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MON 2011 - Slide 32 - D. Schrijvers - Pain control

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  • Neuropathic pain arises following nerve injury or dysfunction. A: After nerve damage, transcription and axonal trafficking of sodium channels to the site of injury is increased, with concomitant attenuation of potassium channels. The altered expression of ion channels results in neurons becoming hyperexcitable and generating ectopic activity, which is thought to lead to the genesis of spontaneous and paroxysmal pain. B: At the cell body of primary afferent neurons within the dorsal root ganglia (DRG), sympathetic neuronal sprouting occurs and may account for sympathetically maintained pain. C: Peripheral nerve injury causes a multitude of changes in gene transcription and activation of various kinases and proteins, including enhanced N-methyl-D-aspartate (NMDA) receptor activity. However, nerve injury also elicits hypertrophy and activation of glial cells, including microglia within the grey matter of the spinal cord. Microglia express P2X4 purinergic receptors, allowing them to be activated by adenosine triphosphate (ATP). Following activation, microglia release various pronociceptive cytokines, such as interleukin-1 (IL-1), tumour necrosis factor alpha (TNF- ) and neurotrophins, including brain-derived neurotrophic factor, which in turn exacerbates nociceptive transmission and contributes to the sensitization and maintenance of neuropathic pain. Note: Aß = A beta neuron, A = A delta neuron, C = C nociceptor, 5HT = serotonin, KCC2 = chloride transporter, NA = noradrenaline, Nav = sodium channel, NO = nitric oxide, Kv = potassium channel, PGs = prostaglandins, PKs = protein kinases, P2X4 = purinergic receptor. 04/14/11
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  • Transcript

    • 1. Palliative care Pain in cancer patients D. Schrijvers, MD, PhD Department Medical Oncology Ziekenhuisnetwerk Antwerpen(ZNA)-Middelheim Antwerp Belgium
    • 2.
      • Definition
        • Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (IASP)
        • Pain is a subjective symptom that cannot be objectively measured. How a person communicates about pain is influenced by factors such as age, gender, underlying disability, and social or cultural norms about acceptable pain behavior. (Strong et al 2002)
      • Pain= multi-dimensional
        • Physical
        • Emotional
        • Socio-cultural
        • Existential
      Pain
    • 3. Prevalence Patients (%) after curative treatment Patients (%) during anticancer treatment van den Beuken-van Everdingen et al. Ann Oncol 2007 33% ( 95%CI 21 - 46%) 59% (95%CI 44-73%) % Study % Study
    • 4. Prevalence Patients (%) with advanced, metastatic or terminal disease All disease stages (%) van den Beuken-van Everdingen et al. Ann Oncol 2007 64% (95%CI 58-69%) % Study 53% (95%CI 43-63%) % Study
    • 5. Prevalence
      • Pain in hospitalized patients at the ZNA-Middelheim
      Van Bosch et al. Eur J Cancer 2009 Pijn Score Timepoint 1 N = 105 Timepoint 2 N = 90 Oncologic n=60 Non- Oncologic n=43 Oncologic n=48 Non-oncologic n=43 Absent (VAS=0) 48% 60% 56% 63% Mild (VAS 1-3) 33% 14% 18% 16% Moderate (VAS 4-6) 17% 19% 17% 19% Severe (VAS 7-10) 2% 7% 9% 2%
    • 6. Prevalence
      • Cancer-related pain
        • 30-40% at diagnosis
        • 40-70% during treatment
        • 70-90% in patients with advanced cancer or terminal phase
      Schrijvers D. Ann Oncol 2007
    • 7. Prevalence in patients with cancer
      • Type of cancer N° reports N° pts Pain (%) (95% CI)
      • Head/neck 3 95 70 (51-88)
      • Gastrointestinal 9 564 59 (44-74)
      • Lung/bronchus 7 1546 55 (44-67)
      • Breast 7 420 54 (44-64)
      • Urogenital 4 336 52 (40-60)
      • Gynecological 6 372 60 (50-71)
      • CI: confidence interval
      van den Beuken-van Everdingen et al. Ann Oncol 2007
    • 8. Causes
      • Cancer: 77-80%
        • Bone pain
        • Compression spinal cord/neural structures with nerve damage
        • Obstruction hollow organs
        • Paraneoplastic syndromes
      • Diagnosis and treatment: 15-25 %
        • Diagnostic procedures (punctions, imaging)
        • Surgery (amputation; thoracotomy; mastectomy)
        • Chemotherapy (neuropathy, mucositis)
        • Radiotherapy (plexopathy, myelopathy, inflammation)
      • Non-cancer-related pain: 3-5 %
      • Pain of unknown origin
      Oxford Textbook of Palliative Care 2007
    • 9. Classification
      • Related to duration
        • Acute pain
        • Chronic pain
        • Breakthrough pain: spikes of pain in patients with otherwise medically controlled pain
