Orphan Symptoms

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Orphan Symptoms

• Pruritus, Hiccup, Cough

Dr Edward Fitzgibbon Medical Director Palliative
Care Program The Ottawa Hospital Halifax
Advanced Learning in Palliative Medicine June 2nd
2007
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Pruritus

• The anguish of itching and the injury of
  scratching
• Doyle et al

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Pruritus

• Pruritus Unpleasant sensation arising from the
  superficial layers of the skin, the mucus
  membranes and conjunctivae that will elicit the
  urge to scratch, which temporarily decreases
  pruritus.
• Prevalence in Palliative Care 2 to 6 of PC
  patient population.
• Itch-Scratch-Itch cycle damage skin integrity
  and Impaired QOL.
• Itch is a neural message that is interpreted in
  the context of signal reception, transmission and
  modulation _at_ each level of the nervous system.
• Itch may be initiated peripherally, systemically
  or centrally.
• Grond 1996

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Pruritogenic Stimuli

• Exogenous activation.
• Physical pressure, thermal, suction, electrical,
  caustic.
• Chemical histamine, proteases, PGs,
  neuropeptides.
• Endogenous activation.
• Occurs at many levels- Per NS, spinal cord, CNS.
• Overlap with endogenous activation pathways.
• Perception and tolerance of pruritus depends on
  the individuals physical and emotional state,
  level of function, adapting and coping mechanisms
  and outlook.

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Potential Chemical Mediators

• Amines histamine, serotonin, dopamine,
  adrenaline, noradrenaline, melatonin.
• Proteases kallikrein, tryptases
• Neuropeptides SP, bradykinin etc
• OPIOIDS met-enkpehalin, B endorphin etc
• Eicosanoids PGE2, PGH2,
• Growth factors
• Cytokines TNF-aß
• Similar to the inflammatory soup of pain
  modulation.

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Causes

• Primary Idiopathic / Essentialcause not
  determined.
• Secondary.
• Dermatological various dermatoses, dermatitis
  etc
• Pruritus caused by both endogenous exgoenous
  factors.
• Systemic
• Biliary hepatic disease cholestasis, PBC,
  sclerosing cholangitis.
• Chronic renal failure
• Endocrine DI, DM, PTH, Thyroid
• Haematopoietic diseases Hodgkins etc
• Infections HIV, fungal, parasitic, Syphilis
• Malignancy
• Neurological disease per neuropathy, CVA, MS,
  brain SOL
• Drugs e.g. Opioids, ASA, Amphetamines.
• Psychogenic causes.

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Pruritus of Chronic Renal Failure

• 25to 33 of uremic patients not on HD.
• 70 to 80 of CRF on HD
• ? Etiology Xerosis, HPTH, mast cell
  proliferation, increased histamine Vit A Mg
  Ca, proliferation of nerve endings in skin.
• Elevated Serotonin endogenous opioids
• MULTIPLE MECHANISMS.
• Cure Renal Transplant.

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Hepatogenic Pruritus

• 20 to 25 of jaundiced patients
• Cholestasis
• Etiology Bile Acids.BUT do not correlate with
  intensity of pruritus.
• Increased Opioiderigic tone
• Elevated Histamine Serotonin levels
• Increased proliferation nerve endings/ mast
  cells.
• Multiple MECHANISMS !!..no single
  target.
• Cure Relief of Cholestasis..stent etc

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Management of Pruritus

• Clinical assessment. Phx Hx of pruritus, onset,
  site, severity, agg rel factors, drug hx.
• Targeted examination.
• Appropriate Investigations.
• Is Cause Known?......Reversible???
• Formulate treatment plan appropriate to cause of
  pruritus and cognizant of the functional status
  and prognosis of patient.

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Management of Pruritus in PC1.General and
Topical Measures

• Reduce boredom, anxiety, dry skin, heat
• Treat skin infections (fungal etc).
• Reduce polypharmacy
• Apply cold i.e. ice compress etc.
• Baths oatmeal, tar, baking soda.
• Lotions menthol/camphor/phenol
• Emollients
• Topical anaesthetics lidocaine, benzocaine.
• Topical antihistamines or doxepin
• ? Topical capsaicin cream for localized itches.
• Twycross RG. Symptom management in advanced
  cancer. Radcliffe Medical Press, 1997246-251

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Stepwise Approach to Managing Systemic Pruritus.

