Dr. Çiğdem Biber Atatürk Chest Disease and Chest Surgery Center

1. APROACH TO PATIENT WITH LUNG CANCER AT THE END OF LIFE HOW TO MANAGE DYSPNEA AND PAIN Dr. Çiğdem Biber Atatürk Chest Disease and Chest Surgery Center

2. Supportive Treatment Plan • Supporting patients, families and caregivers • Ensuring on-going support • Sustaining functions • Making critical treatment decisions with conviction • Extending survival The symptoms that most benefit from the treatment at the end of life Pain – Dyspnea – Depression Ann Intern Med. 2008; 148: 147 - 159

3. PAIN • Pain related to cancer • Affects 50% of patientsat any given disease stage • Rate at the end of life: 75 – 97% • Causes of pain • Neoplastic disease: 60 – 70% • Treatment: 20 – 25% • Not associated with either disease or therapy:5 – 10% • Based on pathophysiological characteristics • Nociceptive: 50 – 70% • Neuropathic: 10 – 30% • Mixed: 20 – 40%

4. PAIN • Severe pain: 30% • Pain areas • In one area: 20% • In 2 – 4 areas: 60% • In more than 4 areas: 20 % Ann Oncol 2008; 19: 5 - 7

5. WHO - Three-Step Analgesic Ladder 3- Severe pain Strong opioids ± Non-opioids ± Adjuvant drugs Weak opioids ± Non-opioids ± Adjuvant drugs 2- Moderate pain 1- Mild pain Non-opioids ± Adjuvant drugs • 90% success rate in pain management • 10% inadequate pain control

6. WHO- Three Step Analgesic Ladder Step 1NSAİD ± Adjuvant therapy • Non-steroid anti-inflamatory drugs • Acetaminophen, diclofenac, ibuprofen, Cox 2 inhibitors, naproxen • Adjuvant therapy • Anti-depressants • Nortriptyline, Amitriptyline, doxsepine, desipramine, duloxetine, venlafaxine • Anticonvulsants • Gabapentin, pregabalin, phenitoin, carbamazepin Step 2Weak opiods ± NSAİD ± Adjuvant therapy • Weak opioids • Codeine, hydrocodeine, tramadol Step 3Strong opioids ± NSAİD ± Adjuvant Therapy • Strong opioids • Morphine, oxycodone hydrocodone, hydromorphone, methadone, fentanyl 5% patients with pain refractory to treatment = Patients at the end of life

7. Pain intensity rating scales • Numerical rating scale 0 1 2 3 4 5 6 7 8 9 10 No pain Worst imaginable pain • Categorical scale 0 1 – 3 4 – 6 7 – 10 No pain Mild Moderate Severe • Wong – Baker Faces Pain Rating Scale Pain treatments at the end of life • Uncontrollable pain treatment • Breakthrough pain treatment • Interventional strategies (4thstep pain treatment ) NCCN 2007

8. PAIN • Uncontrollable moderate and severe pains category 4–6 or 7–10 • Patients in the 2nd or 3rd step of the Three-Step Analgesic Ladder treatment proposed by WHO In patients who are at the end of life and continuing to experience moderate, severe or increasing pain despite receiving treatment, the first step is to treat short-acting opioids

9. Pain score unchanged or increases • Administer double dose • If no response after 2 – 3 dosing cycles, proceed withIV titration Used opioids 5 – 15 mg oral rapid releasing morphineor equivalent Oral Peak effect 60 min. Pain score decreases 4 – 6 - Repeat same dose - Reassess after 60 min. Not used opioids 10 – 20% of the previous 24h total dose Pain score decreases 0 – 3 - Repeat same dose - Reassess after2 – 3 h - After 24 h, proceed with long-acting opioids Pain> 4 - Administer double dose - Monitor for 2-3 dosing cycles Not used opioids 1 – 5 mgIV morphine sulfate Pain score unchanged or increases - Repeat same dose - Monitor Pain score decreases 4 – 6 IV Peak effect 15 min. After monitoring for 2 – 3 h, determine effective dose Pain score decreases 0 – 3 Used opioids Increase previous total dose by 10%

10. Breakthrough Pains • Seen in 89% of the patients at the end of life • Usually develops in previous pain areas • Severe, sudden attacks • Reaches peak intensity in 5 minutes, ends in 30 minutes • Attacks occur more than 2 – 3 times a day at the end of life • Tumoral invasion of visceral organsor nerve roots • Ectopic activity of afferent nerves independent of stimulus • Bone metastasis • Tied to KT and RT • May occur with neuropathic pain

11. Breakthrough Pains • Primarily recommended treatment: WHO pain guidelines • The opioid rescue dose must always be considered in these patients • Other agents used in breakthrough pains Lidokain - Meksiletin: Antiarithmic – localanesthetic • In dire cases, scor iv infusion • Ketamine: NMDA receptor antagonist • Prevents opioid tolerance, effective against neuropathic pains • 0.1 – 0.4 mg/kg/h iv or sc dose results in significant analgesia Anest Analg 2005; 101:175 – 181 J Pain Symptom manage 2000; 4: 256 – 251 Am J Hosp Palliat care 2007; 24: 430

