Transcript Clinical Use of Opioids in Cancer Patients Laksamee Chanvej, M.D .

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
detection
• diagnosis &
treatment
• palliative care
Death rates by leading causes of death
per 100,000 population, Thailand
2000-2004
100
Malignant
80
60
ac c ident,
poisonings
40
c ardiac
20
0
0
20
0
0
20
1
0
20
2
0
20
3
0
20
4
HT ,
c erebrov asc ular
Adapted from: Health Information Devision, Bureau of Health Policy and Plan;
29 September 2006
Integrated model of curative and palliative care for
chronic 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
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
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 Ventafridda V. Cancer pain management. Pain Rev. 1996;3:153-179.
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
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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 clinicalanatomical entities
Associated clinical features
– Continuous
– Superficial
– Radiating etc
Caraceni A. Evaluation and assessment of cancer pain and cancer pain
Treatment. 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
• Cancer related chronic pain syndromes
(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 palliative care
Current Anaesthesia & Critical Care (2001) 12, 296-301
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
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
WHO's three step ladder to use of analgesic drugs
Indirect delivery system
• Systemic analgesia
opioids, non-opioids, adjunctive
analgesics
• Route
– oral, transdermal, transmucosal,subcutaneous
or IV
Non-opioid analgesics
• Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs)
• used in combination with opioids and
adjuvant analgesics
• a ceiling effect
• do not produce physical dependence or
tolerance
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 and gastric ulceration,inhibit
platelet function
• Proton pump inhibitors prevention of peptic ulcers
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
Opioid Therapy in Pain
Opioid therapy is the
mainstay approach for
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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
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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, mreceptor
• 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)
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–
–
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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.
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)
Oral morphine
• morphine immediate release
– Morphine syrup
• MST
– 10 mg, 30 mg, 60 mg
• Kapanol
– 20 mg, 50 mg,100 mg
Opioids used in cancer pain
Drugs
Dose (mg) equianalgesic to morphine 10mg IM/IV
PO
IM/IV
Half-life (h)
Duration (h)
Morphine
(morphine syrup (immediate release)
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
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—
16–24
48–72
Methadone
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A synthetic opioid agonist
Average oral bioavailability approximately 80%
Long and unpredictable half-life
Converting from morphine by oral morphineequivalent daily dose (MEDD)
• A racemic mix of the d-isomer and l-isomer of
methadone
• d-isomer has antagonist activity at the N-methyl-Daspartate (NMDA) receptor and may be beneficial
in controlling neuropathic pain
• Possible prolongation of QTc interval, leading to
torsades de pointes and ventricular arrhythmia
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
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% or
equal 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:
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–
–
–
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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
• 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
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 morphine 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.
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. Opioid titration in cancer pain: A critical review
European Journal of Pain 11 (2007) 823–830.
Opioid: common side effects
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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 neuropathic 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
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
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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
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.
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.
2.
VielhaberA, Portenoy RK. Advances in cancer pain management
Hematology/oncology Clinics of North America Vol 16, No 3, 2002
Fallon M. Palliation of breathlessness. Clinical Medicine Vol 6 No 2
March/April 2006
Thank you