Archive for the HCP Category

Sleep Disturbance

On September 17, 2019 / HCP / Leave a comment

Top tips:

Sleep disturbances occur in 27-70% of patients with cirrhosis
Hepatic encephalopathy must be considered in any patient with cirrhosis and excessive daytime sleepiness
Treat if sleep disturbances are impacting the patient’s quality of life and daily functioning
Consider non-pharmacological interventions before pharmacological therapy
At the end of life (last few days or weeks), sleepiness may increase due to disease progression (and/or medications)

Navigation

Assess for sleep disturbance with validated tools
Consider potential contributing causes
Consider non-pharmacological treatment
When to consider pharmacological treatment
Special considerations for End-of-Life
References
Give us feedback

Approach to Symptom Assessment

End-of-Life Considerations

Step 1: Assess for sleep disturbance with validated assessment tools

Hepatic encephalopathy (HE) is the diagnosis of exclusion in any patient with cirrhosis and excessive daytime sleepiness. In patients with cirrhosis and HE, studies of lactulose or rifaximin have demonstrated improved sleep. See HE page for treatment of suspected HE.

If the presentation does not fit with HE, assess sleep health using validated tools

These tools assess difficulty falling and/or staying asleep, or daytime sleepiness

- Sleep Timing and Sleep Quality Screening Questionnaire takes 2 minutes to complete
  Sleep Timing and Sleep Quality Screening Questionnaire
- Epworth Sleepiness Scale measures excessive daytime sleepiness – score of ≥ 11 is abnormal
  Epworth Sleepiness Scale

Step 2: Consider potential contributing causes

Contributing factors

- Cirrhosis complications – e.g., ascites, muscle cramps, pruritus, pain, breathlessness
- Medications/toxins – e.g., diuretics, alcohol use
- Other acute or chronic comorbidities – e.g., obstructive sleep apnea, mood disorders – anxiety/depression, cognitive impairment

Step 3: : Consider Non-pharmacological management

Consider non-pharmacological management in all patients where sleep disturbance is having a significant impact on the patient’s quality of life and ability to function.

Changing habits by promoting good sleep hygiene

Wake up at the same time every morning
Do not go to bed until you feel sleepy
Develop a relaxing bedtime ritual such as taking a warm shower or reading something relaxing before going to bed
Do not “try” to fall asleep
Avoid napping during the day
Avoid caffeine and nicotine in the evening
Avoid treating sleep problems with alcohol
Exercise early in the day. Avoid exercising before bed as this may keep you up at night
Save your bedroom for sleep (and sex) only
Don’t watch television or use mobile phones, tablets or computers in bed as these activate your brain

Changing environmental factors

Keep bedroom dark and cool at night
If you have gone to bed and are unable to sleep, get out of bed and do something relaxing before returning to bed

Complementary treatments

Cognitive and psychological therapies such as mindfulness: evidence supports 4-weeks of mindfulness and supportive group therapy to improve sleep quality and reduce depression scores
Bright-light therapy: to date there are inadequate studies in cirrhosis, but this treatment is promising. Promote bright light exposure in the early hours of the morning and bright light avoidance, including light that comes from mobile phones, tablets or computers in the evening

Step 4: If symptoms persist, weigh the risks and benefits of Pharmacological therapy

Be VERY cautious of using pharmacological interventions, as they increase risks of cognitive dysfunction and falls especially if daytime sleepiness is already present
Use the sleep assessment tools to reassess the effectiveness of medications 2-4 weeks after prescription
Avoid over the counter sleep aids, and benzodiazepines if possible

There is limited evidence for the pharmacological management of sleep disturbances in cirrhosis. Small randomized controlled trials are available for the use of Zolpidem and for Melatonin.

Medication:	Recommended Dose	Additional information
Zolpidem	5mg PO qhs for SHORT term use (<2weeks)	Limited Evidence - 4-week RCT (Sharma 2019) in Child Pugh A/B patients showed increased sleep time and sleep efficiency
Melatonin	3mg PO/SL qhs For SHORT term use (<2 weeks)	Limited Evidence 2 week RCT (De Silva 2020) in Child Pugh A/B patients showed increased sleep quality and decreased daytime sleepiness

Additional Expert opinion based consideration

Formal studies are required to establish the risks and benefits of these medications in cirrhosis.

