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Pain Control in Renal Impairment

Dr Aoife Lowney Consultant in Palliative Medicine and

Renal Supportive Care October 2019

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Patients with ESRD have complex pathophysiologic mechanisms that can be

thought of as the confluence of cardiovascular disease, chronic inflammation, and bone disease that collectively drive malnutrition and medical

frailty

TIP

Care for patients with CKD and end-stage renal disease (ESRD) benefits from multidisciplinary

input from nephrology, primary care, and palliative care

TIP

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0 20 40 60 80 100

Weakness

Poor Mobility

Pain

Itch

Difficulty Sleeping

SOB

Drowsiness

Restless Legs

Appetite

Anxiety

Depression

Skin Changes

Nausea

Constipation

Vomiting

Diarrhoea

Mouth Changes

% Reporting

Symptom

Overwhelming

Severe

Moderate

Mild

Figure 1. Bar chart showing the proportion of patients reporting each symptom and the severity of the reported symptom. SOB=shortness of breath.

Lowney et al. Do patient-reported measures of symptoms and health status predict mortality in hemodialysis? An assessment of POS-S Renal and EQ-5D. 2016; 20: 618-30.

Symptom OUR STUDY

Pos-S Renal

% (mean)

COPD, CHF, cirrhosis

% (MSAS-SF) CANCER

% (MSAS-SF)

Lack energy 78% 84 73

Itching 56% 26 27

Shortness breath 55% 86 23

Pain 64% 49 63

Muscle cramps _ - -

Symptom Prevalence

Murtagh et al JPM (in press, 2007), Murtagh et al ACKD 2007 Jan 14 (1), Tranmer et al JPSM 2003 25 (5), Portenoy et al Eur J Cancer 1994 3 (3)

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Musculoskeletal pain was most common (50.5%) and equal in severity to pain associated with peripheral neuropathy and peripheral vascular disease

Pain in hemodialysis patients: prevalence, cause, severity, and management 2003

• Due to Primary Renal Disease (PKD)

• Concurrent Comorbidity (DM PN, PVD, osteoporosis, cancer, degenerative disc disease)

• Disease Consequent Upon Renal Failure (calciphylaxis, renal osteodystrophy, dialysis-related amyloid arthropathy, discitis)

Other Classification

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Multiple Causes of pain are not uncommon

“You see the empty bed” Dr K Durley 24/05/2019

Haemodialysis

• Aging population • Multiple co-morbidities

• Poor Prognosis

Figure 1.4. RRT incidence rates between 1980 and 2016

63,162 adult patients receiving renal replacement therapy in UK (2016)

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2019 Public Concern

New York Times Feb 19th 2019

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• It is reasonable to use familiar conventional opioids such as oxycodone and tramadol at low doses and at longer intervals and monitor of signs of opioid toxicity

Pain Control in Mild to Moderate CKD

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Analgesia for Patients with Severely Impaired Renal Function (CKD IV & V) and ESKD on Renal

Replacement TherapyDraft Guideline

Dr Sreenath Pillai & Dr Aoife Lowney

2. Target Audience

Clinicians managing malignant and non-malignant pain in patients with severely impaired renal function (CKD IV & V) and those on renal replacement therapy

Not intended as a guide to post-operative pain management

Pharmacologic focus

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3. Stakeholder Involvement

• Renal MDT including renal pharmacist

• Palliative Medicine Medicines Management Group including pharmacy and CCG representation

• Pain Team

4. Methods

• A Medline search (using the search words – Chronic renal failure / ESRF / advanced chronic kidney disease / dialysis/haemodialysis / haemodiafiltration / haemofiltration / peritoneal dialysis /analgesia/consensus/consensus development / guideline / policy statement)

• As there are no large RCTs or Systematic reviews, available guidelines were also used to make recommendations

• Renal drug Database and palliative care formulary were also referred for guidance

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5. ASSESSMENT OF PAIN & ASSESSMENT OF RENAL FUNCTION

Assessment

• Chronicity of pain and reversible Factors

• Type of pain and aetiology of pain

• Treatment goals

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Patient Reported Outcome Measures

• POS-S (renal)

• Brief pain inventory

• Short-Form McGill Pain Questionnaire (SF-MPQ)

• Modified Edmonton Symptom Assessment System (mESAS

• Dialysis symptom index (DSI)

Creatinine Clearance v eGFR

• OUH reports renal function in adults based on estimated glomerular filtration rate (eGFR) normalised to a body surface area of 1.73 m2—(MDRD) formula

• The information on dosage adjustment in the BNF is usually expressed in terms of eGFR

• In product literature, the effects of renal impairment on drug elimination is usually stated in terms of creatinine clearance as a surrogate for GFR

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Basic principles of pain management

• ‘By mouth’ (when feasible - Transdermal route/subcutaneous if oral route difficult).

