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Clinical Use of Opioids in Cancer Patients

Clinical Use of Opioids in Cancer Patients. Laksamee Chanvej, M. D . Wattanosoth Hospital, Bangkok Hospital Medical Center 10 th March 2008. Contents . WHO Cancer control program Palliative care Pain in cancer Extent of the problem Guideline for cancer pain management

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Clinical Use of Opioids in Cancer Patients

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  1. Clinical Use of Opioids in Cancer Patients Laksamee Chanvej, M.D. Wattanosoth Hospital, Bangkok Hospital Medical Center 10th March 2008

  2. Contents • WHO Cancer control program • Palliative care • Pain in cancer • Extent of the problem • Guideline for cancer pain management • Opioids in palliative care

  3. The four basic components of cancer control • prevention • early detection • diagnosis & treatment • palliative care

  4. Death rates by leading causes of death per 100,000 population, Thailand2000-2004 Adapted from: Health Information Devision, Bureau of Health Policy and Plan; 29 September 2006

  5. Integrated model of curative and palliative care forchronic progressive illness

  6. Palliative Care an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual http://www.who.int/cancer/palliative/definition

  7. Palliative Care(WHO 2003) • uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated • enhance quality of life, and may also positively influence the course of an illness • applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life

  8. Terminal Care an important part of palliative care and usually refers to the management of patients during their last few days, weeks or months of life from a point at which it becomes clear that the patient is in a progressive state of decline

  9. Quality-of-life dimensions of palliative care

  10. Cancer Patientsand Suffering • Most cancer patients have fatigue, pain, other symptoms • Poor symptom control undermines completion of antineoplastic treatment • Symptom control is necessary for patient goals • Psycho social, family and spirituality also determine the suffering in the patients

  11. Cancer Pain Prevalence • 64% of cancer patients suffer from pain, with 75% of those sufferers categorizing their pain as moderate to very severe1 • moderate to severe pain in 50% of cancer patient2 • more than 70% of patients with advanced cancer3 1 Meier DE. United States: Overview of Cancer Pain and Palliative Care. J Pain Symptom manage 2002;24: 265-9. 2 Vainio A, Auvinen A. Prevalence of symptoms among patients with advanced cancer: an international collaborative study. J Pain Symptom manage1996;12: 3-10. 3 Ventafridda V. Cancer pain management. Pain Rev. 1996;3:153-179.

  12. Barriers to Effective Pain Management • Problems related to health care professionals • Knowledge, misconception of opioids, attitude • Problems related to patients • Reporting pain, misconception of pain/opioid, fear, adherence • Problems related to the health care system • Low priority, reimbursement, drug regulation, availability of treatment or access to it

  13. Temporal Acute/chronic Descriptive of different time patterns Etiological Due to cancer Due to cancer treatments Due to other causes According to initiating tissue damage Bone Soft tissue Neurological Muscle spasm Pathophysiological Nociceptive somatic Nociceptive visceral Neuropathic Idiopathic Pain syndrome Check-list of clinical- anatomical entities Associated clinical features Continuous Superficial Radiating etc Criteria for cancer pain classification Caraceni A. Evaluation and assessment of cancer pain and cancer pain Treatment. Acta Anaesthesiol Scand 2001; 45: 1067–1075

  14. Cancer pain • Cancer related acute pain syndromes • Due to procedures and therapies • Acute postoperative pain • Due to neoplasm or related pathology • Cancer related chronic pain syndromes (nociceptive and neuropahic pain) • direct effect of cancer • related to therapy • chronic problems

  15. Factors influencing the perception of pain G. T. Linklater and M. E. F. LengRecent advances in pain management in palliative care Current Anaesthesia & Critical Care (2001) 12, 296-301

  16. Objective of cancer pain management • optimize pain control • minimize side effects, adverse outcomes & costs • enhance functional abilities, physical & psychological well-being • enhance the quality of life

