg po q 12 hours 2.5 mg po q 12 hours 2.5 mg po q 8 hours 5 mg po q 12 hours 2.5 mg po q8 hours Remember therapies, CBT, acupuncture All have been proven to relieve pain May 22-24, 2018 CAHSAH CHAPCA Annual Conference 25 Mr. F 92 year old man hospice has protein calorie malnutrition Generalized aches and pains Recent GI bleed No relief with acetaminophen How would you suggest managing the pain? If choosing methadone, what dose and frequency? May 22-24, 2018 CAHSAH CHAPCA Annual Conference 26 13
Mr. F No interacting meds and frail and likely some stage of kidney disease 1 mg po once daily 1 mg po q 12 h 2.5 mg po by mouth Rescue opioids May 22-24, 2018 CAHSAH CHAPCA Annual Conference 27 Mr. K 74 year old man with stage IV prostate cancer He is thin Pain not well managed on TDF 75 mcg/h Taking MSIR 20 mg q2h as needed- 10 doses a day Decide to switch to methadone May 22-24, 2018 CAHSAH CHAPCA Annual Conference 28 14
Mr. K What is his OME/day? What dose of methadone would you start him on? When you would remove the patch? May 22-24, 2018 CAHSAH CHAPCA Annual Conference 29 Mr K TDF 75 mcg/h is equivalent to a dose of 75 mg of MSIR in 12 hours 5 doses of 20 mg MSIR is 100 MG/day OME is 250 mg/day May 22-24, 2018 CAHSAH CHAPCA Annual Conference 30 15
Mr. K Total OME 250 mg What dose of methadone would you start? Using 20:1 dose of methadone would be 12.5 mg/day Because older reduce the dosage 10 mg or less daily May 22-24, 2018 CAHSAH CHAPCA Annual Conference 31 Mr. B 61 yr. old man with prostate cancer metastatic to bone He is having increased problems with pain Sharp pain over ribs when he breaths Deep aching pain over ischium/ileum on the right Taking Vicodin 5/325 ii every 4 hours 5 doses a day Ibuprofen 200 mg three times a day 16
Mr. B Initially he does well on ibuprofen 600 mg TID and oral morphine 10 mg q4h. His pain worsens and he requires frequent dosing of 5 mg of morphine for breakthrough The morphine is increased to 20 mg q4h Still requiring frequent breakthrough doses Mr. B What type(s) of pain? How would you alter the regimen? 17
Opioid-Induced Hyperalgesia A patient is requiring increasing doses to manage pain Is it tolerance or opioid-induced hyperalgesia? If it is tolerance, initially the pain will get better If it is OIH, there is no response or the pain increases with the increased dose of opioid Mr. B Initially he does well on ibuprofen 600 mg TID and oral morphine 10 mg q4h. His pain worsens and he requires frequent dosing of 5 mg of morphine for breakthrough The morphine is increased to 20 mg q4h Still requiring frequent breakthrough doses He states the increasing doses aren t working and the seems to be worse What is going on? 18
Opioid Induced Neurotoxicity Caused by accumulation of active metabolites Severe sedation Cognitive failure Hallucinations/ delirium Myoclonus/ grand mal seizures Hyperalgesia/ allodynia Treatment of Opioid Neurotoxicity Opioid rotation Hydration Use haloperidol to treat delirium Treat neuromuscular excitation and myoclonus with a benzodiazepine, baclofen, or barbiturate Behavioral excitation will resolve over hours to days 19
Dosing Methadone for Different Routes Oral to parenteral divide by 2 Parenteral to oral divide by 2 which may under dose Dr. Mary Lynne McPherson recommends dividing by 1.3 May 22-24, 2018 CAHSAH CHAPCA Annual Conference 39 Ketamine Know the indications, contraindications, benefits, side effects, and uses of ketamine Understand dosing and administration of ketamine May 22-24, 2018 CAHSAH CHAPCA Annual Conference 40 20
Ketamine Discovered in the 60s Used in Vietnam in the 70s Useful across many settings such as anesthesia, pain medicine and psychiatry May 22-24, 2018 CAHSAH CHAPCA Annual Conference 41 Ketamine Pharmacodynamics and Pharmacokinetics Is a dissociative anesthetic Blocks N-methyl-D-aspartate receptor Other receptors- agonist at opioid, AMPA, cholinergic, dopaminergic and innate repair receptors Antagonist at HCN1, potassium, calcium and sodium channels May 22-24, 2018 CAHSAH CHAPCA Annual Conference 42 21