      • Pathophysiologic mechanism
        • Nociceptive pain
          • Somatic pain
            • Deep
            • Superficial
          • Visceral pain
        • Neuropathic pain
        • Mixed pain types
      Schrijvers D. Ann Oncol 2007
    • 10. Classification: relation to duration Schrijvers D. Ann Oncol 2007 Type pain Acute Chronic Breakthrough Duration Short Long Short Cause Identifiable Difficult to Sometimes identify identifiable Function Protection None None Aim treatment Treatment/ Prevention Prevention/ Prevention Treatment Side effects Acceptable Not acceptable not acceptable
    • 11. Classification: relation to duration Breakthrough pain Idiopatic = stimulus independent Incident pain = stimulus dependent End-of-dose pain Failing analgesia Involuntary Voluntary Ischemia Distension hollow organs Spasm Movement Activity
    • 12. Classification: pathophysiologic mechanism
      • Nociceptieve pain = receptor-linked pain
        • Transduction
    • 13. Classification: pathophysiologic mechanism
      • Nociceptive pain
        • Transmission
    • 14. Classification: pathophysiologic mechanism
      • Nociceptive pain
        • Perception
    • 15. Classification: pathophysiologic mechanism
      • Neuropathic pain = related to nerve damage
      Gilron et al. CMAJ 2006
    • 16. Evaluation
      • Anamnesis
      • Pain evaluation instruments
        • Severity
        • Duration
        • Character
      • Clinical examination
      • Imaging techniques
    • 17. Evaluation
      • Severity
        • Numerical rating scale: 0-10
        • Visual analogue scale
        • Verbal scale: none-very severe
      • Duration
        • Continuous
        • Intermittent
      • Character
        • Burning, dull ache, electric shock, numbness, pressure, shooting, tightness, tingling
    • 18. Evaluation
      • Evaluation instruments
      DN4 questionnaire
    • 19. Treatment
      • Physical aspects
        • Cancer
        • Other physical complaints (e.g. cough, nausea, hiccups)
      • Psychological aspects
        • Frustration, depression, anxiety
      • Socio-cultural aspects
        • Financial, familial problems, work, attitude
      • Existential aspects
        • Meaning of disease, life and pain
      Multidisciplinary team approach
    • 20. Treatment: physical aspects
      • Etiologic treatment
      • Symptomatic treatment: pain modulation
        • Interference with transduction
        • Interference with transmission
        • Interference with perception
          • Analgesics
          • Adjuvant analgesics or co-analgesics
          • Interventional approach
    • 21. Treatment: analgesics
      • Principles of treatment (World Health Organization)
        • By the clock
          • Analgesics on regular basis
          • Escape medication for breakthrough pain
          • Easy accessibility
        • By the easiest way
          • Analgesics by the mouth
        • By the ladder
          • Analgesics according to pain intensity/severity
        • For the individual patient
          • Adapted to organ function/co-morbidity/age
          • Careful and regular monitoring
          • Medication to cope with side effects
    • 22. Treatment: analgesics
      • Pain Ladder World Health Organization
      VAS 1-3 VAS 4-6 VAS 7-10
    • 23. Treatment: analgesics
      • Step 1: modulation transduction
        • Paracetamol
          • Simplest and safest analgesic
          • Interference with cyclo-oxygenase 2
          • Indications
            • Nociceptive pain
            • (Chemotherapy-induced) neuropathy
          • Side effects
            • Hepatotoxicity in case of intake of 150 mg/kg or 10 gram (antidote: N-acetylcysteïne)
            • Hypersensitivity reactions
    • 24. Treatment: analgesics
      • Step 1
        • Non-steroidal anti-inflammatory drugs
          • Diverse group
          • Interference with PG synthesis
          • Indication
            • Bone pain
            • Inflammatory pain
          • Side effects
            • GI ulcerations
            • Interference platelet function
            • Renal insufficiency
    • 25. Treatment: analgesics
        • Opioids
          • May be combined with step 1
          • Interference with opioid receptors
          • Indication
            • Nociceptive pain
            • Neuropathic pain
          • Differences in
            • Receptor
              • Type µ1, µ2, κ, δ
              • Genetic variability
            • Opioids
      • Step 2-3: modulation of transmission and perception
    • 26. Opioid receptor: genetic variability Klepstad P et al. Tidsskr Nor Laegeforen. 2005 Treatment: analgesics