If this Expert opinion based medications is used, it should only be used short term unless the patient is in their last few months of life when symptom control is the priority.

Medication:	Recommended Dose	Additional information
Zopiclone	3.75-5mg PO qhs For SHORT term use (<2 weeks)	Limited Evidence Based on expert opinion only - In non-cirrhosis patients, this can be helpful with early insomnia (insomnia at the earlier hours of sleep)

Titrate to effect, as per pharmaceutical guidelines (CPS in Canada)

Special considerations at End of Life

As a patient’s condition deteriorates, certain non-pharmacological interventions will become less realistic (e.g. exercise). Energy conservation and restoration will become of utmost importance.
Ensure that If the appropriate supports are in place to assist with activities of daily living and that nursing care is available as needed.
Drowsiness may increase as the end of life approaches due to disease progression (and/or medications). Some families and patients may even prefer increased sleepiness if it makes the patient more comfortable.
Hepatic encephalopathy therapy can be continued during this time if the patient is able to swallow.
The following medications can be considered if the first line pharmacological therapies are ineffective.

Medication:	Recommended Dose	Additional information
Mirtazapine (Remeron)	7.5 mg PO qhs	For use at End of Life For use at End of Life -AVOID if taking tramadol or antidepressants -Added benefit of appetite stimulation and elevated mood
Trazadone	25mg PO qhs Max dose 100mg PO qhs	For use at End of Life-Can be helpful in mid-late insomnia
Quetiapine	12.5-25mg PO qhs Maximum: 50 mg po daily	For use at End of Life QT prolongation, hepatic metabolism

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, Sara Montagnese, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

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

Helpful links:

Hepatic Encephalopathy:http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/
Sleep-wake patterns in patients with cirrhosis: All you need to know on a single sheet. A simple sleep questionnaire for clinical use: https://europepmc.org/article/med/19664835
Epworth Sleepiness Scale (ESS): https://epworthsleepinessscale.com/about-the-ess/

References:

Bajaj JS, Elwood M, Ainger T et al. Mindfulness-based stress reduction therapy improves patient and caregiver-reported outcomes in cirrhosis. Clin Transl Gastronenterol 2017;8(7):e108. PMID: 28749453.
Formentin C, Garrido M, Montagnese S et al. Assessment and Management of Sleep Disturbance in Cirrhsois. Current Hepatology Reports 2018 17:52-69. PMID: 29876197.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991; 14(6):540-5. PMID: 1798888.
Montagnese S et al. Sleep-wake patterns in patients with cirrhosis: All you need to know on a single sheet. A simple sleep questionnaire for clinical use. J Hepatol 2009 51:690-695. PMID: 19664835.
Moore C. Evaluation and management of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients. Clin Liver Dis (Hoboken). 2016 Jan 29;7(1):5-7. doi: 10.1002/cld.516. PMID: 31041016; PMCID: PMC6490243.
Newton JL, Jones DE. Managing systemic symptoms in chronic liver disease. J Hepatol. 2012;56 Suppl 1:S46-55. doi: 10.1016/S0168-8278(12)60006-3. PMID: 22300465.
Sharma MK, Kainth S et al. Effects of zolpidem on sleep parameters in patients with cirrhosis and sleep disturbances: A randomized, placebo-controled trial. Clin Mol Hepatol 2019 Jun; 25(2):199-209. PMID: 30856689.

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

Delirium/agitation (excluding HE)

On September 17, 2019 / HCP / Leave a comment

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.

Navigation

Assess for delirium with validated tools
Consider potential contributing causes
Consider non-pharmacological therapies along with PRN pharmacological therapies
PRN pharmacological therapies
Refractory symptoms
Special considerations at End of Life
References
Give us feedback

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

Expand all Collapse all

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

Alcohol withdrawal (see CCAB Alcoholic hepatitis page)
Benzodiazepine withdrawal
Long-term benzodiazepine use

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

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

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.

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.

