Archive for the HCP Category

Delirium/agitation (excluding HE)

Top tips:

    1. Validated assessment tools should be used to assess for delirium
    2. Hepatic encephalopathy is a major contributor to delirium/agitation and must be considered as the diagnosis of exclusion in any patient presenting with confusion.
    3. Before using this algorithm, it is essential to distinguish these two patients*:
      • Advanced cirrhosis not at the end of life where confusion may be due to Hepatic encephalopathy – confusion CAN recover with Hepatic encephalopathy therapy, (see Hepatic encephalopathy page). Some of these patients may still be candidates for liver transplantation if it is in keeping with their goals of care. Hepatic encephalopathy MUST be ruled out before using this algorithm.
      • Advanced cirrhosis at the end of life (last weeks to days) with delirium/agitation who are not candidates for liver transplantation and do not want further management for their Hepatic encephalopathy. Can use the algorithm.

      *This distinction can be challenging. A trial of lactulose can be helpful. Ask for advice from a liver specialist if guidance is required.

    4. In addition to Hepatic Encephalopathy, consider additional workup to identify and manage reversible causes of delirium
    5. Even at end-of-life, if it is in keeping with the patient’s goals of care, therapy with lactulose and/or rifaximin can be continued while the patient is able to swallow.

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Step 1: Assess for anxiety with validated assessment tools
Assess for delirium using validated tools

Use validated tools to define delirium vs. agitation and restlessness (e.g. Confusion Assessment Method, CAM)

 Cam calculator

Step 2: Consider potential contributing causes and treat as appropriate

Consider contributing causes for delirium and investigate & treat if in keeping with the patient’s goals of care.

Hepatic Encephalopathy (HE) is the diagnosis of exclusion in these patients, especially in those with a prior history of HE (see the HE page link for more information).

**Unless there is an obvious non-HE precipitant, provide a trial of lactulose therapy BEFORE moving any further in the algorithm.

Differential diagnosis* includes (DIMS-O)
  • D: Drugs/toxins – Drug/alcohol intoxication or withdrawal. Renal and/or liver dysfunction may increase the risk of drug or toxin accumulation; opioid toxicity can be a contributing factor – rotate opioids and hydrate if this is suspected
  • I: Infection – primary peritoneal, urologic or alternate site
  • M: Metabolic – hepatic encephalopathy, electrolyte abnormalities, thyroid dysfunction, CO2, O2 abnormalities
  • S: Structural – primary CNS – tumour, hemorrhage, edema, seizure, underlying dementia
  • O: Other – psychiatric disease, shock/intravascular, neoplastic, withdrawal, deficiencies, inflammatory/autoimm

 

Step 3: After contributing causes (including HE) are investigated/managed, consider Non-pharmacological therapies alongside PRN pharmacological therapies

Consider Non-pharmacological therapy in addition to PRN pharmacological therapies in patients where delirium and associated symptoms (restlessness, agitation, perceptual disturbances – hallucinations, delusions) are having a significant impact on the patient’s quality of life and ability to function.

Non-pharmacological measures include the following
  • Interactions with and involvement of family
  • Orientation with calendars/clocks/photos
  • Ensuring adequate hydration
  • Ensuring that the patient has glasses and hearing aids if needed,
  • Maintaining sleep-wake cycle
Be aware that delirium may alter the expression of other symptoms
  • Pain: Delirium may mask a patient’s ability to express symptom burden of pain. This is especially true in agitated delirium and pain assessment may be difficult. Ensure any symptoms of pain are adequately managed.
  • Alterations in other bodily functions such as urination (e.g. urinary retention) and defecation (e.g. severe constipation) may be more challenging to assess and may also contribute to restlessness and agitation.

 

As needed (PRN) Pharmacological therapy

Always consider degree of sedation when selecting a medication. It is critical to assess the patient’s preference/tolerance of sleepiness, especially if regular doses are required.

There are only a few instances where benzodiazepines, e.g. lorazepam, should be the first choice as an alternative to or alongside the below mentioned neuroleptic medications

 

Use as needed (PRN) neuroleptic medications (listed from least to most sedating) for intermittent symptoms
  • Start at the lowest dose and titrate (unless symptoms are severe and drowsiness is part of expected goals)
  • More sedating medications can be used for admitted patients
  • Only use one neuroleptic at one time
  • Monitor for Extrapyramidal symptoms (EPS) in all patients taking neuroleptic medications
Medication: Recommended Dose Additional information

Haloperidol

0.5 mg- 1 mg PO/SC q1h PRN

  • Preferable if end of life, given the SC option
  • Anti-nausea effects
  • QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, blood dyscrasias

Quetiapine
(immediate release)

10 mg PO TID
Max:30mg in 24 hours

  • QT prolongation, anticholinergic effects, sedation, extra-pyramidal symptoms, hyperglycemia
  • Does not have an injectable form

Olanzapine

2.5 mg PO q4h PRN
Max: 10 mg in 24 hours

  • Greatest impact on lowering the seizure threshold- avoid if patient is at risk
  • QT prolongation, anticholinergic effects, blood dyscrasias, sedation, extra-pyramidal symptoms
  • Anti-nausea effects

If delirium persists despite PRN, can consider regularly scheduled Pharmacological therapy
  • If patient is requiring several doses of PRN medications, consider increasing Neuroleptic medications to ATC (around the clock) dosing.
  • Typically dosed q4h, but frequently can be modified depending on severity (eg q12 hr to start)
  • Aim for the lowest effective dose to minimize adverse effects and sedation
  • Only use ONE neuroleptic at a time- stop the previous medication when starting another one
  • Start with Haloperidol. If it is ineffective, then titrate in order from least to most sedating.
  • Monitor for Extrapyramidal symptoms (EPS) in all patients taking neuroleptic medications
  • Continue to routinely review medical status with substitute decision-makers. Worsening agitation may indicate irreversible delirium and short prognosis
Scheduled (ATC) Pharmacological Therapy
Medication: Recommended Dose Additional information

Haloperidol

0.5 mg -1 mg PO/SC q 8h ATC AND
0.5 - 1 mg PO/SC q 1h PRN
Max: 8-12 mg in 24 hours (may titrate up to 2 mg/dose and if ineffective, change medication)

  • Preferable if end of life, given the SC option
  • Anti-nausea effects
  • Quetiapine
    (immediate release)

    6.25 mg-12.5 mg PO q4h PRN
    Max: 50 mg in 24 hours

  • QT prolongation
  • Does not have an injectable form
  • Olanzapine

    2.5 mg PO q4h PRN
    Max: 10 mg in 24 hours

  • Greatest impact on lowering the seizure threshold – avoid if patient is at risk.
  • Anti-nausea effects
  •  

    Refractory symptoms

    If symptoms persist despite the management above, review medical status and goals of care.

    Stop Haloperidol or other Neuroleptic

    Medication: Recommended Dose Additional information

    Methotrimeprazine (Nozinan)

    6.5 mg-12.5 mg PO/SC q8 h ATC AND q 1h PRN
    Max: 25 mg PO/SC q4h ATC
    AND q 1h PRN

    -Least risk of seizures.
    -Anti-nausea effects
    -Product monograph suggests use is contraindicated in hepatic impairment. Expert consensus from our group suggests that at end of life, this medication can be used with caution.

     

    End of Life considerations
    • Re-evaluate prognosis and discuss with patient/agent.
    • If focus shifts to comfort only and end of life, Palliative sedation (e.g. Continuous Midazolam infusion) might be indicated now. Palliative consultation is highly recommended for this. See AHS guidelines for palliative sedation.

     

    We gratefully acknowledge the Physician Learning Program for their design assistance.

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful Links: 
    1. Confusion Assessment Method (CAM):
      https://www.albertahealthservices.ca/assets/about/scn/ahs-scn-bjh-hf-delirium-screening-tool.pdf
    2. Hepatic Encephalopathy:
       http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/
    1. Opioid Toxicity:
      https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-peolc-provincial-guideline-for-treatment-opioid-neurotoxicity.pdf
    2. Edmonton Zone Palliative Sedation Guideline:
      http://www.cspcp.ca/wp-content/uploads/2017/11/Palliative-Sedation-Edmonton-Final-Dec-2015.pdf
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com. 
    2. Palliative sedation guidelines: http://www.cspcp.ca/wp-content/uploads/2017/11/Palliative-Sedation-Edmonton-Final-Dec-2015.pdf
    3. Palliative care tips/delirium in patients with advanced cancer and those who are imminently dying: https://albertahealthservices.ca/info/Page16872.aspx
    4. Agar, M. et. al. Efficacy of Oral Risperidone, Haloperidol, or Placebo for Symptoms of Delirium Among Patients in Palliative Care: A Randomized Clinical Trial. JAMA Internal Medicine 177(1): 34-42. PMID: 27918778
    5. Bush, SH., Tierney, S., and Lawlor, PG. Clinical Assessment and Management of Delirium in the Palliative Care Setting. 2017. Drugs 77:1623-1643. PMID: 28864877
    6. Bush, SH., et. al. Treating an Established Episode of Delirium in Palliative Care: Expert Opinion and Review of the Current Evidence Base with Recommendations for Future Development. 2014. JPSM 48(2): 231-248. PMID: 24480529
    7. De la Cruz, M., et. al. Increased Symptom expression among Patients with Delirium Admitted to an Acute Palliative Care Unit. 2017. Journal of Palliative Medicine. 20(6): 638-641. PMID: 28157431
    8. Hui, D. Benzodiazepines for agitation in patients with delirium: selecting the right patient, right time, and right indication. 2018.Curr Opin Support Palliat Care 12: 489-494. PMID: 30239384
    9. Hui, D. et. al. Effect of Lorazepam with Haloperidol vs Haloperidol alone on Agitated Delirium in Patients With advanced Cancer Receiving Palliative Care: A Randomized Clinical Trial. 2017. JAMA. 318(11): 1047-1056. PMID: 28975307
    10. Lewis J. H., Stine J. G. Review article: prescribing medications in patients with cirrhosis – a practical guide. Aliment Pharmacol Ther 2013; 37: 1132–1156. PMID: 23638982
    11. Oh, E. et. al. Delirium in Older Persons: Advances in Diagnosis and Treatment. 2017. JAMA 318(12): 1161-1174. PMID: 28973626

