Scottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease Copyright © NHS Scotland 2019 Page 1 of 11 End Stage Liver Disease Introduction This guideline is for all healthcare professionals involved in the care of patients with end stage liver disease of any aetiology. This guideline is not intended to be a substitute for specialist expertise and should be used in conjunction with careful individual patient assessment. This guideline is intended for use in patients with advanced liver disease who have limited life expectancy, including those in whom active treatment continues (including referral to a liver transplant unit, and placement on the waiting list) but have a high symptom burden, as well as those patients who may be approaching the last days of life. Assessment Cirrhosis represents the irreversible advanced stage of chronic progressive liver disease. This may be relatively asymptomatic and individuals may live for many years with compensated cirrhosis. Progression to decompensated cirrhosis is characterised by the development of one or more of the following liver-related complications: • variceal haemorrhage • ascites • spontaneous bacterial peritonitis • hepatic encephalopathy • hepatorenal or hepatopulmonary syndrome • portopulmonary hypertension. Decompensated cirrhosis requiring admission to hospital is associated with a 50% mortality rate at 12 months. It is therefore recommended that any patient who has decompensated cirrhosis is managed comprehensively, including an assessment of their supportive care needs. This may include referral to the local specialist palliative care team if there are complex physical, psychosocial or spiritual needs identified. The Child-Turcotte-Pugh score is a clinical classification of severity of liver disease and prognosis: Factor 1 point 2 points 3 points Total bilirubin (μmol/L) <34 34-50 >50 Serum albumin (g/L) >35 28-35 <28 PT INR <1.7 1.71-2.30 >2.30
End Stage Liver Disease
Jul 26, 2022
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Scottish Palliative Care GuidelinesScottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease
Copyright © NHS Scotland 2019 Page 1 of 11
End Stage Liver Disease
Introduction
This guideline is for all healthcare professionals involved in the care of patients with end stage liver disease of any aetiology. This guideline is not intended to be a substitute for specialist expertise and should be used in conjunction with careful individual patient assessment. This guideline is intended for use in patients with advanced liver disease who have limited life expectancy, including those in whom active treatment continues (including referral to a liver transplant unit, and placement on the waiting list) but have a high symptom burden, as well as those patients who may be approaching the last days of life.
Assessment
Cirrhosis represents the irreversible advanced stage of chronic progressive liver disease. This may be relatively asymptomatic and individuals may live for many years with compensated cirrhosis. Progression to decompensated cirrhosis is characterised by the development of one or more of the following liver-related complications:
• variceal haemorrhage
• portopulmonary hypertension.
Decompensated cirrhosis requiring admission to hospital is associated with a 50% mortality rate at 12 months. It is therefore recommended that any patient who has decompensated cirrhosis is managed comprehensively, including an assessment of their supportive care needs. This may include referral to the local specialist palliative care team if there are complex physical, psychosocial or spiritual needs identified.
The Child-Turcotte-Pugh score is a clinical classification of severity of liver disease and prognosis:
Factor 1 point 2 points 3 points Total bilirubin (μmol/L) <34 34-50 >50
Serum albumin (g/L) >35 28-35 <28
PT INR <1.7 1.71-2.30 >2.30
Scottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease
Copyright © NHS Scotland 2019 Page 2 of 11
Ascites None Mild Moderate to Severe
Hepatic encephalopathy* None Grade 1-2 (or suppressed with medication)
Grade 3-4 (or refractory)*
*Further guidance on hepatic encephalopathy can be found below.
Mild, moderate and severe hepatic impairment may be equated pragmatically with Child-Pugh class A, B and C respectively, and it can be assumed that patients for whom this guideline is intended will have Child-Pugh class B or C disease. There are limited data on the safety of medications according to grade of liver disease. There is no biochemical marker or specific formula that may accurately predict drug metabolism in hepatic impairment, so liver function tests are an unreliable way of determining how a patient with cirrhosis will tolerate a particular drug.
Class A Class B Class C Total points 5-6 7-9 10-15
1-year survival 100% 80% 45%
Management
Pain
• Good quality evidence on commonly used pain relief medication is limited.
• Undertake comprehensive assessment of pain, choosing appropriate analgesia commensurate with severity of pain (refer to Pain Assessment guideline).