      • Opioid receptor genetic variability
                                                                                                                                                   
    • 27. Treatment: analgesics
          • Receptor interference
          • Receptor affinity
          • Solubility
          • Metabolites
          • Side effects
          • Administration
      • Difference among different opioids
    • 28. Treatment: opioids
      • Receptor interference
      Medication Opioid receptor interference µ   Morphine A(1+2) a a Oxycodone A A Fentanyl A(1) a Methadone A A Hydromorphone A a Buprenorphine a Tramadol a
    • 29. Treatment: opioids
      • Receptor interference = transient effect
    • 30. Treatment: opioids
      • Receptor affinity
      Medication Affinity Low High Morphine + Fentanyl + Methadone + Buprenorphine + Tramadol +
    • 31. Treatment: opioids
      • Solubility in water
      Medication Solubility Low Intermediate High Morphine + Oxycodone + Fentanyl (L) + Methadone (L) + Hydromorphone +
    • 32. Treatment: opioids
      • Metabolism
      Medication Metabolism Metabolite Codeine CYP2D6 Morphine Oxycodone CYP2D6 Morphine UGT3B7 M3G-M6G Hydromorphone UGT3B7 Fentanyl CYP3A4 Methadone CYP3A4 Tramadol CYP2D6 (poor/rapid)
    • 33. Treatment: opioids
      • Activity and side effects
    • 34. Treatment: scheduling and titration of analgesics
      • Choose analgesic according to the intensity of the pain
        • VAS 1-3: non-opioids: paracetamol/NSAID
        • VAS 4-6: weak opioids: codeine
        • VAS 7-10: strong opioids: morphine
      • Start with a normal release medication
      • Use the easiest way of administration
        • Oral route: activity within 30-60 minutes
        • Sublingual, buccal and intranasal route: activity within 15 minutes
        • Parenteral route (intravenous/subcutaneous): activity with 15 minutes
    • 35. Treatment: scheduling and titration of analgesics
      • Start with an adequate dose
        • Paracetamol 4x1 gr/d PO
        • Morphine 6x10 mg/d PO
      • Provide escape medication
        • Repeat dose and titrate up (increase dose with 50-100%) every 1-2 hours until pain control
        • Adequate analgesia if pain reduction >50%
      • Monitor, prevent and treat side effects
    • 36. Treatment: chronic use of analgesics
      • Change to modified-release preparations
        • Overlap 12-24 hours with normal release agent
      • Equi-analgesic table to change to other opioid
    • 37. Treatment: opioid equianalgesic table SC: subcutaneous; IV: intravenous; MR: modified release; TC: transcutaneous Medication Oral (mg) Parenteral (SC, IV)(mg) Other routes Duration (hours) Duration MR (hours) Morphine 10 2.5 3-4 12-24 Hydromorphone 1.5-2 0.8 3-4 12-24 Codeine 100 3-4 Oxycodone 4.5-6 3-4 8-12 Methadone 20 10 6-8 Fentanyl 0.1-0.2 0.12-0.25 TC: 2.5 µg/3 days 72 Tramadol 100 100 Buprenorphine 0.25 TC: 35 µg/3-4 days 72-96
    • 38. Treatment: opioids
      • Side effects
        • Gastro-intestinal symptoms
          • Constipation/Nausea/Vomiting/Dry mouth
        • Dermatological symptoms
          • Itching/Sweating
        • Neurological symptoms
          • Sedation/Confusion/Lethargia/Hallucinations/Behavior changes/Myoclonic jerk
        • Respiratory symptoms
          • Respiratory depression
        • Urinary symptoms
          • Urinary retention
        • Physical dependency ≠ addiction
    • 39. Treatment: opioids
      • Opioid rotation
        • Indications
          • Side effects
          • Insufficient pain control
      Opioid Rotation Pain control possible with correct analgesics use in 80-90% of patients
    • 40. Treatment: co-analgesics
      • Indications
        • Analgesic-sparing effect
        • Rational pain treatment strategy
          • Pathophysiologic mechanism
        • Specific pain problems
          • Neuropathic pain
          • Mixed pain types
    • 41. Medication Indication Oral dose schedule Benzodiazepines Diazepam Muscle spasm/myoclonic jerks 2-10 mg q 6-8 h Midazolam Muscle spasm 0.3-0.5 mg/kg (SC) Spasmolytics Butylhyoscine Visceral spasm/Cramps 10-20 mg q 8 h Corticosteroids Dexamethasone Edema, inflammation 8-16 mg q 24 h Bisphosphonates Zoledronic acid Bone metastases 4 mg q 28 days IV Pamidronate Bone metastases 60 mg q 28 days IV Kg: kilogram; mg: milligram; q: every; h: hour; SC: subcutaneous, IV: intravenous Treatment: co-analgesics
      • Rational strategy in the treatment of pain
    • 42. Treatment: co-analgesics
      • Neuropathic pain
        • Tricyclic anti-depressants
          • All medication equally effective
          • Steady state after 14 days
          • Start low - Go slow