    Pain

    Top tips:

      1. Pain is a complex symptom and requires consideration of many factors for diagnosis and management. This guidance will focus on chronic pain (>3 months).
      2. A separate algorithm is provided for pain at end-of-life (last days/weeks of life).
      3. Separate tips are provided for acute pain management in the hospital setting.
      4. A thorough assessment of pain requires the following three things:
        • Quantify pain and its impact using a standardized pain assessment tool
        • Consider psychosocial contributors to pain and look for co-existing mental health conditions
        • Addiction risk assessment
      5. Set realistic expectations for pain relief, in chronic pain focusing on function and goals rather than complete resolution. In general, the most that can be expected from outpatient drug treatment for chronic pain is a 30-50% reduction in intensity. Prepare the patient that the medication will be discontinued if desired effect is not achieved.
      6. Consider non-pharmacological therapies in all patients
      7. Consider the type of pain when prescribing pharmacological therapies
      8. Opioids are important agents in the correct setting. They should be used with caution in cirrhosis as they can worsen hepatic encephalopathy and increase risk of falls. If needed for pain management, adjust doses and dosing interval to the degree of hepatic dysfunction
      9. Regularly reassess the pain after initiation of pharmacological therapy to determine need for ongoing therapy
      10. At end-of-life, the risk-benefit ratio of pharmacological therapy may change and patients may be more accepting of sedation.

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    Step 1: Consider the differential diagnosis and identify contributing causes

    Is the pain acute with an identifiable non-cirrhosis or cirrhosis related acute cause that can be treated (e.g. a hip fracture after a fall, spontaneous bacterial peritonitis, increasing ascites contributing to abdominal distension). Treat the cause. This guidance statement does not apply to acute pain.

    Is the pain chronic (present for >3 months). Consider the differential diagnosis. Modify what is modifiable if this is in keeping with the patient’s goals of care.

    Step 2: Apply assessment tools specific for pain

    Pain is a complex multidimensional experience with biopsychosocial inputs. Depending upon the situation, assess the following three things as part of a thorough pain assessment:

    1.Quantify the pain using a standardized pain assessment tool

    Use one of the following standardized pain assessment tools to evaluate pain and monitor the effectiveness of pain management.

    2.Consider non-physical (psychosocial) contributors and screen for mental health issues

    Consider psychosocial contributors and screen for co-existing mental health conditions as these will affect the pain experience:

    3.Addiction risk assessment

    Ask about alcohol and other substance use as this may affect your management decisions.

    Screen for opioid risk:

     

    Step 3: Consider Non-pharmacological therapies

    Consider Non-pharmacological therapies

    Consider non-pharmacological management in all patients in addition to pharmacological therapies.

    Analgesics and other drugs are only a partial solution to the management of pain in cirrhosis (see Chronic Pain Tips).

    • Reassess pain on follow-up visits using the PEG, ESAS-r  or the Follow-up Pain Assessment Tool

     

    Various non-pharmacological therapies can be considered

    These may have varying uptake and utility for each person and should be suggested on a case-by-case basis. Common examples:

      • Exercise
      • Mind-body practices (e.g. meditation/yoga)
      • Counselling

     

    Step 4: If symptoms persist, consider Pharmacological therapy

    It is important to consider the type of pain the patient is experiencing – main consideration:

    Nociceptive (somatic/visceral pain) versus Neuropathic (nervous system pain,“burning/electrical”)

    • Reassess pain at least monthly using the PEG, ESAS-r or the Follow-up Pain Assessment Tool to determine if there is benefit to current medication.
      • If the pain is not responding as expected, go back to your differential diagnosis, re-assess for non-physical contributors to pain and review expectations for pain relief.
      • Pain adequately controlled – Continue to reassess monthly
      • Pain somewhat controlled but inadequate – Continue first line medication and add second line medication
      • Pain not controlled (no benefit) – Stop first-line medication and start second line medication
    • The dose of medications may need to be adjusted with deteriorating liver function.

     

    Nociceptive Pain

    Nociceptive pain arises from damage or injury to nociceptors and encompasses both somatic (soft tissue, bone, joints) and visceral pain (from vital organs). This is often the most common type of pain.

    Localized pain may respond to local treatment. For non-localized chronic pain, acetaminophen is recommended as first-line.

    Medication: Recommended Dose Additional information

    Acetaminophen

    325-1000 mg PO q6-12 h/day
    Max: 2-3 grams/day

    First line Dose reduce to a maximum of 2 grams per day if needed regularly, long-term

    Diclofenac gel

    5% or 10% gel applied topically BID or TID. Over the counter products are 1.16% and 2.23%.

    First line for localized joint pain

    REASSESS PAIN AT LEAST MONTHLY - If above therapies are ineffective and pain is significantly impacting quality of life AND function, weigh the risks and benefits of opioid therapy

     

    Neuropathic Pain

    Neuropathic pain arises from structural or functional derangement of the tissues of the nervous system itself. Adjectives like burning or electrical may indicate neuropathic pain.

    True neuropathic pain is uncommon. Gabapentin and pregabalin have the potential for misuse. Avoid prescribing these for pain unless you can make a clear diagnosis of neuropathic pain (see Chronic pain tips ).

    Medication: Recommended Dose Additional information
    (Before use, see the product monograph for complete side effect list)

    Gabapentin

    100 mg PO qhs.
    Max: Standard adult dosing, titrated to tolerance and effect

    First line
    -Sedation, dizziness, confusion, fatigue and possibly peripheral edema.
    -Dose adjust with renal dysfunction (eGFR <50 ml/min)
    -A trial of therapy may require ≥ 2 months
    -Avoid if uncontrolled Hepatic encephalopathy

    Pregabalin

    25-50 mg PO qhs
    Max: Standard adult dosing, titrated to tolerance and effect.

    Alternate First line
    -Same cautions as for Gabapentin
    -Dose adjust with renal dysfunction (eGFR <60 ml/min)
    -Increases the risk of GI bleeding

    Acetaminophen

    325-1000 mg PO q6-12 h/day
    Max: 2-3 grams/day

    Second line
    Dose reduce to a maximum of 2 grams per day if needed regularly, long-term

    REASSESS PAIN AT LEAST MONTHLY - If above therapies are ineffective and pain is significantly impacting quality of life AND function, weigh the risks and benefits of opioid therapy

    When is an opioid indicated in cirrhosis?
    • The risks and benefits of opioid medications need to be very carefully weighed in all patients, but particularly in those patients with cirrhosis.
    • Consider opioids only in patients who have failed non-opioid therapies and have refractory pain that is significantly impacting quality of life and function
    • Unless the practitioner is very experienced, assistance should be sought before using opioids in the following situations:

    -Patients meeting these criteria often benefit from consultation with an inter-disciplinary Pain Clinic (earlier stages of cirrhosis), palliative care (end-of-life), hepatology (uncontrolled hepatic encephalopathy).

    -If clinic wait lists are too long or rapid assistance is required, in Alberta, these specialists can be reached through RAAPID North (780-735-0811) or RAAPID South (403-944-4486).

    Click here for instructions on getting a telephone consultation at the University of Alberta Pain Medicine clinic.

    Initial steps to start an opioid in cirrhosis?
    • Review the results of the opioid risk tool revised. If the patient is at risk, suboxone (buprenorphine/naloxone) is recommended as the drug of choice, unless the prescriber has specific training in Addiction Medicine
    • Educate the patient about expected side effects
    • Review the patient’s Personal Pain Goal (numerical pain intensity they can function in the capacity they are best able, see general approach to symptom assessment box at top of page), in addition to goals for increased function and quality of life. Reinforce that in a best-case scenario, pain typically decreases by 30-50%
    • Start low doses and titrate up slowly to the lowest effective dose
    • Do not initiate long-acting formulations in patients with cirrhosis
    • In physically or cognitively frail patients, some experts start with a single dose of an opioid at qhs to assess tolerance, and to add doses from there
    • All opioids are associated with a risk of constipation and worsening hepatic encephalopathy.
    • Order a bowel routine (see Constipation page) and for the first 3-5 days of therapy (or dose changes), order prn anti-nauseants (see Nausea page).
    • Consider Home Care involvement if the patient is unable to take their own medications
    Initiating Opioid Therapy
    Medication: Recommended Dose Additional information
    (Before use, see the product monograph for complete side effect list)

    Hydromorphone (immediate release)

    Oral: 0.5 or 1 mg PO q6h Max: Titrate up as required/tolerated

    First line (in all).
    -Requires dose adjustment if GFR <60 mL/minute - check product monograph-Advantage - can be provided PO or subcutaneously (end-of-life).
    -Half-life increased in cirrhosis, adjust dose
    -Respiratory and CNS depression

    Morphine sulphate
    (immediate release)

    2.5 mg PO q4 or q6h
    Max: Titrate up as required/tolerated

    Alternate First line
    Do not use if GFR <30 (risk of seizures)
    -Undergoes high first-pass metabolism leading to increased oral bioavailability
    -Metabolites have greater toxicity than hydromorphone

    Buprenophine/Naloxone (Suboxone)

    Starting:: 4 mg SL once daily
    -see monograph for induction and maintenance dosing

    First line if history of substance use disorder
    -Consult pain management specialist
    -Advanced learning is available (click for AHS link to education)
    -Child Pugh B (“moderate impairment”) – not recommended for induction (can precipitate withdrawal). Cautious use for maintenance treatment as naloxone clearance is reduced in cirrhosis and buprenorphine may be less effective.
    -Child Pugh C - contraindicated

    Medications to AVOID or use with CAUTION

    Non-steroidal anti-inflammatory drugs

      • Increases the risk of renal dysfunction and bleeding

    Demerol

      • Build-up of toxic metabolites.