• Use lowest effective dose (reduced dosage and/or extended dose interval), titrate slowly and monitor for toxicity.
• Use transdermal and slow release opioids with caution, and only if liver function and pain control are stable.
• Ensure judicious management of bowels to minimise risk of constipation and encephalopathy.
Recommendations on the use of analgesics in liver disease
Drug1 Recommendations in liver disease
Comment
Paracetamol Consider standard dose 1g four times a day for patients with normal lean body weight Consider dose reduction if less than 50kg or concern about nutritional status In severe impairment use maximum 2g/24 hours orally
Avoid intravenous use
NSAIDs Avoid use Interfere with platelet aggregation; prolong bleeding time; increase risk of gastrointestinal haemorrhage Increased risk of NSAID-induced renal impairment
Codeine Avoid use Reduced/unpredictable analgesic effect
Dihydrocodeine Avoid use Reduced/unpredictable analgesic effect
Tramadol QT Avoid if severe hepatic impairment
Moderate hepatic impairment - increase dose interval (for example to 12 hourly) Severe hepatic impairment – risk of lowering seizure threshold
Morphine or Diamorphine
Use with caution First-line strong opioid of choice Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Oxycodone Use with caution Second-line strong opioid of choice Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
1 † Indicates this use is off licence QT Indicates this medication is associated with QT prolongation
Copyright © NHS Scotland 2019 Page 3 of 11
Copyright © NHS Scotland 2019 Page 4 of 11
Hydromorphone Use with caution Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Alfentanil Use with caution Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Buprenorphine Use with caution Avoid transdermal products unless hepatic function and pain are stable Use if transdermal product preferred and analgesic requirement not sufficient to require transdermal fentanyl (refer to Buprenorphine information sheet)
Fentanyl Use with caution Avoid transdermal products unless hepatic function and pain are stable (refer to Fentanyl information sheet)
Tapentadol* Avoid if severe hepatic impairment Use with specialist palliative care advice
Avoid use or reduce dose and extend dose interval
Methadone QT Use with caution and seek specialist palliative care advice
Requires careful and very slow titration N.B: Complex pharmacokinetics means the accumulation can occur in people with normal hepatic function
Pregabalin QT Not affected by hepatic impairment
Caution due to potential for sedation
Gabapentin Not affected by hepatic impairment
Caution due to potential for sedation
Amitriptyline † QT Avoid in severe liver failure Use with caution in mild to moderate hepatic impairment – start slow, watch for sedation and constipation
Clonazepam † No data Caution with moderate hepatic impairment Contra-indicated in severe hepatic impairment
Copyright © NHS Scotland 2019 Page 5 of 11
*Tapentadol as an immediate release tablet is not recommended by the Scottish Medicine Consortium (SMC), while the prolonged release tablets are accepted for restricted use for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. This is restricted to use in patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. Refer to SMC guidance for prolonged release tablets and for immediate release tablets.
Nausea and vomiting
• Consider specific causes in liver disease: - mechanical gut dysmotility (extra-luminal from hepatomegaly or ascites (which may
also cause early satiety); intra-luminal from gut wall oedema) - centrally mediated (raised bilirubin; other toxins) - drugs (especially diuretics).
• Consider regular rather than ‘as required’ prescription for persistent symptoms.
• Consider route of administration (subcutaneous route may be required).
Recommendations on the use of anti-emetics in liver disease
Ketamine † Use with caution and seek specialist palliative care advice
Dose reduction necessary.
Comment
Domperidone QT Use with caution Dose reduce by 50%
Metoclopramide Use with caution Dose reduce by 50% Cyclizine Use with caution Avoid in those at risk of
decompensation or with encephalopathy Slows gut transit – ensure laxatives co-prescribed
Haloperidol † QT Use with caution Start low and titrate slowly
Levomepromazine † QT Use with caution Sedating – caution in those at risk of encephalopathy
Ondansetron QT Use with caution Reduced clearance in hepatic impairment
Copyright © NHS Scotland 2019 Page 6 of 11
Agitation
• Consider and address specific causes in liver disease: - hepatic encephalopathy - alcohol/drug withdrawal.
• Consider non-pharmacological management if appropriate.