NMDA Receptor Effects Central sensitization: persistent noxious stimuli lead to increasing pain intensity Wind up phenomenon: repeated transmission of noxious stimuli results in summation of the stimuli with co-release of excitatory amino acids and slow lasting potentials leading to hyper-responsive spinal neurons and decreased opioid responsiveness May 22-24, 2018 CAHSAH CHAPCA Annual Conference 43 Other effects Hyperalgesia: an exaggerated response to mildly noxious stimuli Secondary hyperalgesia: perception of pain outside the area initially injured Allodynia: pain caused by ono-noxious stimuli May 22-24, 2018 CAHSAH CHAPCA Annual Conference 44 22
Ketamine Pharmacodynamics and Pharmacokinetics Routes PO, IV, IM, SQ, PR, inhalation Metabolized in the liver by CYP450 Norketamine which is pharmacologically active Lipophilc and easily crosses the BBB Adverse effects: Schizotypical (hallucinations, paranoia, derealization/depersonalization, panic attacks) Drug high, N/V, hypertension May 22-24, 2018 CAHSAH CHAPCA Annual Conference 45 Ketamine Pharmacology Metabolism: 80% 1 st pass liver metabolism Metabolite: Norketamine is as potent as an analgesic as parenteral form Bioavailability: 99% IM to 16% PO Excretion: mainly renal Onset: IV 30 sec, IM 3-5 min, SC 15-30 min, PO 30 min T1/2: 3 hours Steady state : 12-15 min May 22-24, 2018 CAHSAH CHAPCA Annual Conference 46 23
Indications for Ketamine for Pain Pain unresponsive to standard treatment Failure of opioid rotation Severe neuropathic pain Opioid tolerance based on rapid escalation OIH May 22-24, 2018 CAHSAH CHAPCA Annual Conference 47 Studies Kannon 2002: 9 cancer patients with neuropathic pain > 6/ 60 day study Dose ketamine 0.5 mg/kg TID PO 7/9-3 point pain reduction 4 nauseated, 2 loss of appetite 8 of 9 drowsiness which improved for 5 No hallucinations 3 withdrew May 22-24, 2018 CAHSAH CHAPCA Annual Conference 48 24
Ketamine for Chronic Pain Marchetti 2015: 5 year retrospective Study 51 patients intractable chronic pain of which 60% neuropathic Mean effective dose 2 mg/kg May 22-24, 2018 CAHSAH CHAPCA Annual Conference 49 Ketamine Protocol Indications for use: neuropathic pain poorly responsive to opioids and adjuvant analgesics somatic/visceral pain in spite of appropriate opioid therapy adverse effects of increasing opioid therapy severe pain associated with wound care Adjunctive for analgesia May 22-24, 2018 CAHSAH CHAPCA Annual Conference 50 25
Ketamine Protocol IV/SQ: 2.5-5 mg administered over 1 minute and evaluate efficacy over 15 min IV/SQ infusion: reduce total daily opioid dose by 30%, and reduce BZD Continue breakthrough opioid at previous level Loading dose up to 10 mg Starting dose 50 mg over 24 hours Increase dose by 50 mg/24h if needed Usual dosage range 100-400 mg in 24H May 22-24, 2018 CAHSAH CHAPCA Annual Conference 51 Ketamine Protocol Oral dosing: injectable mixture in OJ Reduce total opioid dose by 30%, reduce BZD Continue BT dose at present level Starting dose 10-15 mg Q6H Dose titration if needed 10 mg/dose every 2-3 days Usual maximum 50 mg Q*H May 22-24, 2018 CAHSAH CHAPCA Annual Conference 52 26
Ketamine Protocol Wound care: 2.5-5 mg 30 minutes prior to procedure Topical ketamine for mucositis: injectable ketamine in artificial saliva (20 mg/0.2ml with 5 ml saliva substitute as swish and spit May 22-24, 2018 CAHSAH CHAPCA Annual Conference 53 Ketamine for Oral Use Injectable ketamine 100mg/ml (10 ml vial) Dilute with 9o0 ml of sterile water Resulting concentration is 10 mg/ml Shelf life 7 days refrigerated May be mixed with OJ, cola right before ingestion May 22-24, 2018 CAHSAH CHAPCA Annual Conference 54 27
