Clinical Use of Opioids in Cancer

Patients

Laksamee Chanvej, M.D.

Wattanosoth Hospital, Bangkok Hospital Medical

Center

10th March 2008

Contents

• WHO Cancer control program– Palliative care

• Pain in cancer– Extent of the problem– Guideline for cancer pain

management

• Opioids in palliative care

The four basic components of cancer control

• prevention• early detectio

n• diagnosis & tr

eatment• palliative care

0

20

40

60

80

100

Malignant

accident,poisonings

cardiac

HT,cerebrovascular

Adapted from: Health Information Devision, Bureau of Health Policy and Plan; 29 September 2006

Death rates by leading causes of death

per 100,000 population, Thailand2000-2004

Integrated model of curative and palliative care forchronic progressive illness

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

• 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

Palliative Care (WHO 2003)

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

Quality-of-life dimensions of palliative care

Cancer Patients and 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

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 -19963153179Ventafridda V. Cancer pain management. Pain Rev. ; : .

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

Criteria for cancer pain classification

• 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- anat

omical entities• Associated clinical features

– Continuous– Superficial– Radiating etc

Caraceni A. Evaluation and assessment of cancer pain and cancer painTreatment. Acta Anaesthesiol Scand 2001; 45: 1067–1075

Cancer pain

• Cancer related acute pain syndromes– Due to procedures and therapies– Acute postoperative pain– Due to neoplasm or related pathology

• C ancer related chronic painsyndromes(nociceptive and neuropahic pain)– direct effect of cancer– related to therapy– chronic problems

Factors influencing the perception of pain

G. T. Linklater and M. E. F. Leng Recent advances in pain management in palliativecare

Current Anaesthesia & Critical Care (2001 ) 12 , 296-301

Objective of cancer pain management

• optimize pain control• minimize side effects, adverse outc

omes & costs• enhance functional abilities, physic

-al & psychological well being• enhance the quality of life

Management of cancer pain• Primary therapy surgery,radiation,c

hemotherapy• Pharmacotherapy

indirect delivery system: systemic analgesia

direct delivery system:neuraxial dru g delivery & neuroablation

• O ther modalities

physiatric ,psychological ,neurostim ulatory interventions

WHO's three step ladder to use of analgesic drugs

Indirect delivery system

• S ystemic analgesia

- opioids, non opioids, adjunctive analgesics

• Route– oral, transdermal, transmucosal,sub

cutaneous or IV

- Non opioid analgesics• Acetaminophen and nonsteroidal

- anti inflammatory drugs (NSAIDs)• used in combination with opioids a

nd adjuvant analgesics• a ceiling effect• do not produce physical dependen

ce or tolerance

• - inhibit the enzyme cyclo oxygenase (COX) which c atalyses the conversion of arachidonic acid to pros

taglandins and leukotrienes• a central action at the brain or spinal cord level• opioid sparing eff ects• widely used in metastatic bone pain• r elative contraindications for using in the cancer p

atient with peptic ulcer disease, thrombocytopenia, renal impairment

• - serious side effe cts include renal failure, hepaticdysfunction, bleeding and gastric ulceration,inhib

it platelet function• Proton pump inhibitors prevention of peptic

ulcers

NSAIDs

• COX I prostaglandins– gastric mucosal cytoprotection by incre

asing blood fl ow, mucus production and gastric bicarbonate secretion

• COX II drugs: reduced the risk of GI i njury compared with current genera

tion NSAIDs• Caution: renal insufficiency, fluid

retention, edema

-COX II specifi c drugs

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. Advances in cancer pain management Hematology/oncology Clinics of North America Vol 16, No 3, 2002

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

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)

– d - ry mouth, light headedness and constipation– pruritus, rash– vasodilation, orthostatic hypotension, syncope, and

tachycardia– less constipation in comparison to typical opioids such as

codeine and morphineLeppert 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.