12. Breakthrough Pains • Oral transmucosal fentanyl citrate • Initial dose: 200 – 400 mcg • Titrated based on patient’s pain condition • Fentanyl buccal tablet • Rapid and effective palliation !! Pain med 2005; 4: 305 – 14 J Pain 2006; 7:35

13. Breakthrough Pains Inerventional Pain Strategies • Hemiarthroplasty – intramedullary stabilization • Their effectiveness at the end of life is debatable – unnecessary • Radiotherapyand radioisotope therapies • Are being used with increasing frequency • Complete treatment with RT success rate: %30 • Radioisotopes: radioactive agents administered through iv • Active in multiple metastatic areas • Most frequently used two isotopes: Stronsium-89, Samarium-153 • Easily administered and can reach all metastasized areas • Gives better results when combined with other treatment • Complete pain remission rate of 10 – 30%, decrease in opioid use

14. Breakthrough Pains Interventional Pain Strategies Spinal anesthesia Intrathecal Neuraxial Epidural Analgesia • Should be administered in 5% of all cancer patients – but only done so in 2% • Epidural analgesia • Focal pain • Less than 3 months’ life expectancy • Intrathecal analgesia • Extensive pain • Longer than 3 months’ life expectancy

15. Breakthrough Pains • Vertebroplasty • Performed in pain attacks caused by vertebral fractures • Increases the quality of life in patients at the end of life • A filling substance containing percutan is injected in the problem vertebra • Prevents spinal cord compression caused by fracture J Pain Symptom Manage 2005; 30: 87 – 95 Am J Hosp Palliat Care 2007; 24: 430 - 7 • Cordotomy • Performed in terminal patients when medical treatment and minimal invasive interventions fall short • Successfully performed in one-sided, localized pains Am J Hosp Palliat Care 2007; 24: 430 - 7

16. Dyspnea • Awareness of breathing • Air hunger DYSPNEA • Breathlessness • Psychological factors • Socialfactors • Emotionalfactors • Environmentalfactors • Culturalfactors As effective as physical factors

17. Cancer and Dyspnea • Rate dyspnea in cancer patients: 21 – 70% • Dyspnea early indication of shortened life expectancy • Life expectancy of patients coming emergency room with dyspnea: 12 weeks Median time in lung cancer patients: 4 weeks

18. Reasons for Dyspnea Related to Cancer - 1 Most frequently seen • Primary or metastatic lung tumor load • Pleural or pericardial effusion • Lymphangitic carcinomatosis • Pulmonary emboli • VCSS • Depression – Anxiety • Pneumonia • Muscular dysfunction • Pre-existing KOAH – asthma combination • Anemia • Congestive heart failure • Pain

19. Reasons for Dyspnea Related to Cancer - 2 Related to treatment • Radiation pneumonia • Fibrosis related to chemotherapy • Surgical resection

20. Reasons for Dyspnea Related to Cancer - 3 Rarely seen • Atelektasis • Phrenic nerve paralysis • Tracheal – bronchial obstruction • Tumoral invasion of the chest wall • Abdominal distension • Pneumothorax • Metabolic acidosis • Paraneoplastic syndromes

21. Dyspnea Treatment • Treatment for the underlying disease causing dyspnea and its complications: Primary Treatment • Treatment for the symptom and the pathophysiologic factors that contribute to it

22. Symptomatic Treatment of Dyspnea Related to Cancer • Oxygen treatment • Pharmacologic treatments • General support approaches

23. Oxygen Treatment - 1 • Most frequently performed medical support treatment at the end of life • Performed when cancerous tissue is widespread in the respiratory system and there is an underlying obstructive disease • Few studies are done on the benefits of oxygen support – Its effectiveness in treating dyspnea related to cancer is debatable Semin Oncol Nurs 2008: 24: 57 – 67 Curr Treat Opt Oncol 2005; 6:61 - 8

24. Oxygen Treatment - 2 • Conflicting opinions about its benefits in cancer patients • Some patient groups decrease in dyspnea perception,improvement in hypoxemia • Some patient groups no change • Some patients groups, there is a decrease in dyspnea perception but no improvement in hypoxemia (Placebo effect) Chest 2007; 132: 368 – 403 Nature Clinical Practise Oncology 2008; 2: 90 - 100

25. Oxygen Treatment - 3 • Supporting ViewpointPrescribe if the oxygen treatment improves the hypoxemia parameters in patients with cancer • Opposing Viewpoint Prescribe not based on oxygen saturation, but on patient’s comfort level Oxygen is a prominent symbol of medical treatment and care

26. Heliox • Breathing effort decreases • Alveolar ventilation improves • Helioks 28 (72% helium – 28% oxygen) • Improvement in dyspnea during exercise • Increase in exercise capacity • Improvement in oxygen saturation Nature Clinical Practise Oncology 2008; 2: 90 – 100 Br J Cancer 2004; 90: 366 - 71