  17. Management of cancer pain • Primary therapy surgery,radiation,chemotherapy • Pharmacotherapy indirect delivery system: systemic analgesia direct delivery system:neuraxial drug delivery & neuroablation • Other modalities physiatric ,psychological ,neurostimulatory interventions

  18. WHO's three step ladder to use of analgesic drugs

  19. Indirect delivery system • Systemic analgesia opioids, non-opioids, adjunctive analgesics • Route • oral, transdermal, transmucosal,subcutaneous or IV

  20. Non-opioid analgesics • Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) • used in combination with opioids and adjuvant analgesics • a ceiling effect • do not produce physical dependence or tolerance

  21. NSAIDs • inhibit the enzyme cyclo-oxygenase (COX) which catalyses the conversion of arachidonic acid to prostaglandins and leukotrienes • a central action at the brain or spinal cord level • opioid sparing effects • widely used in metastatic bone pain • relative contraindications for using in the cancer patient with peptic ulcer disease, thrombocytopenia, renal impairment • serious side- effects include renal failure, hepatic dysfunction, bleeding andgastric ulceration,inhibit platelet function • Proton pump inhibitors prevention of peptic ulcers

  22. COX II-specific drugs • COX I prostaglandins • gastric mucosal cytoprotection by increasing blood flow, mucus production and gastric bicarbonate secretion • COX II drugs: reduced the risk of GI injury compared with current generation NSAIDs • Caution: renal insufficiency, fluid retention, edema

  23. Opioid Therapy in Pain Opioid therapy is the mainstay approach for • Acute pain • Cancer pain 80-90% effective* • AIDS pain • Pain in advanced illnesses But undertreatment is a major problem * VielhaberA, Portenoy RK. AdvancesincancerpainmanagementHematology/oncology Clinics of North America Vol 16, No 3, 2002

  24. Codeine • Moderate pain • Metabolized mainly in the liver • Excreted mainly in urine • good antitussive • Dose 30 mg every 4 hours • Children 0.5 mg/kg every 4-6 hours • Constipation, nausea, somnolence

  25. Tramadol • moderate to moderately severe pain • its active M1 metabolite acts as an opiate agonist, m-receptor • inhibits reuptake of certain monoamines (norepinephrine, serotonin) • Dose exceeding 400 mg daily are not recommended • renal or hepatic impairment: decreasing the frequency of administration • Side effects: dizziness or vertigo (dose related) • dry mouth, light-headedness and constipation • pruritus, rash • vasodilation, orthostatic hypotension, syncope, and tachycardia • less constipation in comparison to typical opioids such as codeine and morphine Leppert W, Luczak J. The role of tramadol in cancer pain treatment--a review. Support Care Cancer 2005 ;13(1):5-17. Epub 2004 Nov 18.

  26. Relative potency of oral tramadol compared to other opioids Twycross R, Wilcock A. Symptom management in advanced cancer, 3rd ed. Radcliffe Medical Press, Oxford, pp 17–68 (2001)

  27. Oral morphine • morphine immediate release • Morphine syrup • MST • 10 mg, 30 mg, 60 mg • Kapanol • 20 mg, 50 mg,100 mg

  28. Opioids used in cancer pain

  29. Methadone • A synthetic opioid agonist • Average oral bioavailability approximately 80% • Long and unpredictable half-life • Converting from morphine by oral morphine-equivalent daily dose (MEDD) • A racemic mix of the d-isomer and l-isomer of methadone • d-isomer has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor and may be beneficial in controlling neuropathic pain • Possible prolongation of QTc interval, leading to torsades de pointes and ventricular arrhythmia

  30. Transdermal patch • Fentanyl: peak effect after application  24 hours, patch lasts 48–72 hours • For dysphagia, swallowing difficulties, impaired GI function, renal failure, difficult compliance patient • Buprenorphine: matrix patch • a dosage ceiling • high affinity to the opiate receptor • may have the withdrawal symptoms • 35, 52.5, and 70 micrograms per hour Skaer TL. Transdermal opioids for cancer pain. Health and Quality of Life Outcomes 2006, 4:24