    USE WITH CAUTION

    Codeine

      • Pro-drug that requires conversion to morphine in the liver. Results in variable analgesia as liver dysfunction progresses.
      • Clearance can also be slowed, resulting in depressed ventilation. If used, start with lower doses and longer dosing intervals (15-30 mg PO tid), followed by careful titration. AVOID in Child Pugh C disease.

    Oxycodone

      • Relies on CYP metabolism to its active metabolite. Unpredictable levels. No subcutaneous alternative for end-of-life.

    Fentanyl transdermal patch

      • Do not use in opioid naïve patients
      • Avoid in “severe hepatic impairment”
      • Consult pain management specialist or if the patient is end-of-life, a palliative specialist

    Tramadol/Tramacet

      • Requires activation by hepatic oxidation so effects may be less predictable with hepatic dysfunction. Avoid in Child Pugh C disease.
      • Lowers the seizure threshold.
      • Metabolism decreases with progression of liver disease, reducing the analgesic effect.
      • Be aware that Tramacet contains acetaminophen (daily total limit of acetaminophen is 2-3g over 24h)
      • The British Association for the Study of the Liver guidance recommends against use in cirrhosis
    Titrating Opioid Therapy

    Non-steroidal anti-inflammatory drugs

      • Increases the risk of renal dysfunction and bleeding

    Demerol

      • Build-up of toxic metabolites.

    USE WITH CAUTION

    • Ongoing pain reassessment (q 2-4 weeks) is critical (PEG, ESAS-r, Follow-up pain assessment tool)
    • Uncontrolled pain is defined as >3 breakthrough doses per day for 3 consecutive days

     

     

    Special considerations at End-of-life
    1. Most medications targeting neuropathic pain are not available as injectables when subcutaneous route needed (eg. gabapentin). A switch to opioid medication will likely be necessary.
    2. Given the focus on comfort, CNS side effects are often not as critical for patients. Good discussions are important. Faster titration of medications may result in more CNS depressant effects, which may be aligned with patient goals.
    3. Patients usually require subcutaneous medications at the end of life when they lose the ability to swallow.
    4. A history of substance use may affect the dosing of medications required at the end-of-life and may make the patient and family more reluctant to use opioids. Specialist consultation may be required.

     

    When to Refer to Palliative Care
    1. Pain management remains suboptimal despite above approach.
    2. An opinion about safety and limits of therapy is needed.
    3. Assistance with management of Total Pain Syndrome is needed.
    4. Tertiary palliative care unit or Hospice placement is required (Palliative Care specialist, may be regional variation).
    5. Practitioner uncertain regarding any of the above steps.
    6. Multi-symptom complexity, including pain.
    7. Patient or family psychosocial distress compounding the pain experience.
    8. Complex advance care planning in combination with pain.

     

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Saifee Rashiq, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful links:
    1. General approach to pain: Chronic Pain Tips
    2. Substance use: https://crismprairies.ca/wp-content/uploads/2020/02/Guidance-Document-FINAL.pdf
    3. Fraser Health Symptom tools: https://www.fraserhealth.ca/-/media/Project/FraserHealth/FraserHealth/Health-Professionals/Professionals-Resources/Hospice-palliative-care/SymptomAssessmentRevised_Sept09.pdf
    4. Excellent reference for opioid prescribing for chronic non-cancer pain – Busse JW et al. DOI: https://doi.org/10.1503/cmaj.170363
    5. Alcohol use disorder: AUDIT-C (3 questions)
    6. Drug misuse screening: DAST-10 (10 questions)
    7. Opioid Risk Tool-revised
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
    2. British Association for the Study of the Liver. Clinical Guideline. Symptom Control and End-of-Life care in adults with Advanced Liver Disease. Version 1.0.
    3. Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs. 2012 Aug 20;72(12):1645-69. doi: 10.2165/11635500-000000000-00000. PMID: 22867045.
    4. Busse JW, Craigie S, Juurlink DN, Buckley DN, Wang L, Couban RJ, Agoritsas T, Akl EA, Carrasco-Labra A, Cooper L, Cull C, da Costa BR, Frank JW, Grant G, Iorio A, Persaud N, Stern S, Tugwell P, Vandvik PO, Guyatt GH. Guideline for opioid therapy and chronic noncancer pain. CMAJ. 2017 May 8;189(18):E659-E666. doi: 10.1503/cmaj.170363. PMID: 28483845; PMCID: PMC5422149.
    5. Chandok N, Watt KD. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc. 2010 May;85(5):451-8. doi: 10.4065/mcp.2009.0534. Epub 2010 Mar 31. PMID: 20357277; PMCID: PMC2861975.
    6. Imani F, Motavaf M, Safari S, Alavian SM. The therapeutic use of analgesics in patients with liver cirrhosis: a literature review and evidence-based recommendations. Hepat Mon. 2014 Oct 11;14(10):e23539. doi: 10.5812/hepatmon.23539. PMID: 25477978; PMCID: PMC4250965.
    7. Klinge M, Coppler T, Liebschutz JM, Dugum M, Wassan A, DiMartini A, Rogal S. The assessment and management of pain in cirrhosis. Curr Hepatol Rep. 2018 Mar;17(1):42-51. doi: 10.1007/s11901-018-0389-7. Epub 2018 Feb 22. PMID: 29552453; PMCID: PMC5849403.
    8. Krebs EE, Lorenz KA, Bair MJ, Damush TM et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. Journal of general internal medicine 2009 Jun 1;24 (6):733-8. PMID 19418100.
    9. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis – a practical guide. Aliment Pharmacol Ther. 2013 Jun;37(12):1132-56. doi: 10.1111/apt.12324. Epub 2013 May 3. PMID: 23638982.
    10. Moulin D, Boulanger A, Clark AJ, Clarke H, Dao T, Finley GA, Furlan A, Gilron I, Gordon A, Morley-Forster PK, Sessle BJ, Squire P, Stinson J, Taenzer P, Velly A, Ware MA, Weinberg EL, Williamson OD; Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014 Nov-Dec;19(6):328-35. doi: 10.1155/2014/754693. PMID: 25479151; PMCID: PMC4273712.
    11. Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005 Jun;33(3):311-22. doi: 10.1177/0310057X0503300306. PMID: 15973913.
    12. Rakoski M, Goyal P, Spencer-Safier M, Weissman J, Mohr G, Volk M. Pain management in patients with cirrhosis. Clin Liver Dis (Hoboken). 2018 Jul 26;11(6):135-140. doi: 10.1002/cld.711. PMID: 30992804; PMCID: PMC6385960.
    13. Rogal SS, Winger D, Bielefeldt K, Szigethy E. Pain and opioid use in chronic liver disease. Dig Dis Sci. 2013 Oct;58(10):2976-85. doi: 10.1007/s10620-013-2638-5. Epub 2013 Mar 20. PMID: 23512406; PMCID: PMC3751995.
    14. Schweighardt AE, Juba KM. A Systematic Review of the Evidence Behind Use of Reduced Doses of Acetaminophen in Chronic Liver Disease. J Pain Palliat Care Pharmacother. 2018 Dec;32(4):226-239. doi: 10.1080/15360288.2019.1611692. Epub 2019 Jun 17. PMID: 31206302.
    We gratefully acknowledge the Physician Learning Program for their design assistance.

    Nausea & Vomiting

    Top tips:

    1. Nausea and vomiting are less common than other GI symptoms in cirrhosis however can be experienced in a significant number of patients
    2. Nausea originates from GI or CNS receptor stimulation
    3. Always rule out constipation and dehydration and treat them if they are present
    4. Be aware that nausea and vomiting can impact nutritional intake
    Dr. Sarah Burton McLeod

    Check out the bottom of the page for short videos from Dr. Sarah Burton-Macleod!

    Expand all Collapse all
    Step 1: Consider potential contributing causes and treat appropriately
    The more common causes of nausea in this population include the following:

    The more common causes of nausea in this population include the following:

    • Constipation
    • Ascites
    • Medications e.g. opioids, SSRI antidepressants, antidiabetic meds, beta-blockers, etc.
    • llicit substances
    • Gastroparesis/ileus
    • Acute GI infections (eg gastroenteritis), or other infections
    Rule out a bowel obstruction with an abdominal X-ray if you suspect this as the cause of N/V

     

    Step 2: Consider non-pharmacological therapies
    • Non-pharmacological measures should be considered in all patients where the symptom is having a significant impact on quality of life or ability to function.
    • Nutritional intake may be impacted by chronic nausea and vomiting (see Nutrition page CCAB)
    • Provide patients with the Nausea/Vomiting Patient handout (link after developed).

     

    Changing habits
    • Avoid constipation (LINK to CCAB Constipation page)
    • Encourage good oral hygiene
    • Eater smaller amounts of food slowly and more frequently
    • Drink fluids 30-60 mins prior to meals
    • Avoid foods that are greasy, spicy, or excessively sweet
    • Do not drink alcohol
    Changing environmental factors
    • Minimize triggering aromas (cooking odours, perfumes, smoke, etc)
    • Suggest loose fitting clothing
    • Apply a cool, damp cloth to the forehead or nape of neck
    Complementary treatments
    • Relaxation, acupressure or acupuncture
    • Ginger has been shown to be a promising therapy across clinical studies though the target dose remains unclear. Tablets or real ginger can be used.

     

     

     

    Step 3: If nausea persists, consider Pharmacological therapy
    Lifestyle modification

    These medications should be considered in patients with chronic, persistent nausea.

    The primary goal of therapy is to balance symptom control with the careful protection of physical function and cognition. Be aware that many anti-nausea medications can cause QTc prolongation.