• Ensure patient safety, comfort and dignity are paramount.
• Consider overall goals of care and prognosis. • If terminal agitation, refer to Care in the Last Days of Life guideline.
Recommendations on the use of medications for agitation in liver disease
Pruritus
• Refer to Pruritus guideline.
• Cholestatic pruritus is not histamine dependent so is managed differently to uraemic or opioid-induced itch.
• Address cause and employ simple, non-pharmacological measures, including topical preparations to combat dry skin such as emollients.
Slows gut transit – ensure laxatives co-prescribed Maximum dose of 8mg daily in moderate to severe hepatic impairment
Drug Recommendations in liver disease
Comment
Consider if agitated delirium Start low and titrate slowly
Lorazepam Generally safe in cirrhosis Oral lorazepam may be given sublingually Relatively long half-life
Midazolam † Use with caution Use if agitation severe or oral
route not available
Levomepromazine † QT Use with caution Sedating – caution in those at
risk of encephalopathy.
Copyright © NHS Scotland 2019 Page 7 of 11
• Severity of pruritus is not necessarily proportionally related to degree of biliary obstruction.
Recommendations on the use of medications for pruritus in liver disease
Ascites
• The development of ascites is a poor prognostic indicator in patients with liver disease and carries a mortality of 50% at 2 years.
• Patients with refractory ascites (diuretic resistant or diuretic intolerant) have a median survival of 6 months.
• Ascites carries a high symptom burden with associated pain, nausea, need for hospital admission and limitation of function and mobility.
• Peer reviewed detailed guidance on the management of ascites in cirrhosis and its related complications is available in the EASL Clinical Practice Guidelines (see references).
• Standard treatment includes sodium-restricted diet and the use of diuretics, predominantly aldosterone inhibitors, sometimes in combination with a loop diuretic.
• Use of diuretics may be limited by renal impairment and hyponatraemia.
• Recurrent large volume paracentesis is usually safe and is the first recommended intervention for refractory ascites if there are no contra-indications. Individual patient assessment is recommended. This may be carried out as a day case procedure, however the requirement for close monitoring and infusion of albumin solution limits the practicality of this being performed in the community.
Drug Recommendations in liver disease
Comment
Colestyramine No dose reduction required in hepatic impairment; avoid in complete biliary obstruction
Avoid taking other medications from 1 hour before to 4 to 6 hours after administration, to minimise interference with absorption
Rifampicin † Use with caution Enzyme inducer, so may reduce effect of analgesics
Sertraline † QT Use with caution Avoid in severe hepatic impairment
May inhibit platelet function
Causes sedation without necessarily addressing itch
Copyright © NHS Scotland 2019 Page 8 of 11
• Small volume paracentesis (drainage of less than 5 litres) does not require albumin infusion and may be more suited to community settings.
• Transjugular Intrahepatic Portosystemic Shunt (TIPSS), or liver transplantation, should be considered in patients with refractory ascites. Hepatic encephalopathy is a contra-indication to TIPSS.
• Indwelling peritoneal catheters are sometimes used in the management of malignant ascites. There are small published case series of use in refractory ascites due to cirrhosis. Use is limited by risk of infection. There are insufficient data at present regarding the risks and efficacy of this procedure and this cannot be routinely recommended.
Hepatic encephalopathy
• Hepatic encephalopathy when present may significantly impair a person’s quality of life due to: - poor sleep patterns - lack of ability to concentrate - impairment of independent living.
• Confusion and agitation due to encephalopathy may cause distress to family members and care givers.
• West Haven classification of hepatic encephalopathy: - Grade 1: trivial lack of awareness. Shortened attention span. Impaired addition or
subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.
- Grade 2: lethargy or apathy. Minimal disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, and intermittent disorientation, usually regarding time.
- Grade 3: somnolent but can be aroused, unable to perform mental tasks, gross disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech.
- Grade 4: Coma with or without response to painful stimuli.
• Peer reviewed guidelines on the management of encephalopathy are available (see references).
• Treatment includes the reversal of underlying precipitants, where possible and appropriate.
• Lactulose may be given via nasogastric tube if the patient is too drowsy to swallow.
Scottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease
Copyright © NHS Scotland 2019 Page 9 of 11
• Consideration should be given to the appropriateness of inserting a nasogastric tube on an individual patient basis.
• Sedating and analgesic drugs may precipitate or worsen encephalopathy but, particularly in the last days of life, this must be balanced against the control of distressing symptoms.
Prescribing in liver disease
• Aim to use short acting drugs.
• Start with a small dose and increase slowly or as required.
• Monitor response to titrations closely (for example analgesic control).
• Consider overall goals of care, mindful of prognosis.
Specific considerations
• Hepatic encephalopathy: be aware of increased sensitivity to sedatives, hypnotics and central nervous system depressants; use caution when prescribing constipating agents.
• Be vigilant for concurrent renal impairment and prescribe accordingly.
• In patients with a low albumin: be mindful of prescribing drugs that are highly protein bound (such as warfarin, anticoagulants, oral antidiabetics).
References Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;61(3):642-59. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-60. Albers I, Hartmann H, Bircher J, Creutzfeldt W. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol. 1989;24(3):269-76. D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-31. Davies S. Chief Medical Officer annual report 2011: the public's health. 2011 [cited 2018 Oct 31]; Available from: https://www.gov.uk/government/publications/cmo-annual-report-2011-volume- one-on-the-state-of-the-public-s-health. Ferrier C, Marty J, Bouffard Y, Haberer JP, Levron JC, Duvaldestin P. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology. 1985;62(4):480-4.
Copyright © NHS Scotland 2019 Page 10 of 11
Haberer JP, Schoeffler P, Couderc E, Duvaldestin P. Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis. British journal of anaesthesia. 1982;54(12):1267-70. Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson JO, Sawe J. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol. 1990;29(3):289-97. Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology. 1987;7(4):660-4. Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 2010;49(3):189-206. LaFond JP, Shah NL. Bursting with symptoms: A review of palliation of ascites in cirrhosis. Clin Liver Dis. 2016;8(1):10-2. Magueur E, Hagege H, Attali P, Singlas E, Etienne JP, Taburet AM. Pharmacokinetics of metoclopramide in patients with liver cirrhosis. Br J Clin Pharmacol. 1991;31(2):185-7. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology. 2001;120(1):170-8. NICE. Palliative care for adults: strong opioids for pain relief. 2012 [cited 2018 Oct 31]; Available from: https://www.nice.org.uk/guidance/cg140/resources/palliative-care-for-adults-strong- opioids-for-pain-relief-pdf-35109564116677. North-Lewis P. Drugs and the Liver. A guide to drug handling in liver dysfunction. 1st ed: Pharmaceutical Press; 2008. Pentikainen PJ, Valisalmi L, Himberg JJ, Crevoisier C. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol. 1989;29(3):272-7. Phoolchund A, Murray S, Hogan B, O'Beirne J. Outcome Of Patients Considered Unsuitable For Liver Transplantation – A Missed Opportunity For Palliative Care? Gut. 2014;63(Suppl 1):A17. Poonja Z, Brisebois A, van Zanten SV, Tandon P, Meeberg G, Karvellas CJ. Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management. Clin Gastroenterol Hepatol. 2014;12(4):692-8. Potosek J, Curry M, Buss M, Chittenden E. Integration of palliative care in end-stage liver disease and liver transplantation. Journal of palliative medicine. 2014;17(11):1271-7. Reinglas J, Amjadi K, Petrcich B, Momoli F, Shaw-Stiffel T. The Palliative Management of Refractory Cirrhotic Ascites Using the PleurX ((c)) Catheter. Can J Gastroenterol Hepatol. 2016;2016:4680543. Tallgren M, Olkkola KT, Seppala T, Hockerstedt K, Lindgren L. Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther. 1997;61(6):655- 61. The Scottish Public Health Observatory. Chronic liver disease: key points. 2018 [cited 2018 Oct 31]; Available from: https://www.scotpho.org.uk/health-wellbeing-and-disease/chronic-liver- disease/key-points/. Twycross R, Wilcock A, Howard P. Palliative Care Formulary PCF6. 6th ed. England: Pharmaceutical Press; 2017.