• ‘By the clock’ (at regular intervals & additional breakthrough should be available as PRN)

• ‘For the individual’ (against Individual needs)’

• ‘Attention to detail’ (watch for toxicity and laxatives when using regular opioids).

Basic principles of pain management

• ‘By mouth’ (when feasible - Transdermal route/subcutaneous if oral route difficult).

• ‘By the clock’ (at regular intervals & additional breakthrough should be available as PRN)

• ‘For the individual’ (against Individual needs)’

• ‘Attention to detail’ (watch for toxicity and laxatives when using regular opioids).

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Basic principles of pain management

• ‘By mouth’ (when feasible - Transdermal route/subcutaneous if oral route difficult).

• ‘By the clock’ (at regular intervals & additional breakthrough should be available as PRN)

• ‘For the individual’ (against Individual needs)’

• ‘Attention to detail’ (watch for toxicity and laxatives when using regular opioids).

Basic principles of pain management

• ‘By mouth’ (when feasible - Transdermal route/subcutaneous if oral route difficult)

• ‘By the clock’ (at regular intervals & additional breakthrough should be available as PRN)

• ‘For the individual’ (against Individual needs)’

• ‘Attention to detail’ (watch for toxicity and laxatives when using regular opioids)

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WHO

Step 3

Step 1

Step 2

Paracetamol

NSAIDs with nephrologist agreement

Opioids to Avoid

• Codeine (metabolised to morphine)

• Tramadol (synthetic related to codeine)

• Morphine

• (Oxycodone)

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WHO

Step 3

Step 1

Step 2

Paracetamol

NSAIDs with nephrologist agreement

WHO

Step 3

Step 1

Step 2

(Hydromorphone)

Fentanyl

Alfentanil

Methadone

Bupenorphine

Paracetamol

NSAIDs with nephrologist agreement

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Opioids to Avoid

• Codeine

• Tramadol

• Morphine

• (Oxycodone)

Oxycodone

• Semisynthetic opioid CYP3A4 noroxycodone (active) & CYP2D6 oxymorphone (active)

• Parent drug and active metabolites appear to accumulate in CKD• Recent systematic review -2 studies : adverse events 50% those with

severe CKD v 14% normal renal function (20mg) • Similar analgesic and side effect profile as morphine• HD- study of 20 patients no loss of analgesia

• In the absence of availabilty of hydromorphone: • Recommendations: 1-2mg IR twice a day to start with and titrate up to

maximum of 10mg in 24hrs using short-acting formulation only. • Once pain is controlled consider switching to Transdermal fentanyl or

Buprenorphine. Consult pain/pall med services if encountering difficulties.

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Opioids that are recommended

• (Hydromorphone)

• Buprenorphine

• Fentanyl

• Alfentanil

• Methadone (specialist use)

(Hydromorphone)USA/Canada/Aus/Ire

• Potent μ receptor agonist • Extensive 1st pass to H3G- no analgesic activity

but OIN• H3G removed by HD without a change in pain

scores • Pharmacokinetics parent compound not

substantially altered by CKD ?due to rapid conversion to H3G (trace amounts)

• 0.5mg every 4-6 hrs PO

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Buprenorphine (transdermal)

• Potent semi synthetic opioid & partial μ receptor agonist • Metabolised in liver, eliminated mainly in faeces• Two metabolites: B3G(inactive) and norbuprenorphine (less active)-

excreted through urine• Onset of action: 18-24hrs • Time to peak plasma concentrations: 3 days • Plasma half-life unchanged in CKD (BuTrans): 13-35hrs (after a patch has

been removed & not replaced)• Dialysis- no changes in buprenorphine levels pre & post haemodialysis,

giving stable pain relief • Difficult to reverse with Naloxone due to high mu affinity• Recommendations: Start with 5mcg/hr Patch or Use opioid converting

table to find an equivalent dose –

Fentanyl • Synthetic μ agonist• Compared to Morphine, Fentanyl is 50-100 times potent and 1000

times lipophilic – ideal for transdermal delivery. • Onset of action: 3-23 hrs & steady state plasma concentrations are

achieved in 36-48 hrs • Patients continue to receive the drug up to 24 hours after removal

of patch due to subcutaneous depot • Less histamine release, low incidence of constipation and more

cardiovascular stability than morphine• Poor oral bioavailability. Metabolised in liver (inactive metabolites)

with 5-10% excreted in urine unchanged• No clinically significant accumulation in renal impairment.• Not dialysed (PD/HD)

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Transdermal Opioids• In Opioid Naive patients, please consider

Buprenorphine patches. Because,

• 5mcg/hr Buprenorphine = 10mg Morphine/24 hrs (oral)

• 12mcg/hr Fentanyl = 45mg Morphine/24hrs (oral)

• Usually used when pain is stable.