Case 58 year old man with stage IV lung cancer He has uncontrolled pain with signs of OIH and respiratory depression Using appropriate adjuvants Pain still 8/10 What adjuvants might be used? Methadone makes him too sedated May 22-24, 2018 CAHSAH CHAPCA Annual Conference 55 Case MS Contin 200 mg Q12H MSIR 40 mg Q8H for BT How would you dose the ketamine? May 22-24, 2018 CAHSAH CHAPCA Annual Conference 56 28
Case MS Contin 200 mg Q12H MSIR 40 mg Q8H for BT How would you dose the ketamine? Decrease dose of daily opioid by 30% 120 or 145 mg Q12H Ketamine 10-15 mg Q8H May 22-24, 2018 CAHSAH CHAPCA Annual Conference 57 Case 2 48 year old woman with metastatic breast cancer H/O major depression Depression treated with citalopram, methylphenidate and doses optimized Not a candidate for ECT How can we help her? May 22-24, 2018 CAHSAH CHAPCA Annual Conference 58 29
Ketamine for Depression in Hospice Irwin 2013: studied 14 hospice patients with depression or depression and anxiety 28 day open label, proof of concept trial 0.5 mg/kg oral ketamine at bedtime Assessed results at day 0, 3, 7, 21, 28 May 22-24, 2018 CAHSAH CHAPCA Annual Conference 59 Ketamine for Depression 1 dropped out due to rapid disease progression 1 dropped out due to unrelated mental status changes 4 dropped out due to non-response Of the 8 patients remaining, over the 28 days significant improvement in symptoms of depression and anxiety May 22-24, 2018 CAHSAH CHAPCA Annual Conference 60 30
Ketamine for Depression Significant improvement in depression by day 14 Significant improvement in anxiety by day 3 Improvement for the 28 days Few side effects May 22-24, 2018 CAHSAH CHAPCA Annual Conference 61 References Dr. Mary Lynn McPherson Seasons Hospice and Palliative Care Irwin S et al. Daily oral ketamine for the treatment of depression and anxiety in patients receiving hospice care. A 28 day open-label proof-of-concept trial. J Palliative Med 2013:16(3): 958-965 Kannan, TR et al. Oral ketamine as an adjuvant to oral morphine for neuropathic pain in cancer patients. Journal Symptom Management 2002:23(1): 60-65 May 22-24, 2018 CAHSAH CHAPCA Annual Conference 62 31
Buprenorphine Objectives: List possible advantages of buprenorphine for pain List which patients might benefit form the use of buprenorphine May 22-24, 2018 CAHSAH CHAPCA Annual Conference 63 Buprenorphine Pharmacology Buprenorphone is thought to be 75-100 times more potent than morphine (Sittl et al 2006) Central partial mu activist (high affinity) Antagonist of kappa and delta opioid receptors (Negus et al 2002) Activates ORL-1 receptor in the spinal cord which is analgesic In Brain stem activation of ORL-1 blocks opioid analgesia (partial agonist) Exhibits antihyperalgesic effects May 22-24, 2018 CAHSAH CHAPCA Annual Conference 64 32
Buprenorphine Pharmacology Lipophilic, synthetic opioid Long duration of action (6-8 hours) thought to be due to slow disassociation from mu receptor TDB slow onset of action- 12-24 hours which lasts up to 3 days A dose of 20 mg showed to respiratory depression effects It is reported that there is no ceiling effect for analgesia May 22-24, 2018 CAHSAH CHAPCA Annual Conference 65 Buprenorphine Pharmacology Decreased tolerance of other opioids Metabolism CYP3A4 via glucuronidation as a result low bioavailability of oral buprenorphine Norbuprenorphine is 10 times more potent than buprenorphine in causing respiratory depression This effect can be reversed by naloxone Excretion mainly feces May 22-24, 2018 CAHSAH CHAPCA Annual Conference 66 33
Buprenorphine in the Elderly Physiologic changes occurring with aging affect opioid kinetics and dynamics Resultant narrowing of therapeutic index and increased risk if toxicity and drug interaction Alterations of receptors and of drug distribution in the CNS also occur May 22-24, 2018 CAHSAH CHAPCA Annual Conference 67 Buprenorphine and Renal Function Main excretion in feces Normal doses can be used in face of renal impairment and in hemodialysis patients May 22-24, 2018 CAHSAH CHAPCA Annual Conference 68 34