Copyright © NHS Scotland 2019 Page 11 of 11
Watson M, Armstrong P, Gannon C, Sykes N, Back I. Analgesia in Liver Disease. 2016 [cited 2018 Oct 31]; Available from: http://book.pallcare.info/index.php?tid=227. Williams R, Alexander G, Armstrong I, Baker A, Bhala N, Camps-Walsh G, et al. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet. 2018;391(10125):1097-107.
Drug
Comment
Agitation
Recommendations on the use of medications for agitation in liver disease
Drug
Comment
Pruritus
Recommendations on the use of medications for pruritus in liver disease
Drug
Copyright © NHS Scotland 2019 Page 1 of 11
End Stage Liver Disease
Introduction
This guideline is for all healthcare professionals involved in the care of patients with end stage liver disease of any aetiology. This guideline is not intended to be a substitute for specialist expertise and should be used in conjunction with careful individual patient assessment. This guideline is intended for use in patients with advanced liver disease who have limited life expectancy, including those in whom active treatment continues (including referral to a liver transplant unit, and placement on the waiting list) but have a high symptom burden, as well as those patients who may be approaching the last days of life.
Assessment
Cirrhosis represents the irreversible advanced stage of chronic progressive liver disease. This may be relatively asymptomatic and individuals may live for many years with compensated cirrhosis. Progression to decompensated cirrhosis is characterised by the development of one or more of the following liver-related complications:
• variceal haemorrhage
• portopulmonary hypertension.
Decompensated cirrhosis requiring admission to hospital is associated with a 50% mortality rate at 12 months. It is therefore recommended that any patient who has decompensated cirrhosis is managed comprehensively, including an assessment of their supportive care needs. This may include referral to the local specialist palliative care team if there are complex physical, psychosocial or spiritual needs identified.
The Child-Turcotte-Pugh score is a clinical classification of severity of liver disease and prognosis:
Factor 1 point 2 points 3 points Total bilirubin (μmol/L) <34 34-50 >50
Serum albumin (g/L) >35 28-35 <28
PT INR <1.7 1.71-2.30 >2.30
Scottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease
Copyright © NHS Scotland 2019 Page 2 of 11
Ascites None Mild Moderate to Severe
Hepatic encephalopathy* None Grade 1-2 (or suppressed with medication)
Grade 3-4 (or refractory)*
*Further guidance on hepatic encephalopathy can be found below.
Mild, moderate and severe hepatic impairment may be equated pragmatically with Child-Pugh class A, B and C respectively, and it can be assumed that patients for whom this guideline is intended will have Child-Pugh class B or C disease. There are limited data on the safety of medications according to grade of liver disease. There is no biochemical marker or specific formula that may accurately predict drug metabolism in hepatic impairment, so liver function tests are an unreliable way of determining how a patient with cirrhosis will tolerate a particular drug.
Class A Class B Class C Total points 5-6 7-9 10-15
1-year survival 100% 80% 45%
Management
Pain
• Good quality evidence on commonly used pain relief medication is limited.
• Undertake comprehensive assessment of pain, choosing appropriate analgesia commensurate with severity of pain (refer to Pain Assessment guideline).
• Use lowest effective dose (reduced dosage and/or extended dose interval), titrate slowly and monitor for toxicity.
• Use transdermal and slow release opioids with caution, and only if liver function and pain control are stable.
• Ensure judicious management of bowels to minimise risk of constipation and encephalopathy.