• General measures.if still a problem.
• Mild Pruritus
• Antihistamine Improve sleep. Hydroxyzine 25 75
  mg h.s.
• Trial of Corticosteroids
• Moderate Pruritus
• SSRI Paroxetine 5-20mg, TCA Nortriptylline 10
  to 50mg h.s
• NREMI Mirtazapine 7.5-30 mg h.s.
• Severe Pruritus
• 5HT antagonists Ondansetron 4-8mg i.v q 8-12 hrs
• Opioid antagonists Naloxone CSI/ Naltrexone 50mg
  o.d.
• GABA agonists Midazolam infusion.

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Stepwise Management of Pruritus
Severe
Mild
Moderate
Target Neuronal Pathways Antidepressants (TCA
SSRI) Lidocaine. 5HT antagonists Opioid
antagonists GABA agonists NMDA rec A
Antihistamines /- Corticosteroids
General Topical Measures
Other Rx incl UVB TENS Psychotherapy
Treat Cause
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Hiccups

• an idle inspiratory effort
• Doyle again!

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Hiccups (Singultus) in Palliative Care

• Definition An involuntary, synchronus, clonic
  spasm of the intercostal muscles and diaphragm
  causing sudden inspiration followed by the abrupt
  glottic closure resulting in a characteristic
  sound
• Freq 2 - 60/minute. Regulated by pCO2
• MgtgtF. (5 to 1 or gt)
• Classified as Acute (lt24hrs) and Chronic ( gt
  24hrs)
• Associated with 100s of medical conditions.
• Categories Psychogenic, Organic or Idiopathic
• A Symptom NOT a Disease

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Importance of Hiccups

• Associated with
• Fatigue
• Discomfort/ pain
• Weight loss and malnutrition
• Sleep deprivation
• Depression
• Esophagitis and GERD.
• Wound dehiscence

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Pathophysiology of Hiccups
Stimulus Peripheral or Central
Efferent Limb Motor Phrenic N
Afferent Limb Vagus N Phrenic N T Symp fibres
(T6-12)
Hiccup Reflex Arc
Medulla Desc fibres C3-C5 ?Hiccup Evoking Site
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Causes Hiccups is a symptom not a disease!

• Associated with 100s of conditions including..
• Peripheral (Mainly irritation of vagus nerve)
• Gastric distension.
• Diaphragmatic irritation , mediastinal disease.
• Include SBO, GERD, Abd distension, GI disease,
  drugs.
• Central (Mainly irritation of phrenic nerve)
• Metabolic- uremia, HypoCa, HypoNa, DM
• Drugs Steroids, Etoposide, Midazolam, Sulpha
• Infections
• CNS CVA, brainstem injuries.
• Psychogenic

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Management Of Hiccups

• General Measures
• Hx Physical
• Assess intensity and impact of hiccups to the
  patient.
• Cause Known ?? Reversible.
• Appropriate Investigations.
• Pharyngeal stimulation swab, catether, grannys
  remedies.
• Medications Multimodal approach starting with
  perpherally acting drugs then adding centrally
  acting meds as needed.
• Peripheral Agents
• Reduce GI distension- NG/ PEG etc, d/c drugs,
  Diet, fluids.
• Defoaming antiflatulent Simethicone /-
• Prokinetic agent Metoclopramide 10mg q6hr po/iv,
  Domperidone /-
• PPI / H2 Blocker /-

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Management of Hiccups in PC.

• Central Action Use in Descending Order.
• Baclofen 5mg PO q 8hr..increase by 5mg q 3days
  prn.
• GABA agonist.
• S/es sedation, weakness, dizziness, confusion
• Must be tapered seizures, hallucinations
• Gabapenin 400mg t.i.d OR Pregabalin 50 mg b.i.d
• Nifedipine 10mg b.i.d po
• Haloperidol 1-4mg /day po or sc
• Amitriptylline 25 -75mg/d
• Lidocaine infusion.
• Formulate treatment plan appropriate to cause of
  hiccups and cognizant of the functional status,
  expectations and prognosis of patient.

