SpR topic: ConstipationMichelle Fleming

SpR teaching21st May 2014

1. Prevalence2. Contributors3. NICE clinical knowledge summary4. Summary tables/doses5. Cochrane review6. Methlynaltrexone7. Latest RCT8. Summary

Focus

Constipation is one of the most common symptoms experienced by patients with advanced progressive illness

The prevalence is estimated at 30 90% depending on the population studied1,2

1 Clark K, Urban K, Currow DC. Current approaches to diagnosing and managing constipation in advanced cancer and palliative care. Journal of palliative medicine. 2010 Apr;13(4):473-6

2 Clark K, Smith JM, Currow DC. The prevalence of bowel problems reported in a palliative care population. Journal of pain and symptom management. 2012 Jun;43(6):993-1000

Prevalence

In palliative medicine it is the 3rd most commonly encountered symptom after pain and anorexia3

Common factors that increase the constipation include hospitalisation, illness and the use of opioids4

More problematic in advanced disease5

3Potter J, et al. Symptoms in 400 patients referred to palliative care services: prevalence and patterns. Palliative medicine. 2003;17:310-4

4Larkin PJ et al. The management of constipation in palliative care: clinical practice recommendations. Palliative medicine. 2008;22:796-807

5Fallon MT et al. Morphine, constipation and performance status in advanced cancer patients. Palliative medicine. 1999;13:159-60

Prevalence

How should I treat constipation? Where possible, alleviate contributing

factors (for example, inadequate diet, dehydration, having to use a bedpan, lack of privacy, anal fissure, painful haemorrhoids, or local tumour)

Treat any faecal loading or impaction

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

NICE April 20136

Causes

Start treatment with a stimulant laxative (such as senna)

Titrate the dose of laxative in order to achieve comfortable defecation without colic. For instance, senna may be titrated up to a maximum dosage of 2–4 tablets (15–30 mg) three times a day

Pharmacological treatment

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

If the person finds it difficult to take the required number of tablets, reduce the dose of senna (for example to 15 mg at night) and add in a softener such as docusate (also a weak stimulant)

Increase the dose of laxative in line with any increase in dose of opioid

Step 2

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

Add an osmotic laxative (such as lactulose or a macrogol) or a surface-wetting laxative (such as docusate, which also softens stools) if colic is a problem.

Adjust the dose of softener to produce a comfortable stool (comfort is more important than the frequency or number of stools)

In a palliative care situation, higher and more frequent doses than specified by the product licence may be needed.

Step 3

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

Avoid: Phosphate enemas (if possible) as they can

sometimes cause water and electrolyte disturbances, especially in people aged 65 years or older, and when co-morbidities are present

Bulk-forming laxatives (e.g. bran, ispaghula), especially in opioid-induced constipation

Paraffin6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

Avoid

Do not carry out rectal interventions (such as enemas, suppositories, or manual evacuation) in people:

On chemotherapy, who may be neutropenic (white blood cell count < 0.5 x 109/ L) and therefore at risk of serious infection

With thrombocytopenia (platelet count < 20 x 109/ L), who are at risk of bleeding

With rectal or anal disease

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

MovicolMovicol®® sachetssachets(polyethylene (polyethylene glycol)glycol)

1 od-tds1 od-tds 8 sachets for 8 sachets for impactionimpaction

1-3 days1-3 days

OsmoticOsmotic

Nb FluidNb Fluid

Docusate Docusate sodiumsodium

(dioctyl(dioctyl®®))

100mg b d100mg b d 200mg TDS200mg TDS 1-3 days1-3 days

Softener

SennaSenna

(Senokot(Senokot®)®)

15mg 15mg (2 (2 tabs/liquid tabs/liquid nocte)nocte)

Max 3 TDSMax 3 TDS 8-12 hrs8-12 hrs

BisacodylBisacodyl

(Dulcolax(Dulcolax®)®)

5mg nocte5mg nocte 20mg20mg 8-12 hrs8-12 hrs

Stimulant

Adapted from Twycross RG, Wilcock A, Charlesworth S, Dickman A (Eds). Palliative Care Formulary, 2nd edn. Oxford: Radcliffe Medical Press, 2002.