Recommendations on the use of analgesics in liver disease
Drug1 Recommendations in liver disease
Comment
Paracetamol Consider standard dose 1g four times a day for patients with normal lean body weight Consider dose reduction if less than 50kg or concern about nutritional status In severe impairment use maximum 2g/24 hours orally
Avoid intravenous use
NSAIDs Avoid use Interfere with platelet aggregation; prolong bleeding time; increase risk of gastrointestinal haemorrhage Increased risk of NSAID-induced renal impairment
Codeine Avoid use Reduced/unpredictable analgesic effect
Dihydrocodeine Avoid use Reduced/unpredictable analgesic effect
Tramadol QT Avoid if severe hepatic impairment
Moderate hepatic impairment - increase dose interval (for example to 12 hourly) Severe hepatic impairment – risk of lowering seizure threshold
Morphine or Diamorphine
Use with caution First-line strong opioid of choice Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Oxycodone Use with caution Second-line strong opioid of choice Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
1 † Indicates this use is off licence QT Indicates this medication is associated with QT prolongation
Copyright © NHS Scotland 2019 Page 3 of 11
Copyright © NHS Scotland 2019 Page 4 of 11
Hydromorphone Use with caution Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Alfentanil Use with caution Dose reduction may be necessary (refer to Choosing and Changing Opioids guideline)
Buprenorphine Use with caution Avoid transdermal products unless hepatic function and pain are stable Use if transdermal product preferred and analgesic requirement not sufficient to require transdermal fentanyl (refer to Buprenorphine information sheet)
Fentanyl Use with caution Avoid transdermal products unless hepatic function and pain are stable (refer to Fentanyl information sheet)
Tapentadol* Avoid if severe hepatic impairment Use with specialist palliative care advice
Avoid use or reduce dose and extend dose interval
Methadone QT Use with caution and seek specialist palliative care advice
Requires careful and very slow titration N.B: Complex pharmacokinetics means the accumulation can occur in people with normal hepatic function
Pregabalin QT Not affected by hepatic impairment
Caution due to potential for sedation
Gabapentin Not affected by hepatic impairment
Caution due to potential for sedation
Amitriptyline † QT Avoid in severe liver failure Use with caution in mild to moderate hepatic impairment – start slow, watch for sedation and constipation
Clonazepam † No data Caution with moderate hepatic impairment Contra-indicated in severe hepatic impairment
Copyright © NHS Scotland 2019 Page 5 of 11
*Tapentadol as an immediate release tablet is not recommended by the Scottish Medicine Consortium (SMC), while the prolonged release tablets are accepted for restricted use for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. This is restricted to use in patients in whom morphine sulphate modified release has failed to provide adequate pain control or is not tolerated. Refer to SMC guidance for prolonged release tablets and for immediate release tablets.
Nausea and vomiting
• Consider specific causes in liver disease: - mechanical gut dysmotility (extra-luminal from hepatomegaly or ascites (which may
also cause early satiety); intra-luminal from gut wall oedema) - centrally mediated (raised bilirubin; other toxins) - drugs (especially diuretics).
• Consider regular rather than ‘as required’ prescription for persistent symptoms.
• Consider route of administration (subcutaneous route may be required).
Recommendations on the use of anti-emetics in liver disease
Ketamine † Use with caution and seek specialist palliative care advice
Dose reduction necessary.
Comment
Domperidone QT Use with caution Dose reduce by 50%
Metoclopramide Use with caution Dose reduce by 50% Cyclizine Use with caution Avoid in those at risk of
decompensation or with encephalopathy Slows gut transit – ensure laxatives co-prescribed
Haloperidol † QT Use with caution Start low and titrate slowly
Levomepromazine † QT Use with caution Sedating – caution in those at risk of encephalopathy
Ondansetron QT Use with caution Reduced clearance in hepatic impairment
Copyright © NHS Scotland 2019 Page 6 of 11
Agitation
• Consider and address specific causes in liver disease: - hepatic encephalopathy - alcohol/drug withdrawal.
• Consider non-pharmacological management if appropriate.
• Ensure patient safety, comfort and dignity are paramount.
• Consider overall goals of care and prognosis. • If terminal agitation, refer to Care in the Last Days of Life guideline.
Recommendations on the use of medications for agitation in liver disease
Pruritus
• Refer to Pruritus guideline.
• Cholestatic pruritus is not histamine dependent so is managed differently to uraemic or opioid-induced itch.
• Address cause and employ simple, non-pharmacological measures, including topical preparations to combat dry skin such as emollients.
Slows gut transit – ensure laxatives co-prescribed Maximum dose of 8mg daily in moderate to severe hepatic impairment
Drug Recommendations in liver disease
Comment
Consider if agitated delirium Start low and titrate slowly
Lorazepam Generally safe in cirrhosis Oral lorazepam may be given sublingually Relatively long half-life
Midazolam † Use with caution Use if agitation severe or oral
route not available
Levomepromazine † QT Use with caution Sedating – caution in those at
risk of encephalopathy.
