Pruritus, Hiccup, Cough
Dr Edward Fitzgibbon
Medical Director Palliative Care Program
The Ottawa Hospital
Halifax: Advanced Learning in Palliative Medicine
June 2nd 2007
“The anguish of itching and the
injury of scratching”
Doyle et al
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
Itch may be initiated peripherally, systemically or centrally.
Physical: pressure, thermal, suction, electrical, caustic.
Chemical: histamine, proteases, PGs, neuropeptides.
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,
Proteases: kallikrein, tryptases
Neuropeptides: SP, bradykinin etc
OPIOIDS: met-enkpehalin, B endorphin etc
Eicosanoids: PGE2, PGH2,
Similar to the ‘inflammatory soup’ of pain modulation.
Primary : Idiopathic / Essential……cause not determined.
Dermatological: various dermatoses, dermatitis etc
Pruritus caused by both endogenous + exgoenous factors.
Biliary + hepatic disease – cholestasis, PBC, sclerosing cholangitis.
Chronic renal failure
Endocrine: DI, DM, PTH, Thyroid
Haematopoietic diseases: Hodgkins etc
Infections: HIV, fungal, parasitic, Syphilis
Neurological disease: per neuropathy, CVA, MS, brain SOL
Drugs: e.g. Opioids, ASA, Amphetamines.
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.
20 to 25% of jaundiced patients
Etiology: Bile Acids….BUT do not correlate with intensity
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.
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).
Apply cold i.e. ice compress etc.
Baths: oatmeal, tar, baking soda.
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
General measures………….if still a problem.
Antihistamine: Improve sleep. Hydroxyzine 25 – 75 mg h.s.
Trial of Corticosteroids
SSRI: Paroxetine 5-20mg, TCA: Nortriptylline 10 to 50mg h.s
NREMI Mirtazapine 7.5-30 mg h.s.
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
(TCA + SSRI)
Antihistamines 5HT antagonists
+/- Opioid antagonists
NMDA rec A
Other Rx incl:
T reat C Psychotherapy
“an idle inspiratory effort”
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
Weight loss and malnutrition
Esophagitis and GERD.
Pathophysiology of Hiccups
Peripheral or Central
Efferent Limb Vagus N
Motor Phrenic N Phrenic N
Hiccup Reflex Arc T Symp fibres (T6-12)
Desc fibres C3-C5
?Hiccup Evoking Site
Causes: Hiccups is a symptom not a
Associated with 100’s of conditions including…..
Peripheral: (Mainly irritation of vagus nerve)
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
CNS CVA, brainstem injuries.
Management Of Hiccups
Hx + Physical
Assess intensity and impact of hiccups to the patient.
Cause Known ?? Reversible.
Pharyngeal stimulation: swab, catether, ‘granny’s remedies’.
Medications: Multimodal approach starting with perpherally acting drugs then
adding centrally acting meds as needed.
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.
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
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
Reduce GI Chlorpromazine
General Distension Haloperidol
Pharyngeal Prokinetic agents IV Midazolam.
stimulation PPI/ H2 blockers
reat C ause
A respiratory system protective reflex.
Volitional or reflex
Purpose: to expel mucus, sputum, fluid, foreign body
Pathological cough: reflex cough activity caused by disease…..futile if
there is no abnormal material to be cleared from the airway. ( Hagen 1991)
Lung cancer : 47% to 86% ( > Moderate 17-48%)
Cancer: 23% to 37% ( > Moderate 13%)
Impact of cough
Nuisance or distress to patient
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,
Cough Centers: Medulla / Cortex.
Phrenic + spinal motor nerves TO insp + exp muscles
Recurrent Laryngeal Nerve to larynx.
RESULT: Forced expiratory airflow + closure of glottis, compression of major
= expulsion of mucus and droplets.
Pathophysiology of Cough
Motor: Phrenic N Afferent Limb
Spinal nerves C-Fibres
Cough Reflex Arc J Receptors
(rec laryngeal n)
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
Degree of Success in management is dependant on finding a
Approach to Management:
General assessment, severity + impact of cough on individual.
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
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,
Mucolytics: reduce sputum viscosity.
Oral or nebulzier
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).
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
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
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
Peripheral Agents Reduce sensitization.
Local anaesthetics etc Na+ channel blockers
General Ca+ channel blockers
Measures NMDA rec antag
Fluids Opioids GABA agonists.
< irritants Dextrometorphan
reat C ause
“The dying need the friendship of the heart -
it’s qualities of care, acceptance,
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)
Textbook of Palliative Medicine: 3rd edit Doyle et al
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Moretti R, et al. Gabapentin for hiccups The Neurologist 2004;10:102-106
Bergasa N.V, et al The pruritus of cholestasis.Gastroenterology
Kyriakides K, et al Rx opioid induced pruritus: Br J Anaesth 1999;82:439-
Krajnij M, et al. Understanding pruritus in systemic disease. JPSM
Widdicombe J.G. Neurophysiology of the cough reflex. Eur Respir J
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
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Zbigniew Z, et al What has dry cough in common with pruritus.JPSM