    When choosing an anti-emetic consider the following:

    1. Etiology of the nausea (GI versus opioid/centrally induced).
    2. Side effect profile, choosing the medication that won’t worsen already present conditions (such as constipation, QTC prolongation)
    3. Cost

    Use only ONE of below medications at a time (stop if ineffective, and progress to next line medication).

    Medication: Recommended Dose Additional information
    (Before use, see the product monograph for a complete side effect list)

    Metoclopramide

    5 OR 10 mg PO/SC q6h ATC (often given before meals and Qhs)
    Max: Titrate to effect. Total dose should not exceed 40 mg in 24 hours.

    First line for GI cause.

    • Prokinetic.
    • QTc prolongation, extrapyramidal symptoms.
    • Contraindicated with bowel obstruction.
    • With eGFR between 10-60 mL/min, use 50% of total dose, if eGFR <10 mL/min, use 33% of total dose.
    • Child Pugh B/C max dose 20 mg/day.

    Domperidone

    10 mg PO TID
    Max:30mg in 24 hours

    First line for GI cause, particularly in ambulatory patients with intermittent nausea.

    Haloperidol

    0.5 mg PO/SC q8h ATC and 0.5 mg PO/SC q1 h PRN
    Max: 10mg in 24 hours

    In severe, persistent nausea use BID ATC and q4h PRN

    First line for opioid induced/centrally induced nausea.
    Second line for GI cause.

    • QTc prolongation, extrapyramidal symptoms.
    • Anticholinergic effects, CNS depression.

    Ondansetron

    4 mg PO q4h PRN
    Max: 8 mg PO TID

    Second line for post-surgical or centrally /medication induced nausea (e.g.) chemotherapy.

    Olanzapine

    2.5 mg PO q4h PRN
    Max: Severe, persistent nausea, can use q8-12 h ATC and q4h PRN

    Second line

    • Lowers seizure threshold.
    • QT prolongation, anticholinergic effects.
    • Sedating. Use only if sedation acceptable/preferred by patient.

    Dimenhydrinate

    25-50 mg PO q4h PRN
    Max: Titrate to effect. Maximum in the product monograph is 400 mg daily, but this is ++ sedating and needs to be used with caution.

    Third line

    • Sedating. Use only if sedation acceptable/preferred by patient.

    End of Life Considerations
    • If nausea and vomiting persist despite above treatments, and patient/agent is aware of the potential for increasing sedation, the following titrations can be considered.
    • Again, only use ONE medication at a time, discontinuing the medication before moving onto the next.

     

     Introducing Dr. Sarah Burton-Macleod

    Video 1 – The nausea and vomiting algorithm

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful links:
    1. Alberta Health Services Goals of care
    2. Constipation: http://cirrhosiscare.ca/symptom-management-provider/constipation-diarrhea-hcp/ 
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com
    2. Glare P, Miller J, Nikolova T, Tickoo R. Treating nausea and vomiting in palliative care: a review. Clin Interv Aging. 2011;6:243-59. doi: 10.2147/CIA.S13109. Epub 2011 Sep 12. PMID: 21966219; PMCID: PMC3180521.
    3. Marx W, Kiss N, Isenring L. Is ginger beneficial for nausea and vomiting? An update of the literature. Curr Opin Support Palliat Care. 2015 Jun;9(2):189-95. doi: 10.1097/SPC.0000000000000135. PMID: 25872115.
    4. Palliative care and end-stage liver disease ; 2019; Curr Opin Gastroenterol, 35(3):155-16. PMID: 30925536.
    5. Peng JK, Hepgul N, Higginson IJ, Gao W. Symptom prevalence and quality of life of patients with end-stage liver disease: A systematic review and meta-analysis. Palliat Med. 2019 Jan;33(1):24-36. doi: 10.1177/0269216318807051. Epub 2018 Oct 22. PMID: 30345878; PMCID: PMC6291907.
    We gratefully acknowledge the Physician Learning Program for their design assistance.

    Muscle cramps

    Top tips:

    1. Muscle cramps are common in patients with cirrhosis and can have a significant impact on quality of life (QoL)
    2. The underlying cause of muscle cramps is poorly understood. Potential risk factors include ascites, lower mean arterial pressure, and altered energy metabolism
    3. Identify if there are any modifiable factors that can be treated.
    4. If symptoms are affecting quality of life and function, a trial of pharmacological therapy is reasonable. At this time, pharmacological management recommendations are based on small trials and expert opinion
    2doc

    Check out the bottom of the page for a short video from Dr. Patel!

    Expand all Collapse all
    Step 1: Assess for and address any other potential treatable causes

    There are many non-cirrhosis and cirrhosis causes of muscle cramps.
    If non-cirrhosis causes are suspected, consider specialist referral as appropriate.

    Characteristics of cirrhosis related muscle cramps:
    chronic, involuntary, brief, sudden, intense, worse at night.

     

    Potential contributing factors include
    • Restless legs syndrome (irresistible urge to move or shake the legs)
    • Periodic limb movements,
    • Dystonia,
    • Neurologic disorders, peripheral neuropathy (numbness, tingling),
    • Myalgias, myositis
    • Peripheral vascular disease/claudication, ischemia (deep aching pain, weakness, elevated serum CK), venous insufficiency
    • Motor neuron disorders (abnormal EMG)
    • Anemia
    • Raynaud’s syndrome
    • Opioid withdrawal
    Muscle cramps may also be due to complications of cirrhosis
    • Electrolyte abnormalities: Check potassium, sodium, calcium, magnesium, HCO3, TSH levels, and replete if low.
    • Acid-base disturbances
    • Worsening liver or renal function
    Step 2: Consider non-pharmacological management

    Consider non-pharmacological management in all patients where symptoms significantly impact a patient’s quality of life and function.

    Recommend practical non-pharmacological therapies as a starting point
    • Exercise therapy
    • Passive stretching
    • Deep tissue massage
    Step 3: If symptoms persist, consider Pharmacological management

    Caution: Recommendations are based on small trials and expert opinion

    Medication: Recommended Dose Additional information
    Branched chain amino acids 4 grams PO TID
    • Several small studies show benefit (Vidot 2014)
    • Taste and cost may limit use
    • May be purchased from supplement stores
    Baclofen 10mg PO daily
    Increase by 10 mg PO weekly until at 30 mg PO daily
    • RCT of 100 patients associated with a disappearance of cramps in 72% of patients after 3 months of treatment, without significant side effects (Elfert 2016)
    • Adverse effects may include somnolence and nausea, urinary retention
    Taurine 3 grams PO daily
    • Small, non-randomized studies report benefit
    • May be purchased from supplement stores
    IV Albumin therapy IV 100cc of 25% q weekly
    • Limited data to support this. A single, small RCT showed improvement that stopped once infusions were discontinued (Angeli 1996)

    • Resource heavy
    NOTE: Quinine sulfate (200-300 mg qhs) is not routinely available or recommended. It has been associated with arrhythmias and thrombocytopenia. Tonic water, although often suggested by clinicians only has 83 mg of quinine per liter.

    Special considerations at End-of-life (last few days to weeks)
    Special considerations at End of Life (last few days to weeks)
    • As the patient’s condition deteriorates, muscle cramping may worsen and not be amenable to the above therapies.
    • If muscle cramps are causing significant pain, pain medication may be required (LINK to PAIN CCAB).
    • Discuss with the patient and family that pharmacological therapy may increase drowsiness
    • Consider Palliative Care consultation for refractory symptoms.

     Introducing Dr. Patel

    Video 1 - The top tips that may be useful for you to know about managing muscle cramps

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Arpan Patel, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful Links:
    1. Goals of care: https://www.albertahealthservices.ca/frm-103547.pdf
    2. Exercise Therapy: http://cirrhosiscare.ca/healthy-living-provider/exercise-therapy-hcp/
    3. Pain Control: http://cirrhosiscare.ca/symptom-management-provider/pain-hcp/
    References:
    1. Abd-Elsalam Sherief et al. United European Gastroenterology Journal 2018;6(3) 422-427.
    2. Abd-Elsalam Sherief et al. European Journal of Gastroenterology and Hepatology 2018; 31:499-502.
    3. Abd-Elsalam S, Arafa M, Elkadeem M, Elfert A, Soliman S, Elkhalawany W, Badawi R. Randomized-controlled trial of methocarbamol as a novel treatment for muscle cramps in cirrhotic patients. Eur J Gastroenterol Hepatol. 2019 Apr;31(4):499-502. doi: 10.1097/MEG.0000000000001310. PMID: 30444744.
    4. Angeli P, Albino G, Carraro P, Dalla Pria M, Merkel C, Caregaro L, De Bei E, Bortoluzzi A, Plebani M, Gatta A. Cirrhosis and muscle cramps: evidence of a causal relationship. Hepatology. 1996 Feb;23(2):264-73. doi: 10.1002/hep.510230211. PMID: 8591851.
    5. Elfert AA, Abo Ali L, Soliman S, Zakaria S, Shehab El-Din I, Elkhalawany W, et al. Randomized placebo-controlled study of baclofen in the treatment of muscle cramps in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2016;28:1280-1284. PMID: 27467714
    6. Henry ZH, Northup PG. Baclofen for the treatment of muscle cramps in patients with cirrhosis: A new alternative. Hepatology. 2016 Aug;64(2):695-6. doi: 10.1002/hep.27988. Epub 2015 Aug 22. PMID: 26175073.
    7. Kugelmas M. Preliminary observation: oral zinc sulfate replacement is effective in treating muscle cramps in cirrhotic patients. J Am Coll Nutr. 2000 Feb;19(1):13-5. doi: 10.1080/07315724.2000.10718908. PMID: 10682870.
    8. Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol. 2013 Nov;11(11):1385-91; quiz e80. doi: 10.1016/j.cgh.2013.03.017. Epub 2013 Mar 28. PMID: 23542334.
    9. Peng JK, Hepgul N, Higginson IJ, Gao W. Symptom prevalence and quality of life of patients with end-stage liver disease: A systematic review and meta-analysis. Palliat Med. 2019 Jan;33(1):24-36. doi: 10.1177/0269216318807051. Epub 2018 Oct 22. PMID: 30345878; PMCID: PMC6291907.
    10. Vidot H, Carey S, Allman-Farinelli M, Shackel N. Systematic review: the treatment of muscle cramps in patients with cirrhosis. Aliment Pharmacol Ther. 2014 Aug;40(3):221-32. doi: 10.1111/apt.12827. Epub 2014 Jun 18. PMID: 24942957.
    We gratefully acknowledge the Physician Learning Program for their design assistance.