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Stepwise Management of Hiccups in PC
Mild
Severe
Moderate
Central Agents Baclofen Gabapentin/
Pregabalin Nifedipine Chlorpromazine Haloperidol L
idocaine. IV Midazolam.
Peripheral Agents Reduce GI Distension Prokineti
c agents PPI/ H2 blockers
General Measures Diet Pharyngeal
stimulation Defoaming agents
Treat Cause
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Cough
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Cough

• A respiratory system protective reflex.
• Volitional or reflex
• Purpose to expel mucus, sputum, fluid, foreign
  body from airway.
• Pathological cough reflex cough activity caused
  by disease..futile if there is no abnormal
  material to be cleared from the airway. ( Hagen
  1991)
• Prevalence.
• Lung cancer 47 to 86 ( gt Moderate 17-48)
• Cancer 23 to 37 ( gt Moderate 13)

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Impact of cough

• Nuisance or distress to patient
• Exhaustion
• Sweating
• Insomnia
• Syncope
• Hernia
• Incontinence
• Rib fractures
• Pneumothorax

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Cough Reflex

• Peripheral receptors
• Rapidly adapting stretch receptors (RAR)
• Pulmonary and bronchial C fibre receptors
• J receptors (Juxtapulmonary-capillary )
• Stimuli Mechanical, Inflation/deflation, dust,
  mucus, FB
• Chemical noxious gas, smoke,
  capsaicin
• Inflammatory Immunological
  mediators SP, bardykinin, PG,
  Serotonin, histamine.
• Cough Centers Medulla / Cortex.
• Motor efferent
• Phrenic spinal motor nerves TO insp exp
  muscles
• Recurrent Laryngeal Nerve to larynx.
• RESULT Forced expiratory airflow closure of
  glottis, compression of major airways
• expulsion of mucus and droplets.

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Pathophysiology of Cough
Stimulus Mechanical, Chemical,
Inflammatory, Immunoloigal
Efferent Limb Motor Phrenic N Spinal
nerves Vagus (rec laryngeal n)
Afferent Limb C-Fibres RAR J Receptors
Cough Reflex Arc
Medulla Supraspinal connections Cortex
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Cough Aetiology in PC.

• Non-Malignant
• Post nasal drip
• Asthma
• GERD
• COPD
• Post RTI
• ACE inhibitor
• Eospinophilic bronchitis
• Bronchiectasis
• CHF
• P.E.

• Cancer related
• Major airway lesion
• Pleural disease- effusion
• Lung parenchymal infiltration
• Aspiration (HN Ca, Fistula etc
• Lympangitis carcinomatosis
• Pericardial effusion
• XRT induced fibriosis
• Chemotherapy induced fibrosis
• Pneumonia
• Microembolism

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Management

• Degree of Success in management is dependant on
  finding a reversible cause!
• Approach to Management
• General assessment, severity impact of cough on
  individual.
• General measures.
• Identify and treat underlying cause ( if
  possible)
• Suppression of cough.
• Formulate treatment plan appropriate to cause of
  cough and cognizant of the functional status,
  expectations and prognosis of the patient.
• A. General Measures
• Maintain fluid intake
• Reduce irritants Smoke, Odours, ? Drugs
• Pulmonary toilet chest physiotherapy,
  suctioning, oxygen, humdity, anxiolytics as
  indicated.

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CoughTreat Underlying Cause

• Cause
• Endobronchial tumors
• Metastatic Mediastinal disease
• Tracheo-esophageal fistula
• Lymphangitis carcinomatosis
• Post-irradiation fibrosis
• Effusions pleural/pericardial
• Aspiration pneumonia.
• Congestive heart failure.
• Asthma
• Post nasal drip
• GERD

• Treatment
• Steroid, laser, cryosurgery
• Steroids/ PXRT
• Stent
• Steroid
• Steroid
• Drainage
• Antibiotics, prevention
• Diuretics, inotropes etc
• Steroids/ bronchodilators etc
• Antihistamine etc
• PPI, diet, domperidone etc

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3.Suppression of Cough Antitussives

• Grouped according to their site of activity in
  the cough reflex arc.
• Peripherally acting agents
• inhibit cough stimuli or cough receptors.
• Centrally acting agents
• depress the central nervous system control
  center.