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:

Confusion Assessment Method (CAM):
https://www.albertahealthservices.ca/assets/about/scn/ahs-scn-bjh-hf-delirium-screening-tool.pdf
Hepatic Encephalopathy:
http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/

Opioid Toxicity:
https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-peolc-provincial-guideline-for-treatment-opioid-neurotoxicity.pdf

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
Palliative sedation guidelines: http://www.cspcp.ca/wp-content/uploads/2017/11/Palliative-Sedation-Edmonton-Final-Dec-2015.pdf
Palliative care tips/delirium in patients with advanced cancer and those who are imminently dying: https://albertahealthservices.ca/info/Page16872.aspx
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
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
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
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
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
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
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
Oh, E. et. al. Delirium in Older Persons: Advances in Diagnosis and Treatment. 2017. JAMA 318(12): 1161-1174. PMID: 28973626

Pain

On September 17, 2019 / HCP / Leave a comment

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.

Navigation

Consider differential diagnosis
Apply assessment tools specific to pain
Consider non-pharmacological therapies
When to consider pharmacological therapies
Special considerations at End of Life
References
Give us feedback

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

Expand all Collapse all

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.

PEG 3-Item Scale (Pain, Enjoyment and General Activity scale) Adapted from the brief pain inventory, assesses pain intensity and interference
ESAS-r pain rating
More detailed tool: AHS Initial Pain Assessment Tool

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:

Depression
Anxiety
Others (Post-traumatic stress disorder, psychosis)

3.Addiction risk assessment

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

Links to structured screens:
Alcohol use disorder: AUDIT-C (3 questions)
Drug misuse screening: DAST-10 (10 questions)

Screen for opioid risk:

Opioid Risk Tool-revised

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:

- Contributing psychosocial determinants or untreated mental health disorders (see Total Pain Syndrome under Chronic Pain Tips)
- High addiction risk (Opioid risk tool revised Link)
- Uncontrolled hepatic encephalopathy (see CCAB HE page)

-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

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.
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.
Patients usually require subcutaneous medications at the end of life when they lose the ability to swallow.
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

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

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:

General approach to pain: Chronic Pain Tips
Substance use: https://crismprairies.ca/wp-content/uploads/2020/02/Guidance-Document-FINAL.pdf
Fraser Health Symptom tools: https://www.fraserhealth.ca/-/media/Project/FraserHealth/FraserHealth/Health-Professionals/Professionals-Resources/Hospice-palliative-care/SymptomAssessmentRevised_Sept09.pdf
Excellent reference for opioid prescribing for chronic non-cancer pain – Busse JW et al. DOI: https://doi.org/10.1503/cmaj.170363
Alcohol use disorder: AUDIT-C (3 questions)
Drug misuse screening: DAST-10 (10 questions)
Opioid Risk Tool-revised

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

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

Navigation

Consider potential contributing causes
Consider non-pharmacological therapies
When to consider pharmacological therapies if nausea persists
End of Life considerations
Tutorials
References
Give us feedback

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

Click here to view the videos

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

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:

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:

Etiology of the nausea (GI versus opioid/centrally induced).
Side effect profile, choosing the medication that won’t worsen already present conditions (such as constipation, QTC prolongation)
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. Prokinetic. QTc prolongation. Child Pugh B/C contraindicated.
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. Constipating, QTc prolongation. Child Pugh B/C . Max dose 8mg/day
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

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:

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com
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.
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.
Palliative care and end-stage liver disease ; 2019; Curr Opin Gastroenterol, 35(3):155-16. PMID: 30925536.
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

Muscle cramps are common in patients with cirrhosis and can have a significant impact on quality of life (QoL)
The underlying cause of muscle cramps is poorly understood. Potential risk factors include ascites, lower mean arterial pressure, and altered energy metabolism
Identify if there are any modifiable factors that can be treated.
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

Navigation

Assess and address any other potential treatable causes
Consider non-pharmacological management
When to consider pharmacological management
Special considerations at End of Life
Tutorials
References
Give us feedback

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

Click here to view the videos

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

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

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:

Goals of care: https://www.albertahealthservices.ca/frm-103547.pdf
Exercise Therapy: http://cirrhosiscare.ca/healthy-living-provider/exercise-therapy-hcp/
Pain Control: http://cirrhosiscare.ca/symptom-management-provider/pain-hcp/

References:

Abd-Elsalam Sherief et al. United European Gastroenterology Journal 2018;6(3) 422-427.
Abd-Elsalam Sherief et al. European Journal of Gastroenterology and Hepatology 2018; 31:499-502.
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.
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.
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
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.
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.
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.
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.
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