    Pruritus

    Top tips:

    1. Treat pruritis if it is impairing quality of life or sleep.
    2. Identify additional contributing factors (i.e. extrahepatic biliary obstruction, non-liver causes).
    3. Monitor with validated itch scores.
    4. Non-pharmacological management should be attempted in all patients.
    5. If localized, consider additional topical therapies.
    6. If generalized, systemic treatment may be beneficial.
    2doc

    Check out the bottom of the page for a short video from Dr. Patel!

    Expand all Collapse all
    Step 1: Assess and treat possible contributing factors

    Confirm the diagnosis of cholestatic pruritis

    Liver causes:
    • Consider the etiology of cholestasis with referral made to relevant specialties as required (e.g. Gastroenterology for extrahepatic biliary obstruction, Hepatology for primary biliary cholangitis).
    • Cirrhosis related cholestasis can also cause pruritus.
    • Characteristics of cholestasis associated pruritus: the intensity does not correlate with the severity of underlying liver disease; it has diurnal variation – worse itch in the late evening ; scratching often has little effect on the itch.
    Non-liver causes:
    • Dermatological: xerosis, drug hypersensitivities, allergies, infestations, contact dermatitis
    • Systemic: drug induced, uremia, hypercalcemia, hematologic malignancies- more common in Hodgkin’s lymphoma, multiple myeloma, polycythemia vera
    Step 2: Consider Non-Pharmacological Management

    Non-pharmacological measures should be attempted in all patients prior to considering pharmacological therapy.

    Good skin care and moisturizers are considered first line treatment.
    Some general principles to follow:<
    • Baths are better than showers (daily in lukewarm water for at least 15 minutes)
    • Avoid harsh soaps, body washes, bubble baths, etc. Try gentle, lightweight cleansers (eg. Cerave, Cetaphil- both glycerin based), and only apply to limited areas such as the axilla and the groin
    • Post bath: pat dry and moisturize skin within two minutes of getting out. Skin will still be damp. Ideally use hypoallergenic moisturizers with ceramides (eg. Cerave) that are free from fragrance and additives. Do not use the moisturizers on areas of broken skin.
    • Topical baby oil up to three times a week has shown positive effects on itching, sleep and overall quality of life.
    Other skin care strategies include the following:
    • Keep skin cool by wearing light and cool clothing.
    • Keep skin cool by wearing light and cool clothing.
    • Keep skin cool by wearing light and cool clothing.
    • Avoid scratching – keep fingernails short, encourage massaging rather than scratching, wear gloves at night
    • Maintain a humid home environment, especially in the winter

    See: Itch Patient Handout (in Development)

    Step 3: If pruritis persists AND is LOCALIZED , can consider topical pharmacological treatment
    Over-the-counter creams
    • Benadryl cream, Calamine lotion, Aveeno lotion with oatmeal
    Pramoxine
    • Gold Bond Medicated Anti-Itch products (OTC) – contain pramoxine, dimethicone, menthol
    • Pramox HC (hydrocortisone 1%/pramoxine 1%) – apply two times a day for 4 weeks
    Capsaicin 0.025% cream
    • Can be applied 2-4 times a day to affected areas
    • It may initially cause a burning sensation to the area
    Menthol, Camphor and Phenol
    (Must be compounded by pharmacy)

    • Separate products that can be added to most creams, typically in the range of 0.3-1.0%
    • All three may be added together, commonly with a 0.3% concentration for each, applied 1-2 times daily
    Step 4: If pruritis persists despite topical therapies OR if pruritis is GENERALIZED,
    consider systemic therapies

    Note - Antihistamines have not been systematically evaluated in cirrhosis.

    They may have a non-specific anti-pruritic effect and can be useful adjunctive therapy for some patients. Given their sedating properties they should be administered at nighttime if used. They can worsen hepatic encephalopathy.

    If used, hydroxyzine is used more commonly than Benadryl – start low and titrate to effect.

    Medication: Recommended Dose Additional information

    Cholestyramine

    4g PO before and after breakfast with additional doses at lunch and dinner PRN
    Max: 16 mg/day

    First line

    • Unpleasant taste - mix with fruit juice
    • Affects medication absorption - take meds 1 hr before or 4-6 hours after use
    • Adverse effects: anorexia, constipation, diarrhoea, abdominal discomfort, bloating

    The subsequent therapies should ONLY be initiated with liver specialist guidance. They can be associated with serious side effects. Consultation should also address whether the patient may be a candidate for liver transplantation.

    Rifampicin

    150mg PO daily (titration q 2 weekly to 150-300 mg twice daily if non-response)
    Max: 300mg PO BID

    Second line

    • Check for drug interactions before use
    • Avoid if bilirubin >2.5 mg/dL (43 umol/L)
    • Take on empty stomach - 1 hour prior to meals or 2 hours after meals.
    • Adverse effects: nausea, anorexia, hemolytic anemia, thrombocytopenia, renal impairment, hepatotoxicity

      Monitor CBC and LFTs q2 weeks for first 2 months and monthly thereafter

    Naltrexone

    12.5mg PO daily (titrate by 12.5mg every 3-7 days)
    Max: 50mg/day

    Third line

    Do not use with acute hepatitis, abnormal liver enzymes or decompensated cirrhosis

    Adverse effects: opiate withdrawal-like reactions, reduced threshold to pain, chance of developing hepatitis

    Serially monitor liver enzymes and LFTs given the risk of hepatotoxicity

    Sertraline

    37.5-50mg PO daily
    Max: 50mg PO daily

    Fourth line (Limited evidence for use)

    AVOID in decompensated cirrhosis since it is metabolized by liver

    AVOID in patients taking monoamine oxidase inhibitors (MOA) in previous 14 days

    Adverse effects: bleed risk, QT prolongation

    Serially monitor liver enzymes and LFTs given the risk of hepatotoxicity.

    Alternative salvage therapies
    (at certain specialty centres only)
    1. Ultraviolet B phototherapy
    2. Plasmapheresis
    3. Albumin dialysis using molecular adsorbent recirculating system
    Fifth line (Limited Evidence for use)

    Liver transplantation candidacy should be considered if pruritis is
    severe and uncontrolled.


     Introducing Dr. Patel

    Video 1 - The top tips that may be useful for you to know about managing pruritus

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Arpan Patel, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful Links:
    1. Goals of care: https://www.albertahealthservices.ca/frm-103547.pdf
    2. CKM Itchiness Patient Handout: https://www.ckmcare.com/Resources/Details/135
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
    2. Bhalerao A, Mannu GS. Management of pruritus in chronic liver disease. Dermatol Res Pract. 2015;2015:295891. doi: 10.1155/2015/295891. Epub 2015 Mar 10. PMID: 25861254; PMCID: PMC4377431.
    3. Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic liver disease. Clin Liver Dis. 2012 May;16(2):331-46. doi: 10.1016/j.cld.2012.03.010. PMID: 22541702.
    4. Düll MM, Kremer AE. Treatment of Pruritus Secondary to Liver Disease. Curr Gastroenterol Rep. 2019 Jul 31;21(9):48. doi: 10.1007/s11894-019-0713-6. PMID: 31367993.
    5. European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017 Jul;67(1):145-172. doi: 10.1016/j.jhep.2017.03.022. Epub 2017 Apr 18. PMID: 28427765.
    6. Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, Schwarzer G, Becker G. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev. 2016 Nov 16;11(11):CD008320. doi: 10.1002/14651858.CD008320.pub3. PMID: 27849111; PMCID: PMC6734122.

    We gratefully acknowledge the Physician Learning Program for their design assistance.


    Constipation

    Top tips:

    1. Assess and treat underlying causes of constipation; including opioid induced constipation
    2. An abdominal flat plate can be useful to identify severity of significant fecal loading and rule out bowel obstruction
    3. Non-pharmacological and pharmacological interventions are often required together.
    4. Be aware that constipation may trigger hepatic encephalopathy
    Expand all Collapse all
    Step 1: Consider potential contributing causes and treat appropriately
    Constipation Diagnostic criteriaat least 2 symptoms for at least 3 of the last 6 months:

    ≤ 3 spontaneous BMs per week ; Hard or lumpy stools (Bristol type 1-2), Straining during defecation ; Sensation of incomplete evacuation ; Sensation of anorectal blockage ; Manual maneuvers to facilitate defecation.

    With severe constipation, additional signs and symptoms can include nausea/vomiting, abdominal cramping, distension or overflow diarrhea.

