OUH pain service Analgesia in renal dysfunction July 2015

The use of opioids in renal and hepatic dysfunction

Basic principles of pain prescribing for patients with chronic kidney disease (CKD):

CONCERN CONSIDER
Drug Accumulation
Many drugs accumulate in CKD, because of reduced renal excretion and hepatic DOSE REDUCTION
metabolism
Drug Toxicity
Accumulation may lead to increased toxicity REGULAR AND FREQUENT REVIEW OF
PRESCRIPTIONS
Slower equilibration
Reduced excretion/metabolism leads to slower equilibration TITRATE DOSES UP/DOWN SLOWLY

Co-morbidities
CKD is associated with multiple comorbidities which affect prescribing SEEK SPECIALIST/SENIOR ADVICE (TEAM
APPROACH)
Specific advice if dialysis or transplant
For patients with CKD Stage 5 including those on dialysis or with a kidney transplant SEE SPECIFIC GUIDANCE (see tables below)

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

Specific considerations for advanced/end-stage renal disease patients:

a) Salt and water restriction: most dialysis patients are restricted to 0.5-1.0L/day of fluid. A 500mg dispersible paracetamol contains
approximately 16 mmol sodium and maximal daily dosing may contribute to thirst and hypertension. Give intravenous analgesics neat or in
reduced volumes where possible.
b) Preservation of venous access: all dialysis patients must have cannulas placed away from potential sites of dialysis venous access (i.e.
avoid the wrist, forearms and antecubital fossae; instead use back of the hands, upper arms and lower limbs).
c) Give opioids with regular laxatives: many dialysis patients are constipated (haemodialysis reduces stool water content) and peritoneal
dialysis works poorly if patients are constipated.
d) Do not use NSAIDs: NSAIDs cause reduced renal perfusion, fluid retention and interact with Cyclosporin/Tacrolimus. Dialysis patients
are at increased risk of gastrointestinal bleeding and most have cardiac disease.

eGFR
CKD stage Description
(ml/min/1.73m2)

>90 1 Normal kidney function

Mildly reduced kidney function. Stages 1 and 2 require another sign of kidney
60-89 2
disease, e.g. persistent proteinuria, haematuria, polycystic kidneys

45-59 3A Borderline elevated creatinine; mild renal impairment

30-44 3B Moderate renal impairment

15-29 4 Moderate to advanced kidney failure

< 15 5 Severe kidney failure all dialysis patients are CKD stage 5

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

Recommended use of opioids in patients with CKD

Opioid Recommended usage Comment

Morphine Use cautiously; adjust dose as appropriate and increase dose Metabolites can accumulate causing increased
interval. Avoid long-acting preparations. therapeutic and adverse effects, which may persist
long after morphine discontinuation
NOT recommended at GFR <50ml/min

Oxycodone Use cautiously with careful monitoring, adjust dose if Metabolites and parent drug can accumulate
necessary. Avoid long-acting preparations causing adverse effects

Codeine Use cautiously; adjust dose as appropriate and increase dose Metabolites can accumulate causing adverse effects.
interval. Increased risk of drowsiness and constipation
(caution with patients on peritoneal dialysis)
NOT recommended at GFR <50ml/min

Tramadol Use cautiously; adjust dose as appropriate and increase dose Accumulation may precipitate seizures
interval

Methadone* Appears safe Metabolites are inactive

Fentanyl* Appears safe, however a dose reduction is necessary No active metabolites and appears to have no added
risk of adverse effects

* Not considered first line therapy

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

 OUH pain service Analgesia in renal dysfunction July 2015

Dosing table for principal oral analgesics

Oral/enteral route STARTING doses by CKD stage
Drug Cautions/Side Effects Interactions Dialysability Comments
CKD 1,2 CKD 3 CKD 4 CKD 5

1g 4-6 hrly Avoid in liver failure:

Removed by HD
Paracetamol normal normal 1g 6-8 hrly increased sodium content in None Available PR and IV
only
(max 4g daily) dispersible formulation

Most
normal, but normal, but normal, but Fluid retention; GI bleeding; CNIs, diuretics,
NSAIDs normal considered not Short courses only
avoid avoid avoid AKI; cardiotoxicity ACEi/ARB, others
dialysed

30 - 60mg Unknown; Individual sensitivity

Constipation, sedation,
Codeine normal 30-60mg 6 hrly 30mg 6 hrly None considered not dependent on P450-
narcosis
4-6 hrly dialysed 2D6 phenotype

50-100mg Possible adjuvant/

Carbamazepine
50-100mg 6 Risk of serotonin syndrome; Removed by antidepressant
Tramadol 50mg 6 hrly 50mg 6-12 hrly induces metabolism;
4-6 hrly (max hrly lowers seizure threshold. HD, not by PD effects. Available IV
it enhances warfarin
400mg daily) and MR

Avoid SR
MAO-Is, Cimetidine, formulations. Needs
Constipation, sedation and Removed by HD,
Morphine 5-10mg 2 hrly 5-10mg 4 hrly 5mg 4 hrly 2.5-5mg 4 hrly (??potentiated by regular review of
narcosis not by PD
ciclosporin) dose. IM/IV dose 30%
of oral.

