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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
        Pruritus

“The anguish of itching and the
     injury of scratching”
           Doyle et al
                             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 @ each level of the nervous
    system.

   Itch may be initiated peripherally, systemically or centrally.

                                                    Grond 1996
             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
  individual’s physical and emotional state, level of
  function, adapting and coping mechanisms and outlook.
      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-α+β

   Similar to the ‘inflammatory soup’ of pain modulation.
                             Causes
Primary : Idiopathic / Essential……cause 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.
    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.
             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
         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.
        Management of Pruritus in PC
       1.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, 1997:246-251
      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.
  Stepwise Management of Pruritus
 Mild          Moderate              Severe




                              Target Neuronal Pathways
                                   Antidepressants
                                    (TCA + SSRI)
                                      Lidocaine.
            Antihistamines         5HT antagonists
                  +/-             Opioid antagonists
            Corticosteroids
                                    GABA agonists
General +
                                     NMDA rec A
 Topical
Measures
                                                       Other Rx incl:
                                                           UVB

                          ause
                                                           TENS

                 T reat C                              Psychotherapy
      Hiccups

“an idle inspiratory effort”
         Doyle again!
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
   M>>F. (5 to 1 or >)
   Classified as Acute (<24hrs) and Chronic ( > 24hrs)
   Associated with 100’s of medical conditions.
   Categories: Psychogenic, Organic or Idiopathic
   A Symptom NOT a Disease
          Importance of Hiccups
Associated with
   Fatigue
   Discomfort/ pain
   Weight loss and malnutrition
   Sleep deprivation
   Depression
   Esophagitis and GERD.
   Wound dehiscence
     Pathophysiology of Hiccups

                         Stimulus
                      Peripheral or Central




                                                Afferent Limb
Efferent Limb                                       Vagus N
Motor Phrenic N                                    Phrenic N
                  Hiccup Reflex Arc           T Symp fibres (T6-12)




                         Medulla
                     Desc fibres C3-C5
                     ?Hiccup Evoking Site
    Causes: Hiccups is a symptom not a
                 disease!
Associated with 100’s 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
            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, ‘granny’s 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 +/-
    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.
Stepwise Management of Hiccups in PC
 Mild            Moderate                 Severe




                                     Central Agents
                                         Baclofen
                                   Gabapentin/ Pregabalin
              Peripheral Agents
                                        Nifedipine
                 Reduce GI            Chlorpromazine
General           Distension           Haloperidol
Measures                                Lidocaine.
   Diet
Pharyngeal     Prokinetic agents      IV Midazolam.
stimulation    PPI/ H2 blockers
Defoaming
  agents



                   reat C ause
                 T
Cough
                                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% ( > Moderate 17-48%)
   Cancer: 23% to 37% ( > Moderate 13%)
               Impact of cough
   Nuisance or distress to patient
   Exhaustion
   Sweating
   Insomnia
   Syncope
   Hernia
   Incontinence
   Rib fractures
   Pneumothorax
                        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.
            Pathophysiology of Cough
                         Stimulus
                      Mechanical, Chemical,
                         Inflammatory,
                         Immunoloigal



Efferent Limb
Motor: Phrenic N                               Afferent Limb
 Spinal nerves                                     C-Fibres
     Vagus                                           RAR
                    Cough Reflex Arc             J Receptors
(rec laryngeal n)




                          Medulla
                     Supraspinal connections
                             Cortex
            Cough: Aetiology in PC.
Non-Malignant                     Cancer related
   Post nasal drip               Major airway lesion
   Asthma                        Pleural disease- effusion
   GERD                          Lung parenchymal infiltration
   COPD                          Aspiration (H+N Ca, Fistula etc
   Post RTI                      Lympangitis carcinomatosis
   ACE inhibitor                 Pericardial effusion
   Eospinophilic bronchitis      XRT induced fibriosis
   Bronchiectasis                Chemotherapy induced fibrosis
   CHF                           Pneumonia
   P.E.                          Microembolism
                       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.
    Cough:Treat Underlying Cause
   Cause                                Treatment
   Endobronchial tumors                 Steroid, laser, cryosurgery
   Metastatic Mediastinal disease       Steroids/ PXRT
   Tracheo-esophageal fistula           Stent
   Lymphangitis carcinomatosis          Steroid
   Post-irradiation fibrosis            Steroid
   Effusions – pleural/pericardial      Drainage
   Aspiration pneumonia.                Antibiotics, prevention
   Congestive heart failure.            Diuretics, inotropes etc
   Asthma                               Steroids/ bronchodilators etc
   Post nasal drip                      Antihistamine etc
   GERD                                 PPI, diet, domperidone etc
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.
     Peripherally Acting Antitussives
     Act by different mechanisms
     Choose complimentary therapies.

4.    Expectorants + Mucolytics
5.    Local anesthetics: Neb Lidocaine, benzonante
6.    Bronchodilators: beta agonists
7.    Decrease mucus production: antihistamines,
      anticholinergics, opioids, Sodium cromoglycate.
     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,
       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 + κ )
 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.
          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.
  Stepwise Management of Cough in PC
   Mild                Moderate                      Severe




                                                Other Agents
                   Peripheral Agents         Reduce sensitization.
                       Expectorants
                    Local anaesthetics etc     Na+ channel blockers
                         +/-                          SSRIs
 General                                       Ca+ channel blockers
                   Central Agents
 Measures                                       NMDA rec antag
     Fluids            Opioids                   GABA agonists.
   < irritants     Dextrometorphan
Pulmonary toilet




                          reat C ause
                       T
           Closing thoughts
“The  dying need the friendship of the heart -
 it’s 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)
                    Useful references
   Textbook of Palliative Medicine: 3rd edit Doyle et al
   Zbigniew Z, et al: Paroxetine for pruritus. JPSM 2003;26:1105
   Walker P, et al Baclofen for couh: JPSM 1998;16:125-132
   Jaztka A, aplha 2 delta ligands for Singultus. JPSM 2007 (in press)
   Moretti R, et al. Gabapentin for hiccups The Neurologist 2004;10:102-106
   Bergasa N.V, et al The pruritus of cholestasis.Gastroenterology
    1995;108:1582-1588
   Kyriakides K, et al Rx opioid induced pruritus: Br J Anaesth 1999;82:439-
    441
   Krajnij M, et al. Understanding pruritus in systemic disease. JPSM
    2001;21:151-168
   Widdicombe J.G. Neurophysiology of the cough reflex. Eur Respir J
    1995;8:1193-1202
   Davis, M.P, et al Mirtazapine for Pruritus. JPSM 2003;25:288-291
   Hagen N. An approach to cough in cancer patients. JPSM 1991;6:257-262
   Kamei J. Role of opioidergic and serotonergi mechanisms in cough and
    antitussives. Pul Pharmacology 1996;9:349-356
   Zbigniew Z, et al What has dry cough in common with pruritus.JPSM
    2004;27:180-184

				
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