  31. Transdermal fentanyl for cancer pain Skaer TL. Transdermal opioids for cancer pain. Health and Quality of Life Outcomes 2006, 4:24

  32. Opioid Therapy: Guidelines • Consider use of a long-acting drug and a “rescue” drug—usually 5%–15% of the total daily dose • Baseline dose increases: 25%–100% orequal to “rescue” dose use • Increase “rescue” dose as baseline dose increases • Treat/prophylaxis side effects

  33. Opioid Rotation • A shift from one opioid to another • when the adverse effect/analgesic equation is skewed towards the side effect component, despite an aggressive adjuvant treatment • useful in establishing a more advantageous analgesia/toxicity relationship • improving the opioid responsiveness

  34. Opioid Rotation • Based on large intraindividual variation in response to different opioids • Reduce equianalgesic dose by 25%–50% with provisos: • Reduce less if pain severe • Reduce more if medically frail • Reduce less if same drug by different route • Reduce fentanyl less • Reduce methadone more: 75%–90% Indelicato RA, Portenoy RK. Opioid Rotation in the Management of Refractory Cancer Pain J Clin Oncol. 2003 May 1;21(9 Suppl):87-91.

  35. Opioids to be avoids for cancer pain • Meperidine • Short (2-3 hour) duration of analgesia • Repeated administration may lead to CNS toxicity (tremor, confusion, or seizures) • Agonist-antagonists: pentazocine, nalbuphine • Risk of precipitating withdrawal in opioid-dependent patients • Analgesic ceiling • Possible production of unpleasant psychotomimetic effects (e.g., dysphoria, delusions, hallucinations) • Partial agonist: buprenorphine • Analgesic ceiling • Precipitate withdrawal http://www.cancer.gov/cancertopics/pdq/supportivecare/pain/HealthProfessional

  36. Opioid naive-patients: How should we start? • Start with doses of 10– 15 mg/day of morphine • well tolerated even by older patients • < 45 mg/day of morphine were achieved four weeks after • Transdermal fentanyl 25 mcg/h or oral morphine (about 60 mg/day) induce more adverse effects (nausea) • Mercadante S, Villari P, Ferrera P, Casuccio A. Opioid-induced or pain relief-reduced symptoms in advanced cancer patients? Eur J Pain 2006a;10:153–9. • Mercadante S, Porzio G, Ferrera P, Fulfaro F, Aielli F, Ficorella C,et al. Low morphine dose in opioid-naive cancer patients with pain. J Pain Symptom Manage 2006b;31:242–7.

  37. Opioid titration in patients who have received weak opioids unsuccessfully • Usually start with 10 mg every 4 h (60 mg/day) • A rescue dose of 16% of the total daily dose of the used opioid is commonly prescribed • Transdermal fentanyl 25 mcg/h, withmorphine used as a rescue medication • Satisfactory analgesia was achieved within 24–48 hr • Faster way to be titrated for iv opioids: morphine boluses of 1.5 mg every 10 min then calculate in 1 hour or PCA Mercadante S. Opioid titration in cancer pain: A critical review European Journal of Pain 11 (2007) 823–830.

  38. Patients who are receiving strong opioids and requiredose adjustment • Ineffective management; oral and transdermal opioid • a dose increase of 33– 50% every 24 hr • Severe acute pain: boluses of opioids • intravenous q 5 mins and subcutaneous morphine q 30 mins • doses are proportional to the previous daily opioid consumption (morphine iv 2 mg and 10 mgsc) Mercadante S. Opioid titration in cancer pain: A critical review European Journal of Pain 11 (2007) 823–830.

  39. Opioid: common side effects • Constipation • Sedation • Nausea and vomiting • Delirium • Myoclonus • Pruritus • Respiratory depression McNicol E, Management of Opioid Side Effects in Cancer-Related and Chronic Noncancer Pain: A Systematic Review. The Journal of Pain, Vol 4, No 5 , 2003: pp 231-256 .