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

 OUH pain service Analgesia in renal dysfunction July 2015

MAO-Is. SSRIs inhibit

5mg oral equivalent
metabolism. Removed by
2.5-5mg 4-6 Better tolerated than to 10mg oral
Oxycodone 5mg 4-6 hrly 2.5mg 6 hrly 2.5mg 12 hrly Ciclosporin HD; no data for
hrly morphine morphine. IV dose
bioavailability PD
50% of oral
lowered

Antacids reduce Entirely removed May cause false +ve

0.9-3.6g daily 0.1-0.3g daily
0.4-1.4g per Somnolence, ataxia, weight absorption. Seizure by HD - needs dipstick proteinuria
in 3 divided 0.2-0.7g once
Gabapentin day in 2 divided gain, hypo/hyperglycaemia, threshold lowered by dosing post-HD.
doses (usually daily (or alt die after
doses reversible renal deterioration SSRI, TCA, MAO-Is, Probably removed Start at lowest dose
2.4g) haemodialysis)
antimalarials by PD and uptitrate

Antiarrhythmics,
Antimuscarinic (dry mouth, Introduce/withdraw
50-200mg anticonvulsants, Not considered
Amitriptyline normal normal normal constipation, urinary gradually (avoids
daily antipsychotics, dialysable
retention) postural BP change)
warfarin, others

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

Recommended use of opioids in dialysis patients

Opioid Recommended usage Comment

Morphine Use cautiously and monitor patient Both parent drug and metabolites can be removed by
for rebound pain effect dialysis; watch for rebound pain

Oxycodone Use cautiously and monitor patient Removed by dialysis

for rebound pain effect

Codeine Use cautiously The parent drug and metabolites can accumulate causing
adverse effects

Tramadol Use cautiously and monitor patient Removed by dialysis

for rebound pain effect

Methadone* Appears safe Metabolites are inactive, but use caution because parent
drug is not dialyzed

Fentanyl Appears safe Metabolites are inactive, but use caution because parent
drug is poorly dialyzable

* Not considered first line therapy

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

The following tables are based on information from the Renal Drug Handbook.
[Ashley C & Currie A (eds) The Renal Drug Handbook. 4th edition. Oxford. Radcliffe Medical Press, 2014]

The doses recommended are safe initial doses and must be titrated up (with careful observation) if pain is not controlled.

Patients who have had surgery are likely to need higher doses (guided by the anaesthetist).

Oxycodone is preferred over morphine in renal failure, and tramadol is preferred over codeine.

The eGFR is an estimate and needs to be placed in the clinical context.

If the creatinine is rising steadily over several days, i.e. there is a progressive deterioration in kidney function, one cannot assume that
the dosing recommendations below are accurate.

Similarly, an acutely anuric patient without previous kidney disease will initially have a normal creatinine.

Oligo-anuric patients with acute kidney injury (AKI) have little excretory capacity and should be dosed as per CKD stage 5 (eGFR
<10ml/min) whilst the AKI persists.

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

Recommended dosage adjustments for opioids in renal insufficiency (% of normal dose)

GFR Morphine Oxycodone Codeine Tramadol Methadone Fentanyl
(ml/min) (preferred over (preferred over
morphine) codeine)

>50 100% 100% 100% 100% 100% 100%

20-50 75% 100% 100% 100% 100% 100%

10-20 5mg every 4 hours, 100% 30mg every 4 50-100mg every 100% 75%
increase as hours, increase as 8 hours, increase
tolerated tolerated as tolerated

<10 2.5mg every 4 Start with small 30mg every 6 50mg every 8 50% 50%
hours, increase as doses eg 1.25mg 4 hours, increase if hours, increase
tolerated hourly tolerated as tolerated

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018

OUH pain service Analgesia in renal dysfunction July 2015

Dose in patients undergoing renal replacement therapies

Morphine Oxycodone Codeine Tramadol Methadone Fentanyl
(oxycodone (tramadol
preferred) preferred)

CAPD Dose as in Dose as in Dose as in Dose as in Dose as in Dose as in

GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min

HD Dose as in Dose as in Dose as in Dose as in Dose as in Dose as in

GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min

HDF/high Dose as in Dose as in Dose as in Dose as in Dose as in Dose as in

flux GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min GFR<10ml/min

CAV/VVHD Dose as in GFR 10- Dose as in normal Dose as in GFR Dose as in GFR Dose as in Dose as in GFR
20ml/min renal function 10-20ml/min 10-20ml/min normal renal 10-20ml/min
function

Dr Jane Quinlan (with thanks to Dr David Lewis) for review 2018