Cancer Pain Management Amal Khalifa Professor of Clinical Oncology Breast Division - University of Dammam

Significance of Severe Pain “Worse than torture”

Outcome of Cancer Treatment Curative Treatment 30% Cure 45% Diagnosis of Cancer 15% 55% Terminal Care Palliative Treatment 70%

ECOG Study of 15 Cancer Centers 1998 61% percent of the sample had pain 40% of those with pain rated it as significant (i.e., greater than 5 on a 0 to 10 scale) No patient in this sample was reported to be receiving morphine or a morphine-like opioid

ECOG Study of 15 Cancer Centers Most common reason to seek medical attention 60-90% with advanced cancer have pain 50 to 75% report inadequately relieved pain 25 % die with unrelieved excruciating pain 80-90% can be managed relatively simple with oral analgesics

Indifference to Pain Only a few healthcare professionals will ever experience and understand chronic excruciating pain D. Dumlao

Why?

Barriers to Effective Pain Management Patients and carers reluctant to complain about symptoms fear pain and don’t know how to get help lack knowledge about strong opioid analgesia fear adverse effects leading to poor adherence. Healthcare professionals fail to assess pain adequately reluctant to prescribe and monitor effective analgesia provide insufficient education to promote self-management Healthcare systems fail to recognise patients with cancer pain communicate data on pain ineffectively prevent patients receiving timely analgesia

Risk of Addiction and Substance Use Disorders among Patients Receiving Opioid Medications Actual risk is low The risk is over estimated Physical dependence is not addiction These concerns results in physician reluctance to write opioids and patient reluctance to use them

Barriers involving healthcare systems have been reduced since the standards of the JCAHO 1998---Which asserts that pain management is a patient right However, barriers, such as failure to adhere to standards and guidelines, still exist

Goal of Pain Management Titrate dose until adequate pain control is achieved or Intolerable adverse / toxic effects manifest Determine the dose that will control excruciating pain The best pain medication is the drug that will control pain without adverse effects

The Concept of Total Pain Physical Social Spiritual Psychological

Anger Total pain Physical pain Other symptoms Adverse treatment effects Anger Bureaucratic bunging Delays in diagnosis Unavailable physicians Uncommunicative physician Failure of therapy Friends who do not visit Depression Loss of social position Loss of job Loss of role in family Chronic fatigue &insomnia Sense of helplessness Disfigurement Total pain Anxiety Fears of hospitals Fear of pain Fear of death Worry about family& finances Spiritual unrest, uncertainty about future

Clinical Guideline For Patient Assessment Medical Assessment Physiotherapy Assessment Psychological Assessment Group Meeting with Patient Treatment Pathway Review Meeting with Patient

Assessment of Pain 1- The initial evaluation. 2- The "ABCDE": * Ask about the pain regularly. * Assess pain systematically. * Believe the patient and family. * Choose appropriate pain control options * Deliver interventions in a logical fashion. * Enable patients to control their life. (The Agency for Health Care Policy and Research)

Assessment of Pain

Issue No. 1 - January 2007 23-28 Evaluation of the prevalence, pattern and management of cancer pain in Oncology Department, The Royal Hospital, Oman M. Faris, B. Al- Bahrani, A. Emam Khalifa, N. Ahmad Oncology Department , The Royal Hospital, Muscat Introduction: Pain is under-treated in all parts of the world. Moderate to severe pain is experienced by the majority of patients with advanced disease. The aim of this study is to evaluate the prevalence, pattern and pain management in Oman. Methods: A prospective study was carried out during a 3 months period. We evaluated all admitted patients and only patients who were complaining of pain were eligible. Assessment of pain intensity and pain relief were done using measuring scales. All patients received pharmacological treatment according to WHO analgesic ladder. Results: A total of 335 admissions were recorded during the study period of which 100 patients (30%) were eligible for the study, 52% of cases were males. The mean age was 45 years ± 16.2 years and the most common tumors were GIT and breast cancer. Sixty four patients had pain but did not complain about it. Forty-five patients (45%) had moderate pain but they did not routinely complain about it. The mean hospital stay was 3.5 days and the range 1- 10 days. Conclusions: Most cancer patients deny pain for various reasons. Thorough history and repeated pain assessment are very important. Following the WHO analgesic ladder is simple and effective.