    Consider an abdominal flat plate to assess the severity of constipation and rule out a bowel obstruction. This can also help to determine whether a bowel cleanout is needed prior to starting new bowel regimen.
    More commonly contributing causes

    The more common causes of nausea in this population include the following:

    • Low fiber intake
    • Low fluid intake
    • Medications (e.g. opioids, ondansetron, oral iron supplements, antacids, calcium supplements, beta blockers, diuretics).
    • Metabolic disturbances (e.g. hypercalcemia, hypokalemia, hypothyroidism, diabetes)
    • Pre-existing chronic bowel conditions (e.g. Irritable Bowel Syndrome)
    • Consider Alarm features that may suggest colorectal malignancy
    Step 2: Consider non-pharmacological therapies
    Recommended non-pharmacological therapies (as appropriate)
    • Increasing Fibre intake – if needed, consider referral to a dietitian for nutritional counseling around high fiber foods. Patients should be aware to start low and go up gradually to avoid issues with bloating or gas production (see AHS Constipation handout for patients).
    • Exercise (see CCAB exercise page)
    • Increasing hydration (2.0 L/day for women and 3.0 L for men, provided no fluid restrictions, e.g. with severe hyponatremia)
    • Regular toileting upon waking and post meals

     

    Step 3: If symptoms persist, consider Pharmacological Therapies
    Note: Surfactant laxatives such as Colace have been taken off most formularies due to insufficient evidence.

     

    Bulk Forming Laxatives – First-line

    These are synthetic polysaccharides or cellulose derivatives that absorb water in the gut to increase stool volume and mass. First-line laxatives. Must be taken with adequate fluids. Do not use for opioid-induced constipation.

    Medication: Recommended Dose Additional information
    Psyllium (Metamucil®) 1 tsp daily
    (titrate up as tolerated, following product instructions)
    • Bulk-forming laxative
    • Cramping, bloating, flatus

    Osmotic Laxatives – First-line

    These are poorly absorbable or non-absorbable sugars that increase stool frequency by absorbing water into the bowel. Caution should be applied as excess use can potentially result in volume and electrolyte loss.

    Medication: Recommended Dose Additional information
    (Before use, see the product monograph, for complete side effect list)
    Polyethylene glycol (PEG 3350) 17 grams PO OD dissolved in 250 mL of liquid.
    Max: Titrate to effect or max 68 g/day in divided doses.
    First line if no hepatic encephalopathy
    -Osmotic Laxative
    -Onset of action: within 12 hours
    -Flatus, diarrhea, nausea, abdominal pain, bloating (less than others

    Lactulose 15-30 mL PO OD to TID – starting dose

  • *With constipation, titrate to effect
  • *With hepatic encephalopathy, titrate to
    2-3 soft bowel movements per day
  • First line if hepatic encephalopathy
    -Osmotic Laxative
    -Onset of action: 24-48 hours
    -Abdominal cramping, bloating, flatulence
    -If no bowel movements despite lactulose, consider dysmotility and additional workup.

    Stimulant Laxatives – Second line

    Stimulant laxatives increase intestinal motor activity & alter electrolyte transport. May cause cramping/ nausea
    They should only be used for short-term treatment and not as maintenance therapy unless at end of life.

    Medication: Recommended Dose Additional information
    (Before use, see the product monograph, for complete side effect list)
    Sennosides (Senokot®) 8.6 mg-17.2 mg (1-2 tablets) PO nightly.
    Max: 34.4 mg (4 tablets) PO BID
    -Stimulant laxative
    -Onset of action: 6-24 hours
    - Abdominal cramps, diarrhea, and/or nausea
    Bisacodyl Oral: 5-15 mg PO daily
    Rectal: 10 mg PR daily
    -Stimulant laxative
    -Onset of action: 6-12 hours (oral), 25 min-1 hour (PR)
    -Abdominal cramping, nausea

    Additional Laxative options

    If standard laxatives are ineffective, can see AHS Constipation Primary Care Pathway or talk to GI specialist regarding possible newer therapies (e.g. Secretagogues such as Linaclotide OR Prokinetics such as Prucalopride). These are more costly and may not be covered by existing drug plans.

    In difficult to treat cases, an abdominal flat plate should be carried out in order to identify fecal loading, stool distribution and determine if a full bowel cleanout is needed before starting or changing to a new bowel regimen.

     

    Severe Constipation/Stool impaction

    If there is stool impaction (solid immobile stool in the rectosigmoid), carry out manual fragmentation (if needed), followed by a soap suds enema. Once the stool impaction is cleared, consider a Polyethylene Glycol 3350 (PEG) bowel cleanout.

    PEG Bowel Cleanout: sip on 4 liters slowly over 1-2 days until finished. No dietary changes required. This can be done slowly, with breaks.

     

    Special consideration for Opioid Induced Constipation (OIC)

    If it is evident that constipation is not multifactorial, but caused by opioids only, can attempt treatment per (Fraser Health Document LINK)

    • Always prescribe prophylactic laxatives alongside an opioid prescription. Avoid bulk forming laxatives.
    • While Domperidone and Maxeran can help with constipation in the occasional patient, these prokinetic agents are generally ineffective in the colon
    • Re-evaluate pain scores, response to opioid, and need for current opioid dose.
    • Decrease the opioid dose if possible.
    • If opioid doses are increasing, the dose of laxatives often needs to be increased as well. Evaluate tolerance frequently, holding the laxatives for 1 – 2 days if laxative associated diarrhea occurs

     

    If constipation persists, consider treatment with PAMORAs

    Peripherally acting μ-opioid receptor antagonists (PAMORAs): This class of medications are effective against OIC and has limited ability to cross blood brain barrier (e.g. alvimopan, naloxegol, methylnatrexone, axelopran).

    Adverse side effects include diarrhea, abdominal pain, nausea and vomiting.

    Consider GI specialty consultation if these medications are required.

    Special considerations at End of Life
    Patients continue to produce stool until the last hours of life. Continue stimulant suppositories q3 days if no bowel movement to prevent abdominal discomfort.

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful Links: 
    1. Hepatic Encephalopathy:http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/
    2. Opioid induced constipation: Fraser Health Opioid Induced Constipation
    3. Alberta Health Services Constipation pathway: https://www.albertahealthservices.ca/assets/about/scn/ahs-scn-dh-pathway-constipation.pdf
    4. Alberta Health Services Patient Handout for Managing constipation: https://www.albertahealthservices.ca/assets/info/nutrition/if-nfs-managing-constipation.pdf
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
    2. Pannemans J, Vanuytsel T, Tack J. New developments in the treatment of opioid-induced gastrointestinal symptoms. United European Gastroenterol J. 2018 Oct;6(8):1126-1135. doi: 10.1177/2050640618796748. Epub 2018 Aug 27. PMID: 30288274; PMCID: PMC6169055.
    3. Pantham G, Post A, Venkat D, Einstadter D, Mullen KD. A New Look at Precipitants of Overt Hepatic Encephalopathy in Cirrhosis. Dig Dis Sci. 2017 Aug;62(8):2166-2173. doi: 10.1007/s10620-017-4630-y. Epub 2017 May 30. PMID: 28560484.
    4. Pergolizzi JV Jr, Christo PJ, LeQuang JA, Magnusson P. The Use of Peripheral μ-Opioid Receptor Antagonists (PAMORA) in the Management of Opioid-Induced Constipation: An Update on Their Efficacy and Safety. Drug Des Devel Ther. 2020 Mar 11;14:1009-1025. doi: 10.2147/DDDT.S221278. PMID: 32210534; PMCID: PMC7075239.
    5. Starreveld JS, Pols MA, Van Wijk HJ, Bogaard JW, Poen H, Smout AJ. The plain abdominal radiograph in the assessment of constipation. Z Gastroenterol. 1990 Jul;28(7):335-8. PMID: 2238762.
    We gratefully acknowledge the Physician Learning Program for their design assistance.

    Appetite Loss

    Top tips:

    1. Appetite loss and reduced caloric intake (anorexia) are common in cirrhosis
    2. Consider contributory causes and consider treatment if appropriate depending on patient’s goals of care
    3. If active treatment indicated, consider non-pharmacological therapies first. These include nutrition therapy and exercise.
    4. There is no cirrhosis specific data in support of pharmacological therapy

    Follow this step by step process when dealing with Anorexia in cirrhosis.

    Step 1: Consider potential contributing causes and treat appropriately
    Anorexia is multifactorial, in part related to pro-inflammatory upregulation as liver disease progresses.

    ACCORDION 1.1

    A dietician consult and guidance can help evaluate and improve patient’s nutrition.
    Step 2: Consider non-pharmacological therapies

    Interdisciplinary consultation as appropriate – Dietitian, speech language pathologist, occupational therapist, physical therapist.

    Practical non-pharmacological therapies should be utilized:

    1. Food should be treated as medication- consider setting alarms as reminders to eat
    2. Smaller, more frequent high calorie meals and snacks (q3-4 hourly)
    3. Limit fluid intake when eating to reserve room for food
    4. Avoid drinks that reduce appetite and provide little nutrition such as coffee, tea and water
    5. Liquid nutritional supplements are useful high calorie liquid snacks
    6. Limit intake of spicy, acidic or overly sweet foods
    7. Cold foods may cause less aversion if nausea is an issue

    Initiation of enteral supplementation can be discussed in concert with a Dietitian or Nutrition Specialist.

    Step 3: If anorexia persist, consider Pharmacological therapy if consistent with GOC
    If non-pharmacological therapy alone fails, the risks and benefits of pharmacological therapy need to be discussed with the patient if in keeping with their goals of care.
    There is no data to support the routine use of appetite supplements in the setting of cirrhosis.
    In cancer patients, appetite stimulants have shown only short lived effects, with no survival benefit or improved physical function. Notably, these drugs are associated with side effects.
    ACCORDION 1.2
    Step 4: Special considerations at End of Life (last few days to weeks)
    At End of life, as the patient’s condition deteriorates, anorexia may worsen and may not be amenable to therapy.
    If assistance in managing this is required, a consultation from Palliative Care should be obtained.

    Additional Content:

    For a comprehensive review on breathlessness, please refer to the links below.