• DO NOT ADJUST PATCH STRENGTH DAILY.

Alfentanil - Specialist (Palliative

medicine/Pain Team) use only

• Not dialysed

• Recommendations: Opioid of choice for syringe driver use in patients with eGFR<30ml/min/1.73m2. Please consult Palliative Medicine team as per OUH Trust guidelines

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Methadone

• Palliative medicine/Pain/Hospice Use only• Potent synthetic opioid mainly acting at the μ receptor• NMDA antagonist • Hepatic metabolism to inactive metabolites with 20%

excreted unchanged in urine (in anuria excreted in faeces – no accumulation)

• No T1/2 change in CKD but slower release from tissue reservoirs

• Not removed by HD• 1-2mg very 12-24 hours

Adjuvants

• Gabapentin√ (100mg alt days or 100mg after each HD)

• Pregabalin√ (25mg alt days or 25mg after each HD)

• Carbamazepine√

• Amitriptyline (no dose reduction required but 10mg nocte recommended)

• Ketamine (no dose reduction- not studied in HD)

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BREAKTHROUGH PAIN

“A transient exacerbation of pain that occurs eitherspontaneously, or in relation to a specific predictable orunpredictable trigger, despite relatively stable andadequately controlled background pain”

Davies AN (2009). The management of cancer-related breakthrough pain:

European Journal of Pain, 13, 331-8.

Definition

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Breakthrough Cancer Pain

Spontaneous Pain

Incident PainVolitional ( eg Walking)

Non-

volitional

Procedural

Oral Morphine Profile

BTP Profile Overmedication

Pain relief gap

Time (minutes)5 30 60

Pain

In

ten

sity

BTP Profile

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BTcP Therapies: Target Product Profile

• Concentration–time profile that closely mirror the

pain intensity–time profile of the BTcP episode

• Delivery systems with potential to:

– Enhance dissolution

– Enhance absorption

– Minimize the first-pass effect

Fentanyl

Estimated potency of 80 to 100 times that of morphine

1. Anderson R et al. J Pain Symptom Manage. 2001;21:397-400.

2. Pereira J et al. J Pain Symptom Manage. 2001;22:672-687.

BTcP Therapies: Delivery Systems

1998 2006/2008 2009 2008

Oral trans

-mucosal

fentanyl

citrate

OTFC

FENTORA®(US)/

EFFENTORA™(EU)ONSOLIS™

(US) FBSF

Rapinyl™/

Abstral

(EU) SLF

2009

Instanyl™(EU) INFS

2009

Nasalfent ®

(EU) FPNS

Effervescent Buccal

TabletFentanyl Buccal

Soluble Film

Oral

Transmucosal

Lozenge

Intranasal

Fentanyl Spray

Sublingual

FentanylF Pectin

Nasal Spray

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Special Circumstances

Gout:

• Observational studies demonstrate that CKD is the third most common independent risk factor for gout after obesity and hypertension

• Colchicine: Reduce dose by 50% in patients with GFR 10-50ml/min. • GFR <10 : 500mcg, 3-4 times/day (max of 3mg) (7)

HD/PD - Dose as in GFR <10.

• NSAIDs: See earlier discussions.•

• Glucocorticoids: Short course 0.5mg/kg/day.

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• Muscle cramps: – Despite lack of large studies, Quinine remains the

main stay of treatment for dialysis associated muscle cramps. Attention must be given to optimising other factors such as fluid shift and dry weight adjustments. • Quinine sulphate 300mg prior to HD session• Magnesium supplementation

• Restless legs/Itch :– Gabapentin has been found to be useful in restless

legs and also useful in treating itch

Calciphylaxis:

• Mixed nociceptive and neuropathic pain

• Difficult to manage

• Specialist palliative medicine support should be sought early

• For those who don’t respond, consider NMDA receptor antagonists (methadone or Ketamine)

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Quick ReferenceStep 1.

Paracetamol (1g four times daily per orally)

NSAIDs – Usage restricted in anuric dialysis patient, only after discussion with renal team

Topical NSAIDs

Step 2.

Oxycodone (1-2mg twice a day to start with and titrate up to maximum of 10mg in 24hrs. Once pain stabilised, consider switching to buprenorphine/fentanyl patch)

Step 3

Buprenorphine Patch: dose equivalent to previous opioid or start with 5 mcg/hr and change every 7 days

OR

Fentanyl Patch: only when pain is stable ( for dose equivalence use the description/opioid conversion table above )

Step 4. Difficult to control pain or Patient may need Alfentanil or Methadone or Ketamine - Please Contact Pain team Or Palliative Medicine for review

Neuropathic Pain – Consider Adjuvants: Eg.,Gabapentin (see Detailed guidelines)

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