Copyright © NHS Scotland 2019 Page 7 of 11
• Severity of pruritus is not necessarily proportionally related to degree of biliary obstruction.
Recommendations on the use of medications for pruritus in liver disease
Ascites
• The development of ascites is a poor prognostic indicator in patients with liver disease and carries a mortality of 50% at 2 years.
• Patients with refractory ascites (diuretic resistant or diuretic intolerant) have a median survival of 6 months.
• Ascites carries a high symptom burden with associated pain, nausea, need for hospital admission and limitation of function and mobility.
• Peer reviewed detailed guidance on the management of ascites in cirrhosis and its related complications is available in the EASL Clinical Practice Guidelines (see references).
• Standard treatment includes sodium-restricted diet and the use of diuretics, predominantly aldosterone inhibitors, sometimes in combination with a loop diuretic.
• Use of diuretics may be limited by renal impairment and hyponatraemia.
• Recurrent large volume paracentesis is usually safe and is the first recommended intervention for refractory ascites if there are no contra-indications. Individual patient assessment is recommended. This may be carried out as a day case procedure, however the requirement for close monitoring and infusion of albumin solution limits the practicality of this being performed in the community.
Drug Recommendations in liver disease
Comment
Colestyramine No dose reduction required in hepatic impairment; avoid in complete biliary obstruction
Avoid taking other medications from 1 hour before to 4 to 6 hours after administration, to minimise interference with absorption
Rifampicin † Use with caution Enzyme inducer, so may reduce effect of analgesics
Sertraline † QT Use with caution Avoid in severe hepatic impairment
May inhibit platelet function
Causes sedation without necessarily addressing itch
Copyright © NHS Scotland 2019 Page 8 of 11
• Small volume paracentesis (drainage of less than 5 litres) does not require albumin infusion and may be more suited to community settings.
• Transjugular Intrahepatic Portosystemic Shunt (TIPSS), or liver transplantation, should be considered in patients with refractory ascites. Hepatic encephalopathy is a contra-indication to TIPSS.
• Indwelling peritoneal catheters are sometimes used in the management of malignant ascites. There are small published case series of use in refractory ascites due to cirrhosis. Use is limited by risk of infection. There are insufficient data at present regarding the risks and efficacy of this procedure and this cannot be routinely recommended.
Hepatic encephalopathy
• Hepatic encephalopathy when present may significantly impair a person’s quality of life due to: - poor sleep patterns - lack of ability to concentrate - impairment of independent living.
• Confusion and agitation due to encephalopathy may cause distress to family members and care givers.
• West Haven classification of hepatic encephalopathy: - Grade 1: trivial lack of awareness. Shortened attention span. Impaired addition or
subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria, depression, or irritability. Mild confusion. Slowing of ability to perform mental tasks. Asterixis can be detected.
- Grade 2: lethargy or apathy. Minimal disorientation. Inappropriate behaviour. Slurred speech. Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, and intermittent disorientation, usually regarding time.
- Grade 3: somnolent but can be aroused, unable to perform mental tasks, gross disorientation about time and place, marked confusion, amnesia, occasional fits of rage, present but incomprehensible speech.
- Grade 4: Coma with or without response to painful stimuli.
• Peer reviewed guidelines on the management of encephalopathy are available (see references).
• Treatment includes the reversal of underlying precipitants, where possible and appropriate.
• Lactulose may be given via nasogastric tube if the patient is too drowsy to swallow.
Scottish Palliative Care Guidelines – Symptom Management: End Stage Liver Disease
Copyright © NHS Scotland 2019 Page 9 of 11
• Consideration should be given to the appropriateness of inserting a nasogastric tube on an individual patient basis.
• Sedating and analgesic drugs may precipitate or worsen encephalopathy but, particularly in the last days of life, this must be balanced against the control of distressing symptoms.
Prescribing in liver disease
• Aim to use short acting drugs.
• Start with a small dose and increase slowly or as required.
• Monitor response to titrations closely (for example analgesic control).
• Consider overall goals of care, mindful of prognosis.
Specific considerations
• Hepatic encephalopathy: be aware of increased sensitivity to sedatives, hypnotics and central nervous system depressants; use caution when prescribing constipating agents.
• Be vigilant for concurrent renal impairment and prescribe accordingly.