Relative potency of oral tramadol compared to other opioids

Twycross R, Wilcock A. Symptom management in advanced cancer, 3 rd ed. Radcliffe Medical Press, Oxford, pp 17–68 (2001)

Oral morphine • morphine immediate release

– Morphine syrup

• MST – 10 mg, 30 mg, 60 mg

• Kapanol – 20 mg, 50 mg,100 mg

Drugs Dose (mg) equianalgesic to morphine 10mg IM/IV

PO IM/IV - Half life (h) Duration (h)

Morphine (morphine syrup (immediate re

lease)

20–30 10 2–3 2–4

Morphine controlled release (MST)

20–30 10 2–3 8–12

Morphine sustained release (Kapanol)

20–30 10 2–3 24

Hydromorphone 7.5 1.5 2–3 2–4

Oxycodone 20   2–3 3–4

Oxycodone CR 20   2–3 8–12

Methadone 20 10 8–>120 4–12

Fentanyl — — 7–12 —

Fentanyl TS — — 16–24 48–72

Opioids used in cancer pain

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

• Fentanyl: peak effect after

application 24 hours, patch lasts

48–72 hours• For dysphagia, swallowing

difficulties, impaired GI function,renal failure, difficult c ompliance 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

Transdermal patch

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

Transdermal fentanyl for cancer pain

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

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

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

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.

Opioids to be avoids for cancer pain

• M eperidine– Short (2-3 hour ) duration of analgesia– Repeated administration may lead to CNS toxicity

(tremor, confusion, or seizures)• Agonist-antagonists: pentazocine, nalbuphi

ne– Risk of precipitating withdrawal in opioid-

dependent patients– Analgesic ceiling– Possible production of unpleasant

psychotomimetic effects (e.g., dysphoria, delusions, hallucinations)

• Partial agonist: buprenorphine – A nalgesic ceiling– Precipitate withdrawalhttp://www.cancer.gov/cancertopics/pdq/supportivecare/pain/HealthProfessional

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.

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, with morphi ne used as a rescue medication

• Satisfactory analgesia was achieved within 2 448– 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. O pioid titration in cancer pain: A critical reviewEuropean Journal of Pain 11 (2007) 823–830.

Patients who are receiving strong opioids and require

dose 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 mg sc)

Mercadante S. O pioid titration in cancer pain: A critical reviewEuropean Journal of Pain 11 (2007) 823–830.

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 .

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

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

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

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

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

Adjuvant analgesics

• Medications that supplement primary

analgesics

– may themselves be primary analgesics

– use at any step of WHO ladder

Adjuvant analgesics for neuropathicpain

• A ntidepressants : amitriptyline,desipramine

• A nticonvulsants: carbamazepine,phenytoin, valproate, clonazepam,gabapentin, lamotrigine, oxcarbazepine

• O ral local anesthetics: mexiletine• A - lpha 2 adrenergic agonists: clonidine• NMDA antagonists: dextromethorphan,

ketamine• M iscellaneous: baclofen, calcitonin

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.)

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

Non-Pharmacological Pain Interventions

- A. The 3 step analgesic ladder developed by the World Health Organization. WHO. Cancer Pain Relief. Geneva: WHO; 1986.

4B. The proposed th step. Miguel R. Interventional Treatment of Cancer Pain: The Fourth Step in the World Health Organizat ion Analgesic Ladder? Cancer Control2 000, 7 (2 ): 149-56.

The WHO analgesic ladder

Other discomfort management in cancer patients

• Breathlessness (an ‘uncomfortable awareness of breathing’)– Fan– Oxygen– Opioids– Bronchodilators– Corticosteriods– Benzodiazepines

Breathlessness

Fallon M. Palliation of breathlessness. Clinical Medicine Vol 6 No 2 March/April 2006

Breathlessness

Fallon M. Palliation of breathlessness. Clinical Medicine Vol 6 No 2 March/April 2006

Opioid Therapy in Cancer Pain

• Opioid therapy is the mainstay approach in cancer pain with 90% effectiveness

• Other symptom control in palliative care: breathlessness

• Palliative care concept with good palliation of symptom

1. VielhaberA, Portenoy RK. Advances in cancer pain management Hematology/oncology Clinics of North America Vol 16, No 3, 2002

2. Fallon M. Palliation of breathlessness. Clinical Medicine Vol 6 No 2 March/April 2006

Thank you