    1. Goals of care
    2. Frailty and Malnutrition
    3. Physical Activity
    4. Nutrition Therapy
    5. Constipation
    6. Depression

    References:

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors: —————–, Dr. Puneeta Tandon

    References:

    1. Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition. BMJ 1997;315:1219
    2. Bunchorntavakul C, Reddy KR. Review article: malnutrition/sarcopenia and frailty in patients with cirrhosis. Aliment Pharmacol Ther 2020;51:64-77
    3. Sevastianos VA, Dourakis SP. J Nutr Food Sci 2016;6:2.
    4. Guillaume Economos et.al. What is the evidence for mirtazapine in treating cancer-related symptomatology? A systematic review Supportive Care in Cancer (2020) 28:1597–1606
    5. Zheng , Zheng. The effects of megestrol acetate on nutrition, inflammation and quality of life in elderly haemodialysis patients.  International Urology and Nephrology[0301-1623] yr:2019 vol:51 iss:9 pg:1631-1638
    6. Ruiz García, V . Megestrol acetate for cachexia-anorexia syndrome. A systematic review. Journal of Cachexia, Sarcopenia and Muscle[2190-5991] yr:2018 vol:9 iss:3 pg:444-452
    7. Bolen JC, Andersen RE, Bennett RG. Deep vein thrombosis as a complication of megestrol acetate therapy among nursing home residents. J Am Med Dir Assoc. 2000 Nov-Dec;1(6):248-52
    8. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, Gonzalvez Perales JL, Bort-Martí S. Megestrol acetate for treatment of anorexia-cachexia syndrome. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD004310. DOI: 10.1002/14651858.CD004310.pub

    Depression

    Top tips:

    1. Depression is common in cirrhosis, and should be differentiated from isolated somatic symptoms
    2. Validated tools should be used to screen for depression
    3. Treatment is dependent on the severity.
    4. Treatment options include lifestyle modification, psychotherapy and pharmacotherapy
    5. Limited research exists on the use of antidepressants in cirrhosis. Dose adjustments are often necessary to account for decreased hepatic metabolism
    6. Suicidality and severe depression with loss of function warrant more urgent assessment and treatment
    Mitchell

    Check out the bottom of the page for short videos from Dr. Mitchell!

    Expand all Collapse all
    Step 1: Apply additional Assessment tools specific for depression:

    Depression is common in patients with cirrhosis. It may predate liver disease or occur as a result of physiological or psychological changes associated with the illness process.

    There are a variety of validated screening tools to identify ‘at risk’ individuals. The diagnosis of depression requires a clinical interview.

     

    The Patient Health Questionnaire-9 (PHQ-9)
    It is important to recognize when more urgent assessment is needed

    More urgent assessment and possible admission is warranted in the situations of suicidality, depression with emergent psychotic features (hallucinations or delusions) and/or severe depression with functional impairment.

     

    Step 2: Consider potential contributing causes and treat appropriately

    The diagnosis of depression can be complicated by overlapping somatic symptoms (such as low energy, fatigue, and low appetite)

    Potential contributing factors include
    • Biological: anemia, uremia, neurotoxins and possibly inflammation
    • Comorbidities: diabetes, cardiovascular disease
    • Functional impairment: due to pain, dyspnea, edema or increased abdominal girth, as well as comorbidities such as dementia
    • Treatment-related: medications, pain, fatigue, discomfort, personal or family history of mood disorders
    • Psychological: difficulty with adaptation, role changes, life goals, uncertainty, body image, traumatic experience(s)
    • Social: changes in relationships, job, financial stressors, social roles, intimacy-sex, social isolation, recent move, poverty, cultural or language barriers
    • Lifestyle: lack of exercise, poor nutrition, sleep disturbances

     

     

    Step 3: Consider Non-pharmacological therapies for treatment of mild depression

    Consider non-pharmacological management in all patients with mild depression.

    These therapeutic techniques can be learned using online resources (apps) or bibliotherapy in situations where access to a therapist is difficult.

    CBT and MBSR
    Always weigh the risks and benefits of opioids with the patients in the context of their goals of care.

    Cognitive Behavioral Therapy (CBT) and Mindfulness-Based Stress Reduction (MBSR) are both effective for the management of depression in chronic illness.

     

     

    Step 4: A combination of pharmacological and non-pharm therapies are often needed for moderate-severe depression

    If non-pharmacological therapy alone fails, consider adding pharmacological therapy, especially in cases of moderate to severe depression. There is limited evidence to guide the use of specific antidepressants in cirrhosis.


    For individuals already on an antidepressant, treatment can be continued with dose adjustment.

    For individuals not on an antidepressant, therapy should be selected based on co-existing symptoms

    Selection of an antidepressant should take into account potential interactions with co-existing medication

    • SSRIs and SNRIs need to be dose adjusted by 50% given impaired hepatic metabolism
    • SSRIs may also increase the risk of bleeding, especially if on an antiplatelet agent
    • Desvenlafaxine is the only antidepressant that does not undergo significant metabolism by the liver

    Medication: Recommended Dose Additional information
    (Before use, see the product monograph, for complete side effect list)
    Well-tolerated

    Citalopram (SSRI)

    10 mg PO daily
    Max: 20mg PO daily

    GI bleed risk, can lower seizure threshold, risk of QT prolongation, caution with eGFR <20 mL/min.

    Mirtazapine

    15 mg PO nightly
    Max: 30 mg PO nightly

    Caution with eGFR <30 mL/min (start with 7.5-15 mg, and titrate with close monitoring.
    Sedating.

    Escitalopram (SSRI)

    5 mg PO daily
    Max: 10mg PO daily

    GI bleed risk, can lower seizure threshold, risk of QT prolongation, caution with eGFR <20 mL/min.

    Sleep disturbance

    Sertraline (SSRI)

    25 mg PO daily
    Max: 100mg PO nightly

    GI bleed risk.
    NOT recommended in Child Pugh B/C disease.

    Mirtazapine

    15 mg PO daily
    Max: 30mg PO nightly

    Caution with eGFR <30 mL/min (start with 7.5-15 mg, and titrate with close monitoring.
    Sedating.

    Fatigue/Low energy

    Fluoxetine (SSRI)

    10 mg PO daily
    Max: 20mg PO nightly

    GI bleed risk.

    Venlafaxine (SNRI)

    37.5 mg PO daily
    Max: 112.5mg PO nightly

    GI bleed risk, nausea.
    NOT recommended in Child Pugh B/C disease.

    Desvenlafaxine (SNRI)

    50 mg PO daily
    Max: 100mg PO nightly

    GI bleed risk, nausea.

    Low Appetite/Nausea

    Mirtazapine

    15 mg PO daily
    Max: 30mg PO nightly

    Caution with eGFR <30 mL/min (start with 7.5-15 mg, and titrate with close monitoring.
    Sedating.

    Co-morbid Neuropathic Pain

    Venlafaxine (SNRI)

    37.5 mg PO daily
    Max: 112.5 mg PO nightly

    GI bleed risk, nausea.
    NOT recommended in Child Pugh B/C disease.

    Desvenlafaxine (SNRI)

    50 mg PO daily
    Max: 100 mg PO nightly

    GI bleed risk, nausea.

    Co-morbid Anxiety

    Venlafaxine (SNRI)

    37.5 mg PO daily
    Max: 112.5 mg PO nightly

    GI bleed risk, nausea.
    NOT recommended in Child Pugh B/C disease.

    Desvenlafaxine (SNRI)

    50 mg PO daily
    Max: 100 mg PO nightly

    GI bleed risk, nausea.

    Sertraline (SSRI)

    25 mg PO daily
    Max: 100 mg PO nightly

    GI bleed risk.
    NOT recommended in Child Pugh B/C disease.

    Paroxetine (SSRI)

    10 mg PO daily
    Max: 40 mg PO nightly

    GI bleed risk.

     

     

    Ensure the patient’s symptoms are reassessed, using validated tools listed

    Once initiated, an antidepressant treatment should be re-assessed at 2 weeks using validated questionnaires (e.g. PHQ-9, HADS) to evaluate response.

    If there is no change in symptoms at 2 weeks, there is a low likelihood of remission at 8 weeks, and an adjustment in dose or a change of medication is warranted.

    A full trial of an antidepressant at an effective dose is 6 to 8 weeks.

     

    Consider referral to psychiatrist or mental health specialist
    • Non-response to at least two trials of treatment (at an effective dose for a sufficient duration) OR
    • Severe symptoms and functional impairment.

     

     

     

     Introducing Dr. Mitchell

    Video 1 - The top tips that may be useful for you to know about managing depression

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Nicholas Mitchell, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon, Sarah Tymchuk

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful links:
    1. Patient Health Questionnaire-9 (PHQ-9): https://www.albertahealthservices.ca/frm-19825.pdf
    References:
    1. Barboza KC, Salinas LM, Sahebjam F, Jesudian AB, Weisberg IL, Sigal SH. Impact of depressive symptoms and hepatic encephalopathy on health-related quality of life in cirrhotic hepatitis C patients. Metab Brain Dis. 2016 Aug;31(4):869-80. doi: 10.1007/s11011-016-9817-y. Epub 2016 Mar 31. PMID: 27032930.
    2. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com. 
    3. Mullish BH, Kabir MS, Thursz MR, Dhar A. Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation. Aliment Pharmacol Ther. 2014 Oct;40(8):880-92. doi: 10.1111/apt.12925. Epub 2014 Sep 1. PMID: 25175904.
    4. Wilcock A, Charlesworth S, Prentice W, Selby P, McKenna M, Cripps S, Considine A, Orr A, Wright M, Mihalyo M, Oxberry S. Prescribing in Chronic Severe Hepatic Impairment. J Pain Symptom Manage. 2019 Sep;58(3):515-537. doi: 10.1016/j.jpainsymman.2019.04.034. Epub 2019 May 9. PMID: 31077785.
    We gratefully acknowledge the Physician Learning Program for their design assistance.