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Peripherally Acting Antitussives

• Act by different mechanisms
• Choose complimentary therapies.
• Expectorants Mucolytics
• Local anesthetics Neb Lidocaine, benzonante
• Bronchodilators beta agonists
• Decrease mucus production antihistamines,
  anticholinergics, opioids, Sodium cromoglycate.

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Exopectorants and Mucolytics

• Expectorants increase sputum volume, promote
  expulsion of secretions or modify their
  character.
• ( useful if thick sputum produced).
• e.g. Ipecac, guaiacol, peppermint, camphor,
  terpin hydrate, guanifensin.
• Mucolytics reduce sputum viscosity.
• Oral or nebulzier
• N-acetylcysteine, bromhexine,

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Centrally Acting Antitussives

• Exhibit their effect through an inhibition of
  glutamatergic synaptic transmission of the
  afferent input from the sensory airway receptors
  as a result of facilitation of serotonergic
  mechanisms ( ? 5HT1A).
• Opioids
• Act via opiate receptors (µ2 ? )
• Codeine 8 to 30mg q4hr prn ( peak effect 4hrs)
• All opioids have anti-tussive effects
• Effective antitussive doses usually loweer than
  analgesic doses
• Non-Opioids e.g.Dextrometorphan (15 to 30 mg
  q.i.d. PO)
• Acts centrally to increase cough threshold.
• Receptors in medulla ( NMDA Calcium channel)
• Fewer side effects or constipation.
• May Cause histamine release bronchospasm
  combine with antihistamine.
• Antitussive effect approx 25 that of
  dihydrocodeine.

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Other Treatment Options

• Cough modulated by central inhibitory mechanisms
  similar to pain and pruritus.
• Will get central sensitization..lowering of cough
  threshold.
• Serotonergic, Adrenergic and Gabaergic systems
  are all involved in central inhibition.
• 5HT1A receptors ? Most important.
• ?? Role for SSRIs e.g. Paroxetine
• ? Calcium Channel blockers ? Pregabalin
• ? NMDA Receptor Antagonists ? Ketamine
• GABA agonists Baclofen/ Midazolam.

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Stepwise Management of Cough in PC
Mild
Severe
Moderate
Other Agents Reduce sensitization. Na channel
blockers SSRIs Ca channel blockers NMDA rec
antag GABA agonists.
Peripheral Agents Expectorants Local
anaesthetics etc /- Central Agents Opioids Dextro
metorphan
General Measures Fluids lt irritants Pulmonary
toilet
Treat Cause
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Closing thoughts

• The dying need the friendship of the heart -
  its qualities of care, acceptance, vulnerability
  
• but they also need the skills of the mind
  --the most sophisticated treatment that medicine
  has to offer.
• On its own, neither is enough.
• Dame Cecily Saunders (1918-2005)

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Useful references

• Textbook of Palliative Medicine 3rd edit Doyle
  et al
• Zbigniew Z, et al Paroxetine for pruritus. JPSM
  2003261105
• Walker P, et al Baclofen for couh JPSM
  199816125-132
• Jaztka A, aplha 2 delta ligands for Singultus.
  JPSM 2007 (in press)
• Moretti R, et al. Gabapentin for hiccups The
  Neurologist 200410102-106
• Bergasa N.V, et al The pruritus of
  cholestasis.Gastroenterology 19951081582-1588
• Kyriakides K, et al Rx opioid induced pruritus
  Br J Anaesth 199982439-441
• Krajnij M, et al. Understanding pruritus in
  systemic disease. JPSM 200121151-168
• Widdicombe J.G. Neurophysiology of the cough
  reflex. Eur Respir J 199581193-1202
• Davis, M.P, et al Mirtazapine for Pruritus. JPSM
  200325288-291
• Hagen N. An approach to cough in cancer patients.
  JPSM 19916257-262
• Kamei J. Role of opioidergic and serotonergi
  mechanisms in cough and antitussives. Pul
  Pharmacology 19969349-356
• Zbigniew Z, et al What has dry cough in common
  with pruritus.JPSM 200427180-184