If the response to laxatives is insufficient, consider adding in a prokinetic agent such as metoclopramide, domperidone, or erythromycin 250–500 mg four times a day (off-label use). Do not use a pro-kinetic if the person has symptoms of colic

Adjuvants

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

If the person is terminally ill and has not had an adequate response despite these measures, consider the use of a dantron-containing laxative

Seek specialist advice if constipation still persists despite these measures

Combination

6 NICE Clinical Knowledge Summaries. Palliative cancer care : Constipation. April 2013

Combination

Codanthramer Codanthramer

(Danthron + poloxamer)(Danthron + poloxamer)

CodalaxCodalax®®

Caps/suspensionCaps/suspension

25/200mg25/200mg

2 nocte – 2 bd2 nocte – 2 bd

Max 2 tdsMax 2 tds

6-12 hrs6-12 hrs

Nb avoid if incontinent of Nb avoid if incontinent of urine/faeces = rashurine/faeces = rash

Codanthramer strongCodanthramer strong 37.5/500mg37.5/500mg

Consider using when dose Consider using when dose exceeds 2 bdexceeds 2 bd

Peripheral opioid receptor antagonist

Oxycodone/Naloxone (Targin®) Targeting peripheral receptors whilst

sparing central analgesic function through combining oxycodone with naloxone has emerged as a promising approach

3 x Phase III RTC in non-cancer pain 1 x Phase II RTC in cancer pain

Methylnatrexone

Two studies7,8

287 participants Compared SC methylnaltrexone with placebo Methylnaltrexone was found to be more effective than

placebo at inducing a laxation response, and this response was rapid (four to 24 hours)

However, an undisclosed proportion of participants continued to take conventional laxatives during these trials

 7Thomas J, Karver S, Cooney GA. et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced

illness patients. N Engl J Ned 2008;358:2332-23438Slatkin N, Thomas J, Lipman AG, Wilson G, Boatwright ML, Wellman C, et al. Methylnaltrexone for treatment of opioid-

induced constipation in advanced illness patients. Journal of Supportive Oncology 2009;7:39-46

Evidence

The evidence for the efficacy and safety of laxatives in palliative care is very limited

Evidence

A Cochrane systematic review that addressed the use of laxatives for the management of constipation in palliative care found seven studies (n = 616 in total) suitable for inclusion [Candy et al, 2011]9

9 Candy B, Jones L, Goodman ML, Drake R, Tookman A. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Syst Rev 2011; 1:CD003448.

Summary

Lactulose, senna, danthron combined with poloxamer, misrakasneham and magnesium hydroxide combined with liquid paraffin

There is some evidence that methylnaltrexone is effective (in comparison with a placebo) at inducing laxation (bowel relaxation) in patients taking opioids who have not had a good response to conventional laxatives

The evidence in the other studies was more limited due to lack of overlap in laxatives evaluated

Further rigorous, independent trials with longer follow up are needed to evaluate the effectiveness of laxatives, including methylnaltrexone

A randomized, double-blind, placebo-controlled trial (n = 74) compared the use of docusate plus senna (n = 35) with placebo plus senna (n = 39) in adults in a hospice setting over 10 days [Tarumi et al, 2013]10.

There was no significant benefit of docusate plus senna compared with placebo plus senna in the primary outcome measures, which were: stool frequency, volume, consistency

Since cochrane

Malignant/non-malignant Placebo group had mean daily morphine dose 66%

higher than docusate group Dose of senna varied substantially compared with

constant dose of docusate

Tarumi et al, 2013

10Tarumi, Y., Wilson, M.P., Szafran, O. and Spooner, G.R. (2013) Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. Journal of Pain and Symptom Management 45(1), 2-13.

Constipation should be anticipated Bowel regimen initiated with the commencement of opioid In the management of constipation, the combination of a

softener and stimulant laxative is generally recommended The current evidence is too limited to provide evidence-

based recommendations for the choice of laxative and selection should be made on an individual basis

The use of opioid receptor antagonists should be restricted to those patients who treatment is resistant to conventional laxative therapy

CEBM level 5/Recommendation D

Summary

Thank youThank you