Opioid Rotation. Dr Bruno Gagnon, M.D., M.Sc.

Opioid Rotation Dr Bruno Gagnon, M.D., M.Sc. Associate Professor Department of Family Medicine and Emergency Medicine, Faculty of Medicine, Université Laval Consultant in Palliative Medicine CHU de Québec-Université Laval, L Hôtel-Dieu de Québec

Disclosure of Financial Support This program has not received financial support This program has not received in-kind support No conflict of interest

Faculty/Presenter Disclosure Faculty: Faculty of Medicine, Laval University Relationships with financial sponsors: None

As a result of attending this presentation, the learner will become competent with the rationale for the practice of rotating narcotics when, how and why one would choose to alter treatment in this manner. be able to discuss the most common pitfalls in rotating narcotics.

Plan Definition Brief explanation of scientific basis Indications and process 3 clinical vignettes Comments on methadone Take home tips

Level of evidences Animal studies Retrospective cohort studies Experts opinions

Opioid rotation (switching) Process of substituting on opioid to another Objectives: Improve pain control Reduce intensity of adverse effects Mercadante S., Cancer, 1999

Genetic variabilities in opioid receptors Tolerance development to analgesic and toxic effects time; analgesic toxic effects morphine dose analgesic < toxic between different opioids Analgesic/toxic is influenced by: Exposure time Illness progress Incomplete cross tolerance Opioid switching or rotation

In conclusion: opioids differ in Effectiveness Ability to induce toxicity

Fractional Receptor Occupancy Efficacy Minimum % of receptors occupancy necessary Efficacy is inversely proportional to receptor occupancy Receptor Occupancy June 24th, 2012

Receptor Occupancy and Efficacy % Receptor occupancy 80 % Fentanyl (F) High efficacy/low occupancy requirement Morphine (M) Low efficacy/high occupancy requirement Efficacy June 24th, 2012

Trials and errors

Indications and Process Clinical Vignette 1 Clinical Vignette 2 Clinical Vignette 3

Clinical Vignette 1 You are seen M. John in outpatient clinic 62 year s old man Diagnosed 6 months previously with NSCLC RLL Chest wall invasion and liver metastases No comorbidities Chimotx as a palliative modality

Clinical Vignette 1 Initially R lateral chest wall pain 7/10 (7 th - 8 th ribs) Mildly burning BTP: electric shocks like Initiation and titration up of morphine Gabapentin

Clinical Vignette 1 No more chemotherapy Diffuse R chest wall pain 9/10 From sternum to back Burning pain 3/10 in both arms and legs No other complaints

Clinical Vignette 1 Gabapentin 75 mg PO BID Morphine LA 120 mg PO BID Since 4 days, 5-6 BTA of 25 mg of IR Morphine/day

Clinical Vignette 1 What is the underlying pathophysiological process responsible for the sudden worsening of the pain syndrome? 1. Opioid neurotoxicity 2. Opioid tolerance 3. Specific opioid low responsiveness 4. Hyperalgesia 5. Progression of disease

Question What is the underlying pathophysiological process responsible for the sudden worsening of the pain syndrome? 1. Opioid neurotoxicity 2. Opioid tolerance 3. Specific opioid low responsiveness 4. Hyperalgesia 5. Progression of disease

Hyperalgesia: Rotation from Morphine to Hydromorphone Hydromorphone % of Response 80 % Ratio 1 Ratio 2 Morphine Hyperalgesia Ratio 1 < Ratio 2 Dosage 20 June 24th, 2012

Decision to switch to hydromorphone What is the conversion ratio of Morphine to hydromorphone? 1. 2:1 2. 3:2 3. 5:1 4. 10:1

How do we proceed? Many ways to skin a cat! Morphine: 240 (325 BTA) mg orally/day = 48 (65) mg of hydromorphone orally/day Discontinue morphine Start HM at 36 mg orally/day ( 25 40 %) (6 mg q 4 hrs) BTA: 4 mg q 1 hr % of is a clinical judgement issue Pitfall: too much or not enough

Clinical Vignette 2 Clara is 42 year old 12 months previously recurrence of breast cancer with 4 bone metastases Treated with chemotherapy No comorbidities Bisphosphonate I.V.