          • Side effects: accommodation disturbances, palpitations, tachycardia, orthostatic hypotension, dry mouth, constipation, nausea, increase in weight, sweating, somnolence, tremor, dizziness, headache
          • Amitriptyline
            • Start 10-30 mg/d; increase every 5-7 days until 50-75 mg/d
    • 43. Treatment: co-analgesics
      • Neuropathic pain
        • Anticonvulsants
          • Carbamazepine, oxcarbazepine, lamotrigine
            • Interactions with Na + -channels
            • Serious side effects possible: aplastic anemia, agranulocytosis, skin reactions, hypersensitivity reactions, liver function disturbances
            • Carbamazepine : 200 mg/d; increase dose every 3-4 weeks
    • 44. Treatment: co-analgesics
      • Neuropathic pain
        • Anticonvulsants
          • Gabapentine (Neurontin ® )
            • Interaction with Ca 2+ -channels
            • Daily dose: 300 mg/d
            • Side effects: increase in weight, dizziness, somnolence, ataxia, headache, tremor, visual disturbances
          • Pregabaline (Lyrica ® )
            • S-enantiomer of gabapentine
            • Interaction with Ca 2+ -channels
            • Daily dose: 150-600 mg/d
            • Side effects: increase in weight, dizziness, somnolence, ataxia, headache, tremor, visual disturbances
    • 45. Treatment: co-analgesics
      • Neuropathic pain
        • Local anesthetics
          • Transdermal lidocaine patch 5% (Versatis ® )
            • Indications
              • Peripheral neuropathies
              • Areas of sensory disturbances and/or pain
              • Painful bone structures (e.g. spine)
            • No systemic absorption
            • Quick onset pain control
            • No tolerance
            • Side effects: skin reactions
    • 46. Undertreatment of cancer pain Deandrea et al. Ann Oncol 2008 Author Year N° patients % negative Pain Management Index (95% CI) Cleeland 1994 597 42 (38–46) Larue 1995 270 51 (45–57) Elliott 1997 314 16b, 41b Trowbridge 1997 320 38 (31–46), 35 (28–42) Saxena 1999 200 79 (73–85) de Wit 1999 313 49 (43–55) Mystakidou 2001 220 76 (70–82) Sabatowski 2001 905 13 (11–15) Beck 2001 426 31 (27–35) Shvartzman 2003 218 75 (69–81) Hyun 2003 508 41 (37–45) Di Maio 2004 752 82 (79–85) Russell 2006 864 7 (3–11), 9 (7–11) Enting 2007 244 65 (59–71)
    • 47. Under-treatment of cancer pain
      • Variables affecting under-treatment
        • Advanced age
        • Female gender
        • Race
        • Education
        • Performance status
        • Stage of the disease and/or presence of metastasis
        • Pain intensity
        • Discrepancy between the pain rate given by patient and by physician
      • Opiophobia
        • Addictive
        • Is not effective in a late stage of disease when started early
        • Induces earlier death
        • Respiratory depression
      Deandrea et al. Ann Oncol 2008
    • 48. Conclusion
      • Pain influences the quality of life of cancer patients importantly
      • Pain can be treated adequately
        • Good anamnesis and clinical examination
        • Good pain evaluation and follow up
        • Pharmaceutical treatment adapted to pathophysiologic mechanism
      • Success is unfortunately not ensured in all patients
      Importance of multi- and interdisciplinary cooperation Neuroleptics (Tricyclic) Anti depressants Local anesthetics Analgesics Anti- epileptics Anti- spasmotics Cortico- steroids
    • 49. Resolution on the Access to Adequate Pain Treatment
      • The right to access to pain management for all people without discrimination
      • Physicians and other health professionals have an ethical duty
        • To offer patients with pain quality assessments
        • To prescribe medications, including opioids, in adequate quantities to all people who need pain medication.
        • Including children and others who cannot always adequately express their pain
      • Instruction on pain management, including clinical training and lectures, should be included in all mandatory medical and nursing curricula and continuing medical and nursing education
      British Medical Association 2011
    • 50. Resolution on the Access to Adequate Pain Treatment
      • Governments must ensure the adequate availability of controlled medicines, including opioids, for the relief of pain and suffering
      • International and national drug control policies should balance the need for adequate availability and accessibility of controlled medicines with efforts to prevent the misuse of these substances
      • Each government should provide the necessary resources for the development and implementation of a national pain treatment plan
      British Medical Association 2011
    • 51.