    The Safety of Diabetes, Hyperlipidemia, Hypertension and Meds with Cirrhosis

    Pain Medications
    Pain Medications Recommended dose Additional Information
    NSAIDs Refer to Symptom Management→ Pain for dosing and additional information

      Pain – Cirrhosis Care

    Acetaminophen Refer to Symptom Management→ Pain for dosing and additional information

      Pain – Cirrhosis Care

    Opioids Refer to Symptom Management→ Pain for dosing and additional information

      Pain – Cirrhosis Care

    Lipid Lowering Therapies
    Lipid Lowering Therapies Recommended Dose
    Statins Refer to Cirrhosis →Etiology management specific to cirrhosis for dosing and additional information
    Etiology management specific to cirrhosis – Cirrhosis Care

    Ezetimibe Child-Pugh Class A: No dosage adjustment necessary

    Child-Pugh Class B/C: Contraindicated

    Fenofibrate Contraindicated
    Alirocumab (PCSK9 Inhibitor) Child-Pugh Class A/B: No dosage adjustment necessary

    Child-Pugh Class C: Has not been studied

    Evolocumab (PCSK9 Inhibitor) Child-Pugh Class A/B: No dosage adjustment necessary

    Child-Pugh Class C:Has not been studied

    Diabetes Medications
    Diabetes Medications Recommended Dose Additional Information
    Acarbose Contraindicated
    Metformin Initial: 500 mg PO twice daily OR 850 mg PO once daily with meals; may adjust dose in 500 mg increments weekly OR 850 mg every 2 weeks.

    Max: 2550 mg/day

    Use cautiously in those with advanced liver disease, and in patients at risk of lactic acidosis (e.g. patients with renal impairment, alcohol use).
    Contraindicated in hepatic failure.
    Metformin may reduce the risk of hepatocellular carcinoma.
    Rosiglitazone (Thiazolidinedione) Contraindicated
    Pioglitazone (Thiazolidinedione) Contraindicated
    Glyburide (Sulfonylurea) Initial: 2.5 – 5 mg PO once daily

    Max: 20 mg/day

    Contraindicated in Child-Pugh Class C. Least likely sulfonylurea to cause clinically apparent liver injury. Discontinue if the transaminase levels go above 2.5x the upper limit of normal.
    Gliclazide (Sulfonylurea) Initial: 40 – 80 mg PO once daily with breakfast

    Max: 320 mg/day

    Contraindicated in Child-Pugh Class C. Discontinue if the transaminase levels go above 2.5x the upper limit of normal.
    Glimepiride (Sulfonylurea) Initial: 1 – 2 mg PO once daily

    Max: 8 mg/day

    Contraindicated in Child-Pugh Class C. Discontinue if the transaminase levels go above 2.5x the upper limit of normal.
    Repaglinide Initial: If HbA1c < 8%, 0.5 mg PO within 30 minutes before a meal, 2 to 4 times daily. If HbA1c > 8%, 1 – 2 mg PO within 30 minutes before a meal, 2 to 4 times daily.

    Max: 4 mg/dose (16 mg/day).

    Do not take dose if meal is skipped.

    Use with caution. Consider longer intervals between dosage adjustments. Increased risk of hypoglycemia in patients with hepatic dysfunction.
    Nateglinide Initial: 60 mg PO three times daily, within 30 minutes before a meal.

    Max: 120 mg PO three times daily, within 30 minutes before a meal.

    Use with caution. Consider longer intervals between dosage adjustments. Increased risk of hypoglycemia in patients with hepatic dysfunction. Theoretically safer than repaglinide based on pharmacokinetic observations from trials.
    Sitagliptin (DPP-4 Inhibitor) Initial: 100 mg PO once daily with or without food DPP-4 inhibitors are minimally metabolized by the liver and are relatively safe in cirrhosis patients.
    Alogliptin (DPP-4 Inhibitor) Initial: 25 mg PO once daily with or without food DPP-4 inhibitors are minimally metabolized by the liver and are relatively safe in cirrhosis patients. However, there have been post-marketing reports of hepatic failure with alogliptin.
    Linagliptin (DPP-4 Inhibitor) Initial: 5 mg PO once daily with or without food DPP-4 inhibitors are minimally metabolized by the liver and are relatively safe in cirrhosis patients.
    Saxagliptin (DPP-4 Inhibitor) Initial: 2.5 mg – 5 mg PO once daily with or without food DPP-4 inhibitors are minimally metabolized by the liver and are relatively safe in cirrhosis patients.
    Liraglutide (GLP-1 Agonist) Initial: 0.6 mg subcutaneous once daily for 1 week; maintenance 1.2 mg once daily. May increase to 1.8 mg/day after at least 1 week of treatment with the 1.2 mg/day regimen.

    Max: 1.8 mg/day

    Use with caution due to limited experience. Few studies have demonstrated that liraglutide may decrease hepatic inflammation, liver fibrosis, and body weight.
    Dapagliflozin (SGLT2 Inhibitor) Initial: 5 mg PO once daily in the morning.

    Max: 10 mg/day

    Studies have demonstrated higher systemic drug levels compared to healthy subjects. Long term efficacy has not been well studied. Use with caution in severe impairment.
    Empagliflozin (SGLT2 Inhibitor) Initial: 10 mg PO once daily in the morning.

    Max: 25 mg/day

    Studies have demonstrated higher systemic drug levels compared to healthy subjects. Long term efficacy has not been well studied. Use with caution in severe impairment.
    Canagliflozin (SGLT2 Inhibitor) Initial: 100 mg PO once daily taken before the first meal of the day

    Max: 300 mg/day (if eGFR < 60 mL/min/1.73 m2, max 100 mg/day)

    Studies have demonstrated higher systemic drug levels compared to healthy subjects. Long term efficacy has not been well studied. Use with caution in severe impairment.
    Ertugliflozin (SGLT2 Inhibitor) Initial: 5 mg PO once daily

    Max: 15 mg/day

    Studies have demonstrated higher systemic drug levels compared to healthy subjects. Long term efficacy has not been well studied. Use with caution in severe hepatic impairment.
    Insulin (many formulations) Patient specific Insulin requirements can change based on the severity of cirrhosis. Decompensated cirrhosis patients have decreased hepatic metabolism and reduced capacity for gluconeogenesis therefore lower doses are required. Compensated patients are predominantly insulin resistant which would potentially require higher doses of insulin.
    Anti-hypertensives
    Antihypertensives Recommended Dose Additional Information
    Non-Selective Beta Blockers Refer to Treatment → Varices for dosing and additional information
    Varices - Cirrhosis Care

    ACE Inhibitors/ARBs Max: 20 mg PO once daily

    Avoid in patients with ascites.
    Nifedipine XL (CCB) Initial: 30 mg PO once daily

    Max: 90 mg/day

    Has not been studied in patients with hepatic dysfunction; use with caution. May cause small transient rises in liver enzymes which will resolve with continued drug use. However, clearance in cirrhotic patients is reduced, leading to increased systemic exposure. Monitor closely for adverse effects/toxicity and consider dose adjustments.
    Amlodipine (CCB) Initial: 2.5 mg PO once daily

    Max: 10 mg PO once daily

    Titrate slowly in patients with cirrhosis/hepatic impairment.
    Felodipine (CCB) Initial: 2.5 mg PO once daily

    Max: 10 mg PO daily

    Diltiazem (CCB) Initial:30 mg PO four times daily (immediate release), or 120 mg PO once daily (extended release)

    Max: 360 mg PO daily

    Increased half-life in patients with cirrhosis therefore use with caution. Mild and significant elevations in hepatic transaminases have been observed, reversible upon discontinuation.
    Verapamil Immediate Release (CCB) Initial: 20 mg PO three times daily

    Max: 480 mg/day in three divided doses

    Max: 360 mg PO daily

    Verapamil Extended Release (CCB) Initial: 100 mg PO at bedtime

    Max: 480 mg/day in one or two divided doses

    Thiazide Diuretics Avoid use in ascites due to risk of hyponatremia
    Furosemide (Loop Diuretic) Refer to Treatment →Ascites for dosing and additional information
    Ascites - Cirrhosis Care
    Spironolactone (Potassium-Sparing Diuretic) Refer to Treatment →Ascites for dosing and additional information
    Ascites - Cirrhosis Care
    Antidepressants
    Antidepressants Recommended Dose Additional Information
    SSRIs Refer to Symptom Management →Depression for dosing and additional information
    Depression – Cirrhosis Care

    SNRIs Refer to Symptom Management →Depression for dosing and additional information
    Depression – Cirrhosis Care

    Amitriptyline (TCA) For depression:

    Initial: 25 mg PO once daily or in divided doses

    Max: 100 mg PO once daily

    Nortriptyline (TCA) For depression:

    Initial: 25 mg PO once daily or in divided doses

    Max: 100 mg PO once daily

    Bupropion (NDRI) Child-Pugh Class A: Manufacturer recommends dose and/or frequency reduction. No specific recommendations provided, however, some experts recommend decreasing initial dose to 50% of usual dose and reducing dosing frequency

    Child-Pugh Class B/C: Max 150 mg every other day.

    Half-life for active metabolites increased 2- to 5-fold in patients with severe hepatic impairment.
    Mirtazapine Refer to Symptom Management →Depression for dosing and additional information
    Depression – Cirrhosis Care
    Sedatives
    Sedatives Recommended Dose Additional Information
    Zopiclone Refer to Symptom Management → Sleep Disturbance for dosing and additional information
    Sleep Disturbance – Cirrhosis Care

    Proton Pump Inhibitors
    Proton Pump Inhibitors Recommended Dose Additional Information
    Esomeprazole Max: 20 mg PO once daily Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing
    Pantoprazole Max: 20 mg PO once daily

    Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing
    Lansoprazole 15 – 30 mg PO once daily

    Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing
    Rabeprazole 20 mg PO once daily

    Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing
    Dexlansoprazole Max: 30 mg PO once daily Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing
    Omeprazole Max: 20 mg PO once daily Consider deprescribing. Algorithm can be found at: Proton Pump Inhibitor (PPI) Deprescribing