2012

2014

Management of Cancer Pain

World Health Organization (WHO) Step Ladder Approach Severe Pain 7-10/10 Potent opioids (e.g. morphine) +/- non-opioids Moderate Pain 4-6/10 Weak opioids +/- non- opioids (e.g. Tylenol #3®) Mild Pain 1-3/10 Note: Ask students to provide clinical example from the wards of each level of pain. ASA, Tylenol, NSAIDS

Adjuvants to Opioid Therapy Common indication Alpha agonists Neuropathic pain Anticonvulsants Antihistamines Nausea, pruritus Benzodiazepines Pain w/Anxiety Bisphosphanates Bone pain (cancer) Corticosteroids NSAIDs / COX-2 I Musculoskeletal pain Tricyclic anti-depressants

Pharmacokinetics of Opioids Renal Excretion Metabolized in the liver Concern is with toxic metabolites which can cause neurotoxicity 6 morphine glucuronide Normeperdine Norpropoxyphene 6 hydromorphone Norfentanyl Onset of action ranges from 0 to 15 minutes (IV) or 15 to 30 minutes (po) (depends on lipid solubility) Duration of action

Pharmacokinetics of Commonly Used Opioids Dilaudid (Hydromorphone): Half life: 1 to 3 hours Morphine: Duration of analgesia: 2 to 6 hours Half life: 2 to 4 hours  Fentanyl: Duration of analgesia: 0.5 – 1 hour I.V half life: 2 - 4 hours Transdermal patch half life: 17 hours (13-22 hours, half-life is influenced by absorption rate) Transmucosal half life: Lozenge: 7 hours Buccal film: 14 hours Buccal tablet half life: 100-200 mcg: 3-4 hours, 400-800 mcg: 11-12 hours Methadone Duration of analgesia: Oral: 4-8 hours, increases to 22-48 hours with repeated doses Half-life elimination: 8-150 hours

Which Opioid Analgesic to Use? Pharmacokinetics Patient co-morbidities ( Kidney and liver Disease: Methadone or Fentanyl) Intensity of pain Previous experience with opioid analgesics Considerable inter-individual variability in response to each opioid Adverse events True allergy to opioids (Drugs of choice: Methadone or Fentanyl) Etiology of pain Nociceptive Neuropathic Opioid Induced Hyperalgesia Total daily dose of pain medications

Morphine There is no standard dose of morphine for the treatment of cancer related pain The correct dose of morphine is that which controls the pain with tolerable side effect The dose must be individualizes Morphine should be given with caution to patients with: Renal impairment Severe hepatic dysfunction CNS depression from any cause

Administration of Morphine Oral morphine is the preparation of choice for patients with moderate or severe pain who are able to take oral medications. Oral morphine mixture (Short acting) Morphine mixture is commercially available in 2mg/ml, 5mg/ml, 10mg/ml strengths Cheap, well absorbed, well tolerated Effective in 85% of patients Easy to take (30-100ml/24h)

Initial dose Patients on Tramal, 20% of total dose/day Patients receiving oxycodone, same dose (mg/d) Patients not previously receiving opioids, start with 10mg PO q4h, if frail, elderly or with renal impairment, start 5mg PO q4h. Frequency 4-hourly, 2 am dose should be given unless patient sleeps through and does not wake with pain which is difficult to control. May be avoided by giving increased dose at 10pm. Breakthrough pain is treated with an extra dose, as often as required. The dose is the same as the 4-hourly dose.