Buprenorphine and Liver Disease Buprenorphine levels stable in mild to moderate liver disease May 22-24, 2018 CAHSAH CHAPCA Annual Conference 69 Buprenorphine Side Effects Nausea, vomiting Sedation Euphoria Papillary constriction Delayed gastric emptying Respiratory depression (more likely at lower doses) Appears to have a greater margin of safety May 22-24, 2018 CAHSAH CHAPCA Annual Conference 70 35
Indications for Buprenorphine Moderate to severe cancer pain Non-cancer pain that is severe and unresponsive to non-opioid analgesics Neuropathic pain or chronic persistent pain Opioid rotation Study 42 patients receiving 120-240 mg/day IRMS) Pain relief from 5% to 75% Improved sleep from 14% to 74% May 22-24, 2018 CAHSAH CHAPCA Annual Conference 71 Routes of Administration Transdermal buprenorphine been shown to be an effective analgesic in several studies Matrix formulation of the patch dose not allow dose dumping in the event the patch is damaged Patch provides long term pain relief May 22-24, 2018 CAHSAH CHAPCA Annual Conference 72 36
Buprenorphine Opiate naïve patients should be started at the lowest dose 21 hours to minimum therapeutic effect May 22-24, 2018 CAHSAH CHAPCA Annual Conference 73 Buprenorphine/Naloxone Ratio 4:1 (Suboxone) Studies show Suboxone can be safely used in primary care setting to treat opioid addiction Some data suggests could be used to treat chronic pain in opioid dependent or addicted patients May 22-24, 2018 CAHSAH CHAPCA Annual Conference 74 37
Buprenorphine/Naloxone for Pain Possible uses: Research into use in non-opioid dependent patients minimal if any Opioid dependence: studies have shown efficacy, reduced pain level, lower doses of bup/nal over time Some stopped opioids Decreased opioid withdrawal symptoms Decreased abuse for those using oxycodone May 22-24, 2018 CAHSAH CHAPCA Annual Conference 75 Bup/nal vs Methadone Methadone has more side effects One study showed no difference in analgesic efficacy in patients with opioid dependent pain but methadone patients Bup/nal greater improvement in mood, energy, personality, and psychological component of chronic pain Methadone better at reducing illicit drug use May 22-24, 2018 CAHSAH CHAPCA Annual Conference 76 38
Dosage Transdermal Opiate naïve patient: 5 mcg/h patch change every 7 days Max dose 20 mcg/h patch On opioid: dose < 30 mg/day use 5 mcg/h 30-80 mg/day taper daily opioid to 30 mg and start 10 mcg/h Above 80 mg/ day consider different opioid May 22-24, 2018 CAHSAH CHAPCA Annual Conference 77 Dosage SL Opioid Naive 75 mcg bucally once a day If tolerated, 75 mcg q 12h for 4 days then increase to 150 mcg q 12h and titrate 150 mcg q12h q 4 days May 22-24, 2018 CAHSAH CHAPCA Annual Conference 78 39
Dosage for Chronic Opioid OME < 30 mg/day- 75 mcg qd or q 12h OME 30-89 mg/day- taper ATC opioid to 30 mg/day then start 150 mcg q 12H OME 90-160 mg/day_ taper ATC opioid to 30 mg/day then start 300 mcg q 12h OME > 160 mg/day consider alternative May 22-24, 2018 CAHSAH CHAPCA Annual Conference 79 References Cote, J and Montgomery, L: Sublingual buprenorphine as an analgesic in chronic pain: a systematic review. Pain Medicine 2014; 15: 1171-1178 Chen, KY et al: Buprenorphine-naloxone therapy in pain management. Anesthesiology. May 2014; 120(5): 1262-1274 May 22-24, 2018 CAHSAH CHAPCA Annual Conference 80 40
Acupuncture for Palliative Care Several studies have shown benefit for pain May reduce the need for analgesics Useful for chronic musculoskeletal pain and headache Useful for chemo-therapy induced neuropathy Benefit radiation induced xerostomia, N&V, breathlessness May 22-24, 2018 CAHSAH CHAPCA Annual Conference 81 Other Non-pharmacologic Treatments Cognitive behavioral therapy Guided imagery Reiki Massage Hypnosis Physical therapy May 22-24, 2018 CAHSAH CHAPCA Annual Conference 82 41
Speaker Information James McGregor MD, DABFP ACQ HPM Supplemental Physician SMG 530 913-1551 mcgregj@outlook.com May 22-24, 2018 CAHSAH CHAPCA Annual Conference 84 42