  40. Constipation • Opioid effects on CNS, spinal cord, myenteric plexus of gut • Increase fluids, dietary fiber • Exercise, if appropriate • Easier to prevent than treat • Medications • Stimulant laxative • senna, bisacodyl, glycerine, casanthranol, etc • Combine with a stool softener • senna + docusate sodium • Prokinetic agent: metoclopramide, cisapride • Osmotic laxative:MOM, lactulose, sorbitol • Bulk forming agents not recommended

  41. Sedation • Onset with start of opioids • distinguish from exhaustion due to pain • tolerance develops within days • Complex in advanced disease • Assess for other causes of sedation (e.g., CNS pathology, other sedating medications, hypercalcemia, sepsis) • If persistent, alternative opioid or route of administration • Psychostimulants may be useful • methylphenidate, 5 mg q am and q noon, titrate

  42. Nausea / vomiting • Assess for other causes of nausea (e.g., constipation, CNS pathology, chemotherapy, radiation therapy, hypercalcemia) • Opioid-induced 10-40% • Tolerance develops within 2-3 days • Alternative opioid if refractory (> 1 wk ) • Treatment • prochlorperazine, 10 mg q 6 h • haloperidol, 1 mg q 6 h • metoclopramide, 10 mg q 6 h

  43. Delirium • Assess for other causes of delirium (e.g., hypercalcemia, CNS metastases, other psychoactive medications, etc.) • Presentation • Opioid induced neurotoxicity • confusion, bad dreams, hallucinations • restlessness, agitation • myoclonic jerks, seizures • depressed level of consciousness • respiratory depression • haloperidol, 0.5-2 mg PO q4-6h or alternative neuroleptic agents

  44. Respiratory depression • pain is a potent stimulus to breathe • loss of consciousness precedes respiratory depression • pharmacologic tolerance rapid • Management • identify, treat contributing causes • reduce opioid dose • observe • if unstable vital signs • naloxone, 0.1-0.2 mg IV q 1-2 min

  45. Adjuvant analgesics • Medications that supplement primary analgesics • may themselves be primary analgesics • use at any step of WHO ladder

  46. Adjuvant analgesics forneuropathic pain • Antidepressants : amitriptyline,desipramine • Anticonvulsants: carbamazepine,phenytoin, valproate, clonazepam,gabapentin, lamotrigine,oxcarbazepine • Oral local anesthetics: mexiletine • Alpha- 2 adrenergic agonists: clonidine • NMDA antagonists: dextromethorphan,ketamine • Miscellaneous: baclofen, calcitonin

  47. Metastatic Bone Pain • Constant, worse with movement • Pathologic fractures( 8-30%), spinal cord compression (5%), hypercalcemia (10%) • Management as in WHO’s guideline with specific drugs • Bisphosphanates • External beam radiation • External bracing • Radiopharmapheuticals • Calcitonin * (no support data) • Martinez-Zapata MJ, et al. Calcitonin for metastatic bone pain. Cochrane Database of Systematic Reviews 2006 issues 3.)

  48. Corticosteroids • Many uses: • Somatic pain that does not response to opioids, hypersensitivity with NSAIDs • Nerve compression, cord compression • Adverse effects • steroid psychosis; mild euphoria • proximal myopathy • other long-term adverse effects • Dexamethasone • long half-life (>36 h), dose once a day • minimal mineralocorticoid effect • doses of 2–20 mg/d

  49. Non-Pharmacological Pain Interventions

  50. The WHO analgesic ladder A. The 3-step analgesic ladder developed by the World Health Organization. WHO. Cancer Pain Relief. Geneva: WHO; 1986. B. The proposed 4th step. Miguel R. Interventional Treatment of Cancer Pain: The Fourth Step in the World Health Organization Analgesic Ladder? Cancer Control 2000, 7 (2): 149-56.

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