What Dose to Give an Opioid Naïve Patient? For opioid naïve start at a morphine equivalent of 2 to 5 mg IV or 10 mg PO Dose escalation should be more than 30 to 50% of base dose to observe a meaningful change Frequency of parenteral dosing can be as often as every 15 to 30 minutes until adequate analgesia is achieved

Opioid Analgesic Usual Starting Dose Drug Equianalgesic parenteral dose Starting iv dose iv:po ratio Starting dose po /transdermal Duration of Action Morphine 10 mg Bolus dose=0.05-0.1 mg q 2-4 hours Continuous infusion=0.01-0.04 mg/kg/hr 1:3 0.15-0.3 mg/kg/dose q 4 hours 3-4 hours Hydromorphone 1.5 mg 0.015-0.02 mg/kg q 4 1:5 0.06 mg/kg q 3 to 4 hours 2-4 hours Oxycodone 5-10 mg N/A 0.1-0.2 mg/kg q 3 to 4 Fentanyl 100mcg 1 to 2 mcg/kg/hr as continuous infusion 25 mcg patch 72 hours Methadone 0.1 mg/kg q 4 to 8 hours 1:2 0.2 mg/kg q 4 to 8 hours 12 to 150 hours

Once Analgesia is Achieved A regular dosing schedule of every four hours can be started Rescue or breakthrough dosing 30% to 50% of every 4 hour dosing 10 to 15 percent of total 24 hour dose Best time to give rescue dose is time of peak onset Convert to PO or transdermal if possible

Breakthrough Pain Patients on long-acting med always need second, short-acting med, for breakthrough pain to take Q 4 hours or less. Generally, dose of breakthrough opioid should be: 10% of 24 hour dose of analgesics and made available Q 2-4 hours. Example: MS Contin 60mg q12hrs breakthrough dose should be immediate release morphine (MSIR), 10-15 mg Q 2-4 hrs prn.

Shifting from one opioid to another (Incomplete cross-tolerance) If switching from one opioid to another, recommended to start the new opioid at ~50% of equi-analgesic dose. Why? :Because the tolerance a patient has towards one opioid, may not completely transfer (“incomplete cross-tolerance”) to the new opioid. from 100% to 50% of new Opioid

Fentanyl

Conversion Table for Fentanyl Morphine PO 3 1 Dilaudid IV 5 20 Dilaudid PO 2 8 Methadone PO 6 Oxycodone PO 1.5 10 4 Morphine IV 10 mcg IV Fentanyl =1 mg IV morphine 25 mcg TD Fentanyl/HR = 45 mg PO Morphine IV Fentanyl 1:4 TD Fentanyl 200 mcg Actiq = 10 mg oxycodone Morphine to Methadone ratio 30 to 90 mg morphine = 4:1 91 to 300 mg = 8:1 >300 mg =12:1 1mg IV methadone = 2 mg PO methadone

Patient –Controlled Analgesia

Disadvantages of Dosing with PCA May increase adverse effects like Sedation Nausea Respiratory depression

Clinical Questions

Clinical Question #1 A 40 yr. old women with stage IV ovarian cancer reports mild to moderate burning pain in her hands and feet. Ibuprofen has not been effective. You suggest: a. A COX-2 inhibitor b. Topical capsaicin c. A steroid d. An adjuvant with activity in neuropathic pain Note: Ask students what this burning pain is (peripheral neuropathy) and what it may be due to (chemotherapy). Have students seen other cases of peripheral neuropathy on the wards (e.g. diabetic, alcohol)?