27. Pharmaceutical Treatment • Central point of dyspnea treatment Pharmaceutical treatment • Opioids • AdjuvantTreatments • Benzodiazepines • Phenothiazines

28. Opioids Their effectiveness have been shown in randomised controlled studies done in dyspnea cases related to both malign and non-malign lung cancer

29. Opioids CONCLUSION Oral or parental opioid use is vital and the first step in the treatment of dyspnea related to cancer, especially in advanced cases

30. Opioids What is the optimal dose in opioid treatment? • Patient history of prior opioid use is important • If opioid is currently being administered, increase dose by 25 – 50%

31. Opioids The initial principle in cases without prior opioid use for any reason, elderly patients and when seen together with COPD ‘’START LOW AND GO SLOW’’

32. Opioids Dyspnea treatment related to advanced disease FIRST STEP TREATMENT: Opioids and doses • Dose in patients with opioid tolerance: 25 – 50% • Patients without prior Opioid use or elderly patients • Hydromorphone: 0.5 – 1 mg po every 4 hoursmild • Oxycodone: 2.5 – 5 mg po every 4 hours dyspnea • Morphinesulfate: 2.5 – 5 mg po every 4 hours • To break dyspnea, 10 – 20% of total daily dose is given every hour, or dose is increased by 25 – 50% every 24 hours • May start with twice the total dose in young patients

33. Opioids • In patients who also have serious COPD and other chronic lung diseases, the dose is reduced by 50%

34. Opioids Constipation, nausea Most important side effects • Tolerance is developed against all other side effects in 1 – 2 weeks • All patients should be treated simultaneously with effective intestinal diets and laxatives for constipation

35. Opioids Can nebulized form be used? Use of nebulized forms not recommended Random controlled studies still needed Widely used today

36. Opioids Nebulized opioid use 2.5 – 10 mg morphine, 0.25 – 1 mg hydromorphone 25 µg fentanyl Given by adding 2 mL 09% NACL solution with nebulization

37. Adjuvant Treatment: Neuroleptics Anxyolitics SECOND STEP TREATMENT Neuroleptics No randomised controlled study showing their effectiveness • Most widely used agent: Chlorpromazine • Use in terminal cancer patients is highly emphasized • Chlorpromazine: 7.5 – 25 mg po or subcutan. Every 6 – 8 hours (when necessary or regularly) • Methotrimeprazine: 2.5 – 10 mg po or subcutan. Every 6 – 8 hours (when necessary or regularly) • Levomepromazine: 6 – 25 mg oral

38. Adjuvant Treatment: Benzodiazepines • No meta-analysis or randomised controlled study showing their effectiveness against dyspnea related to cancer • Widely used for dyspnea caused by cancer

39. Anxyolitics • Occurs in patients with dyspnea Dyspnea Anxiety • Even though opioids by themselves break the relation between dyspnea and anxiety, tolerance is quickly developed against anxyolitic effects • They are not the primary option in dyspnea treatment

40. Anxyolitics Anxyolitic treatment in dyspnea • Lorazepam: 0.5 – 1 mg po every 6 – 8 hours Most widely used agent • Diazepam: 5 – 10 mg po every 6 – 8 hours • Clonazepam: 0.25 – 2 mg po every 12 hours Midazolam • Effective when added to opioids at the end of life • With sc infusion 10 – 60 mg/24 hours • Breaks opioid tolerance

41. Corticosteroids • Lymphangitic carcinomatosis • Radiation pneumonia – fibrosis • VCSS • BOOP developed post-Adjuvant RT • COPD – presence of inflammatory component such as asthma • Has negative functional and pathological effects on certain muscle groups starting with the diaphragm

42. Fans Stimulating mecanoreceptors – decrease in the skin surface temperature Trigeminal nerve is stimulated Central inhibition Reduction in dyspnea perception

43. Approach to Terminal Dyspnea Patient is immediately and aggressively treated with parenteral opioids and sedatives until breathing comfortably

44. Approach to Terminal Dyspnea • Doctor should attend the patient at all times • Opioids must always be parenterally given • 2.5 – 5 mg morphine iv or sc is immediately administered to patients without opioid use history. The dose is increased to 50 – 100% right away in patients with opinoid tolerance • Reassessment every 10 minutes if iv is given, and every 20 minutes if sc is given • Parenteral opioid dose is increased by 25% every 10 or 20 minutes until dypsnea starts to improve • In addition to opioids, 2.5 – 10 mg methotrimeprazine can be sc administered immediately

45. Approach to Terminal Dyspnea • If the patient has severe anxiety or agitation • Midazolam 2.5 – 5 mg is iv or sc givenand patient is monitored • Lorazepam 0.5 – 1 mg is iv or sc given and patient is monitored • Must be extremely cautious when giving anxyolitics to the patient Risk of death • Opioids alone are not adequate and reliable for sedation

46. Thank You