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Clinical Use of Opioids in Cancer Patients


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Title: Clinical Use of Opioids in Cancer Patients

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

  • 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
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//

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
  • 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
    200224 265-9.
  • 2 Vainio A, Auvinen A. Prevalence of symptoms
    among patients with advanced cancer an
    international collaborative study. J Pain Symptom
    manage199612 3-10.
  • 3 Ventafridda V. Cancer pain management. Pain
    Rev. 19963153-179.

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
  • 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

Caraceni A. Evaluation and assessment of cancer
pain and cancer pain Treatment. Acta Anaesthesiol
Scand 2001 45 10671075
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 systemneuraxial drug delivery
  • Other modalities
  • physiatric ,psychological ,neurostimulatory

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

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

  • 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
  • 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,

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

  • 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

  • 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.
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 1768 (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 Dose (mg) equianalgesic to morphine 10mg IM/IV Dose (mg) equianalgesic to morphine 10mg IM/IV Dose (mg) equianalgesic to morphine 10mg IM/IV
Drugs PO IM/IV Half-life (h) Duration (h)
Morphine (morphine syrup (immediate release) 2030 10 23 24
Morphine controlled release (MST) 2030 10 23 812
Morphine sustained release (Kapanol) 2030 10 23 24
Hydromorphone 7.5 1.5 23 24
Oxycodone 20   23 34
Oxycodone CR 20   23 812
Methadone 20 10 8gt120 412
Fentanyl 712
Fentanyl TS 1624 4872
  • 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
  • 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

Transdermal patch
  • Fentanyl peak effect after application ? 24
    hours, patch lasts 4872 hours
  • For dysphagia, swallowing difficulties, impaired
    GI function, renal failure, difficult compliance
  • 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, 424
Transdermal fentanyl for cancer pain
Skaer TL. Transdermal opioids for cancer pain.
Health and Quality of Life Outcomes 2006, 424
Opioid Therapy Guidelines
  • Consider use of a long-acting drug and a rescue
    drugusually 515 of the total daily dose
  • Baseline dose increases 25100 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 2550 with
  • Reduce less if pain severe
  • Reduce more if medically frail
  • Reduce less if same drug by different route
  • Reduce fentanyl less
  • Reduce methadone more 7590

Indelicato RA, Portenoy RK. Opioid Rotation in
the Management of Refractory Cancer Pain J Clin
Oncol. 2003 May 121(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,
  • Partial agonist buprenorphine
  • Analgesic ceiling
  • Precipitate withdrawal

Opioid naive-patients How should we start?
  • Start with doses of 10 15 mg/day of morphine
  • well tolerated even by older patients
  • lt 45 mg/day of morphine were achieved four weeks
  • Transdermal fentanyl 25 mcg/h or oral morphine
    (about 60 mg/day) induce more adverse effects

Mercadante S, Villari P, Ferrera P, Casuccio A.
Opioid-induced or pain relief-reduced symptoms in
advanced cancer patients? Eur J Pain
2006a101539. 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 2006b312427.
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 2448
  • 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) 823830.
Patients who are receiving strong opioids and
require dose adjustment
  • Ineffective management oral and transdermal
  • 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) 823830.
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 .
  • 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 laxativeMOM, lactulose, sorbitol
  • Bulk forming agents not recommended

  • 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
  • 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 (gt 1 wk )
  • Treatment
  • prochlorperazine, 10 mg q 6 h
  • haloperidol, 1 mg q 6 h
  • metoclopramide, 10 mg q 6 h

  • 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
  • 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,
  • 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 WHOs guideline with specific
  • 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.)

  • 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 (gt36 h), dose once a day
  • minimal mineralocorticoid effect
  • doses of 220 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
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
  • Fan
  • Oxygen
  • Opioids
  • Bronchodilators
  • Corticosteriods
  • Benzodiazepines

Fallon M. Palliation of breathlessness. Clinical
Medicine Vol 6 No 2 March/April 2006
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
  • Palliative care concept with good palliation of
  • 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