Answer #1 d. An Adjuvant with activity in neuropathic pain Pain characterized by sharp, shooting, electric shocks, parethesias, dysesthesias, cold extremities Neuropathic pain often responds poorly to NSAIDs and opioids Note: Ask students

Clinical Question #2 A 63 yr. old man with advanced prostate cancer has been stable on oral morphine 30 mg every 4 hours. He is now NPO and you are going to switch him to IV morphine. The correct IV dose is: a. 4 mg IV q 4 hours b. 6 mg IV q 4 hours c. 10 mg IV q 4 hours d. 30 mg IV q 4 hours

Answer #2 c. 10 mg IV q 4 hours Rationale: Equianalgesic ratio for morphine is 1 mg IV = 3 mg PO. When writing start time for the first dose, consider time of last oral dose. ORAL DOSE (MG) MED PAREN-TERAL DOSE (MG) 30 Morphine 10 7.5 Hydro-morphone (Dilaudid ®) 1.5 20 Oxycodone -- Hydro-codone

Clinical Question #3 A 69 yr. old patient with metastatic prostate cancer to the lumbar spine is taking OxyContin® (sustained release oxycodone) 100 mg every 8 hours. What should be the opioid for his breakthrough pain and at what dose and interval? a. Oxycodone 30 mg PO every 4 hours b. Oxycodone 30 mg PO every 8 hours c. Morphine 10 mg PO every 4 hours d. Morphine 10 mg IV every 8 hours

Answer #3 a. Oxyocodone 30 mg PO every 4 hours Rationale: In general, keep PRN, short acting opioid the same drug as the long-acting opioid. Starting dose for breakthrough pain is 10% of the total daily dose (and you can always titrate). Here total daily dose = 300 mg, so 10% of this = 30 mg. The PRN interval should never be longer than the expected analgesic duration (~4 hours in this case), and can often be less.

Clinical Question #4 A 45 yr. old woman with colon cancer metastatic to the liver, had been admitted for uncontrolled pain. Her pain is now controlled and stable on PCA morphine of 10 mg/hr. The boluses are 5 mg q15 minutes PRN and work very well but she rarely needs to use the bolus doses for breakthrough pain. She is to be discharged home on oral opioids. What opioid/formulation and what dose would you recommend? a. MS Contin 120 mg PO Q 12 hours b. MS Contin 240 mg PO Q 12 hours c. MS Contin 360 mg PO Q 12 hours d. Fentanyl patch 50 mcg Q 72 hours e. Dilaudid 8 mg PO Q 8 hours

Answer #4 c. MS Contin 360 mg PO every 12 hours Rationale: Patient already on morphine, so use same opioid. Using long-acting formulation is the oral equivalent of a continuous infusion. Total daily dose of morphine IV is 240 mg and the oral equivalent is 720 mg of morphine, can be given as 360 mg of MS Contin PO every 12 hours.

Equianalgesic Doses: Opioid Analgesics ORAL DOSE (MG) ANALGESIC PARENTERAL DOSE (MG) 30 Morphine 10 7.5 Hydromorphone (Dilaudid ®) 1.5 20 Oxycodone -- Hydrocodone Note: before showing table ask students: What is the most potent opiate they know? Which ones are they comfortable using? Do they know equianalgesic doses? Handout laminated card.

Clinical Question #5 What breakthrough pain opioid/formulation would you recommend for the same patient if she takes MS Contin 360 Mg Q 12 hours? a. Morphine elixir 20 mg PO every 2-4 hours PRN b. Morphine immediate release tablets 40 mg PO Q 2-4 hours PRN c. Morphine immediate release tablets 60 mg PO Q 2-4 hours PRN d. Morphine immediate release tablets 70 mg PO Q 2-4 hours PRN

Answer #5 d. Morphine immediate release tablets 70 mg PO every 2-4 hours PRN. Rationale: Breakthrough pain requires a short-acting formulation. Preferable to use same opioid as long-acting. PRN initially 10% of the total daily dose = 10% of 720mg = 72mg. Dosing interval is q2-3h PRN. We don’t expect that pts will need to take 12 doses in 24hr (our pain regimen would be really off). If patient requires >5 PRN doses/day, either the PRN dose needs adjusting or the basal dose or both.

“Freedom from pain should be seen as a right for every cancer patient” The under-treatment of pain is still a major issue in both oncology and palliative medicine “Freedom from pain should be seen as a right for every cancer patient”

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