Clinical Vignette 2 3 weeks previously Apparition bone pain (6-7/10) multiple sites Bone scan confirmed now wide spread bone metastases Prescription: NSAID Hydromorphone 2 mg PO q 4hrs and BTA 2 mg q 1 hr PRN

Clinical Vignette 2 2 weeks previously: Her Pain 6/10 despite 4-5 BTA per day Increase Oral HM to 4 mg q 4 hrs and 3 mg q 1 hr PRN

Clinical Vignette 2 1 weeks previously: Her Pain 7/10 despite 3-4 BTA per day Increase Oral HM to 6 mg q 4 hrs and 3 mg q 1 hr PRN

Clinical Vignette 2 Today Pain 6/10; somnolence + Hydromorphone 6 mg PO q 4 hrs with BTA 4 mg (5-6/day) (36+20=46 mg/day) Mild constipation No other complains

Question Why is the pain not responding to opioid treatment? 1. Opioid neurotoxicity 2. Opioid tolerance 3. Specific type of opioid low responsiveness 4. Opioid Hyperalgesia 5. Progression of disease

Question Why is the pain not responding to opioid treatment? 1. Opioid neurotoxicity (A) 2. Opioid tolerance 3. Specific type of opioid low responsiveness 4. Opioid Hyperalgesia 5. Progression of disease

Poor response to one opioid/uncontrolled pain % of Response 80 % Oxycodone Morphine Important side effects Dosage June 24th, 2012

Rotating to oxycodone What is the conversion ratio of oxycodone to hydromorphone? 1. 4.3:1 2. 6.3:1 3. 1.3:2 4. 3.3:1

How do we proceed? Hydromorphone 46 mg orally/day Morphine 230 mg orally/day Oxycodone 154 mg orally/day (M/0: 1.5 (2)/1; 230/1.5=154) Oxycodone 20 mg ( 20%) orally q 4 hrs and 12 mg q 1 hr PRN Pitfall: Risk of undertreatment

Clinical Vignette 3 Asked to see Robert on the oncology floor 72 years old Found to have a metastatic pancreatic cancer Tumor resistant to chemotherapy Previously had a well controlled pain Now: Epigastric pain 7/10, knife like Fentanyl patch 100 mcg/hr q 3 days

Clinical Vignette 3 Cachectic Confused with mild agitation Hallucinations Myoclonus +++ Dehydrated Chest X-Ray normal Urine culture positive High WBC and creatinine

Question Why is the pain not responding anymore to opioid treatment? 1. Opioid neurotoxicity 2. Opioid tolerance 3. Hyperalgesia 4. Progression of disease 5. Delirium

Delirium: Rotation from Fentanyl Fentanyl % of Response Morphine Delirium threshold Dosage 39 June 24th, 2012

Clinical Vignette 3 Complex situation Rotation to morphine s/c Fentanyl to morphine: 25 mcg/hr = 25 mg (25-50) morphine s/c daily Fentanyl 100 mcg/hr = morphine 100 mg (100-200) s/c daily by at least 50% (50-100 mg s/c) Patient is cachectic (absorption?) further decrease, how much? Fentanyl remains available 12 hrs (fat reserve?)

Personnal approach by 50-60 % the lower equivalent ratio (morphine 100 mg) Start Morphine 8 mg s/c q 4hrs (48 mg/day) 12 hrs after removal of Fentanyl patch Immediately allow Morphine 5 mg s/c q 1 hr for BTA Treat delirium (symptoms+infection+hydration)? Pitfall: dose still too high; multiple rotations Rotating to fentanyl: keep original opioid for 12 hrs; more chalenging

Rotation to Methadone Indications Failure of multiple rotations High doses of opioids Neuropathic pain Hyperalgesia Severe renal failure

Morphine/Methadone R = 0,11 p=0,5 Previous dose of morphine not predictive of final methadone dose Bruera E, et al. Pal Med, 2002.

Switching to Methadone Age Daily Dose of Methadone Day 0 Day 1 α Day 2 α Day 3 α Day 4 α MEDD* 2/3** 1/3** 0/3** Final Dose < 65 > 60 and 200 mg 3 mg TID 9-15 mg 65 > 60 and 200 mg 2 mg TID 6-15 mg All# > 200 and 600 mg 5 mg TID 15-30 mg rarely > 45 mg * Morphine Equivalent Daily Dose ** = of initial MEDD # Get help

Take home tips Indications of switching opioids Poor pain control ( 20%) Hyperalgesia ( 20-40%) Delirium ( 50%) Rotation form and to Fentanyl patch more complex Rotation to Methadone Expertise needed Expert s support Could be quite beneficial

Enjoy Quebec City!!!

Opioid switching in cancer pain: From the beginning to nowadays; Sebastiano Mercadante, Eduardo Bruera, Critical Reviews in Oncology/Hematology 99 (2016) 241 248