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

Navigation

Assess and treat possible contributing factors
Consider non-pharmacological treatment
When to consider topical pharmacological treatment
When to consider systemic therapy
Tutorials
References
Give us feedback

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

Click here to view the videos

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

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)	Ultraviolet B phototherapy Plasmapheresis 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

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:

Goals of care: https://www.albertahealthservices.ca/frm-103547.pdf
CKM Itchiness Patient Handout: https://www.ckmcare.com/Resources/Details/135

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
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.
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.
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.
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.
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

Assess and treat underlying causes of constipation; including opioid induced constipation
An abdominal flat plate can be useful to identify severity of significant fecal loading and rule out bowel obstruction
Non-pharmacological and pharmacological interventions are often required together.
Be aware that constipation may trigger hepatic encephalopathy

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

Expand all Collapse all

Step 1: Consider potential contributing causes and treat appropriately

Constipation Diagnostic criteria – at 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.

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:

Hepatic Encephalopathy:http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/
Opioid induced constipation: Fraser Health Opioid Induced Constipation
Alberta Health Services Constipation pathway: https://www.albertahealthservices.ca/assets/about/scn/ahs-scn-dh-pathway-constipation.pdf
Alberta Health Services Patient Handout for Managing constipation: https://www.albertahealthservices.ca/assets/info/nutrition/if-nfs-managing-constipation.pdf

References:

Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
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.
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.
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.
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

Appetite loss and reduced caloric intake (anorexia) are common in cirrhosis
Consider contributory causes and consider treatment if appropriate depending on patient’s goals of care
If active treatment indicated, consider non-pharmacological therapies first. These include nutrition therapy and exercise.
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:

Food should be treated as medication- consider setting alarms as reminders to eat
Smaller, more frequent high calorie meals and snacks (q3-4 hourly)
Limit fluid intake when eating to reserve room for food
Avoid drinks that reduce appetite and provide little nutrition such as coffee, tea and water
Liquid nutritional supplements are useful high calorie liquid snacks
Limit intake of spicy, acidic or overly sweet foods
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.

References:

Authors: —————–, Dr. Puneeta Tandon

References:

Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition. BMJ 1997;315:1219
Bunchorntavakul C, Reddy KR. Review article: malnutrition/sarcopenia and frailty in patients with cirrhosis. Aliment Pharmacol Ther 2020;51:64-77
Sevastianos VA, Dourakis SP. J Nutr Food Sci 2016;6:2.
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
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
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
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
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

On September 17, 2019 / HCP / Leave a comment

Top tips:

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

Navigation

Additional assessment tools for depression
Consider potential contributing causes
Mild depression: consider non-pharmacological therapy
Moderate to severe depression: consider pharmacological and non-pharmacological therapies
Reassess using validated tools
References
Tutorials
Give us feedback

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

Click here to view the videos

Knowing your
Patient

Approach to Symptom Assessment

Symptom Management Principles

Drug Dosing
in Cirrhosis

End-of-Life Considerations

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)

PHQ-9 Depression scale calculator

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.

Lifestyle modification

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

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:

Patient Health Questionnaire-9 (PHQ-9): https://www.albertahealthservices.ca/frm-19825.pdf

References:

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.
Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
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.
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

On September 17, 2019 / HCP / Leave a comment

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

Archive for the HCP Category

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Introducing Dr. Sarah Burton-Macleod

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Caution: Recommendations are based on small trials and expert opinion

Introducing Dr. Patel

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

Introducing Dr. Patel

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Constipation Diagnostic criteria – at least 2 symptoms for at least 3 of the last 6 months:

Note: Surfactant laxatives such as Colace have been taken off most formularies due to insufficient evidence.

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

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Appetite loss and reduced caloric intake (anorexia) are common in cirrhosis

Consider contributory causes and consider treatment if appropriate depending on patient’s goals of care

If active treatment indicated, consider non-pharmacological therapies first. These include nutrition therapy and exercise.

There is no cirrhosis specific data in support of pharmacological therapy

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

Anorexia is multifactorial, in part related to pro-inflammatory upregulation as liver disease progresses.

A dietician consult and guidance can help evaluate and improve patient’s nutrition.

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

Practical non-pharmacological therapies should be utilized:

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

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

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.

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Introducing Dr. Mitchell

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