• In patients with a low albumin: be mindful of prescribing drugs that are highly protein bound (such as warfarin, anticoagulants, oral antidiabetics).
References Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;61(3):642-59. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-60. Albers I, Hartmann H, Bircher J, Creutzfeldt W. Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol. 1989;24(3):269-76. D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217-31. Davies S. Chief Medical Officer annual report 2011: the public's health. 2011 [cited 2018 Oct 31]; Available from: https://www.gov.uk/government/publications/cmo-annual-report-2011-volume- one-on-the-state-of-the-public-s-health. Ferrier C, Marty J, Bouffard Y, Haberer JP, Levron JC, Duvaldestin P. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology. 1985;62(4):480-4.
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Haberer JP, Schoeffler P, Couderc E, Duvaldestin P. Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis. British journal of anaesthesia. 1982;54(12):1267-70. Hasselstrom J, Eriksson S, Persson A, Rane A, Svensson JO, Sawe J. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol. 1990;29(3):289-97. Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology. 1987;7(4):660-4. Johnson TN, Boussery K, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. A semi-mechanistic model to predict the effects of liver cirrhosis on drug clearance. Clin Pharmacokinet. 2010;49(3):189-206. LaFond JP, Shah NL. Bursting with symptoms: A review of palliation of ascites in cirrhosis. Clin Liver Dis. 2016;8(1):10-2. Magueur E, Hagege H, Attali P, Singlas E, Etienne JP, Taburet AM. Pharmacokinetics of metoclopramide in patients with liver cirrhosis. Br J Clin Pharmacol. 1991;31(2):185-7. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology. 2001;120(1):170-8. NICE. Palliative care for adults: strong opioids for pain relief. 2012 [cited 2018 Oct 31]; Available from: https://www.nice.org.uk/guidance/cg140/resources/palliative-care-for-adults-strong- opioids-for-pain-relief-pdf-35109564116677. North-Lewis P. Drugs and the Liver. A guide to drug handling in liver dysfunction. 1st ed: Pharmaceutical Press; 2008. Pentikainen PJ, Valisalmi L, Himberg JJ, Crevoisier C. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol. 1989;29(3):272-7. Phoolchund A, Murray S, Hogan B, O'Beirne J. Outcome Of Patients Considered Unsuitable For Liver Transplantation – A Missed Opportunity For Palliative Care? Gut. 2014;63(Suppl 1):A17. Poonja Z, Brisebois A, van Zanten SV, Tandon P, Meeberg G, Karvellas CJ. Patients with cirrhosis and denied liver transplants rarely receive adequate palliative care or appropriate management. Clin Gastroenterol Hepatol. 2014;12(4):692-8. Potosek J, Curry M, Buss M, Chittenden E. Integration of palliative care in end-stage liver disease and liver transplantation. Journal of palliative medicine. 2014;17(11):1271-7. Reinglas J, Amjadi K, Petrcich B, Momoli F, Shaw-Stiffel T. The Palliative Management of Refractory Cirrhotic Ascites Using the PleurX ((c)) Catheter. Can J Gastroenterol Hepatol. 2016;2016:4680543. Tallgren M, Olkkola KT, Seppala T, Hockerstedt K, Lindgren L. Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther. 1997;61(6):655- 61. The Scottish Public Health Observatory. Chronic liver disease: key points. 2018 [cited 2018 Oct 31]; Available from: https://www.scotpho.org.uk/health-wellbeing-and-disease/chronic-liver- disease/key-points/. Twycross R, Wilcock A, Howard P. Palliative Care Formulary PCF6. 6th ed. England: Pharmaceutical Press; 2017.
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Watson M, Armstrong P, Gannon C, Sykes N, Back I. Analgesia in Liver Disease. 2016 [cited 2018 Oct 31]; Available from: http://book.pallcare.info/index.php?tid=227. Williams R, Alexander G, Armstrong I, Baker A, Bhala N, Camps-Walsh G, et al. Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK. Lancet. 2018;391(10125):1097-107.
Drug
Comment
Agitation
Recommendations on the use of medications for agitation in liver disease
Drug
Comment
Pruritus
Recommendations on the use of medications for pruritus in liver disease
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