MEDICATIONS IN PERSISTENT PAIN

KRISTIN TYNAN

CLINICAL PHARMACIST

PRINCESS ALEXANDRA HOSPITAL &

METRO SOUTH PERSISTENT PAIN MANAGEMENT SERVICE

AGENDA •Brief revision of opioids

•Opioid conversion tables and how to use them

•Opioid rotation to Tapentadol

•Neuropathic pain and treatments

•Update on the forgotten NSAIDs

THE ANALGESIC TOOL BOX

• Simple analgesics

• Paracetamol/NSAIDs

• Opioids

• Pure/partial agonists/Strong & weak affinity

• Antidepressants

• Anticonvulsants

OPIOIDS

•Codeine•Tramadol•Tapentadol •Morphine•Oxycodone•Buprenorphine (partial agonist)•Hydromorphone

NOT ALL OPIOIDS ARE CREATED EQUAL

• High Fat solubility – such as fentanyl

• VOD

• Onset / Offset Time

• Tissue Accumulation –Methadone

• Mode of Clearance

• Hepatic vs renal (most hepatic)

• Toxic Metabolites

• Analgesic Effects beyond mu receptors

• Noradrenergic ( Tramadol,

Tapentadol)

• NMDA antagonism ( Methadone,

Tramadol)

• mu Receptor agonism

• Pure agonists ( morphine, fentanyl)

• Partial agonist or agonist/ antagonist

(Buprenorphine)

Sedatives (Benzos, sedating antihistamines)

Increase CNS depression, respiratory depression, sedation Increase cognitive impairment

Antiepileptic drugs (egcarbamazepine, phenytoin, phenobarbital, St John’s Wort)

CYP 3A4 inducing affect on, codeine, fentanyl, methadone, tramadol, Decrease opioid serum levels

TCAs Increase the sedative effects of opioidsIncrease of toxic effects (serotonin eg tramadol)Inhibition of morphine glucuronidation

SSRIsFluoxetine and Paroxetine (CYP 2D6, 3A4 inhibitors)

Serotonin toxic effects, tramadol, fentanyl,

Cardiac meds, Amiodarone, Diltiazem, verapamil

Inhibitors of CYP may increase Codeine, fentanyl, methadone, tramadol, Buprenorphine

Anti-infectives Ciprofloxacin can decrease the concentration of opioids (CYP3A4)Macrolides , Azoles and HIV antivirals increase opioid concentration.Rifampicin decreased opioid concentration

INTERACTIONS WITH OPIOIDS

OPIOID ADRS• CNS

• Drowsiness/Sedation

• Cognitive effects

• Impaired coordination, psychomotor fn

• Respiratory Depression

• Dose dependent, avoid with careful titration

• Sleep apnoea

• Gastrointestinal

• Constipation

• Nausea/vomiting

• Immune suppression

• Pruritus – histamine release

• Urinary retention & incontinence

• Endocrine

• Osteoporosis -loss of bone mineral density

• Hypogonadism,

• Psychological impacts, higher rates of depression/mood changes/sleep

• Patients become tolerant

• Hyperalgesia – CNS glial cells

• Dependence, addiction & diversion

OPIOIDS IN THE ELDERLY

• Start low and go slow

• Gastrointestinal absorption slower

• Prolonged effect, constipation

• Distribution

• Increased fat to lean ratio- fat soluble- incr

Vd

• Liver and renal function decline

• Anticholinergic, impaired balance and falls

• Movement disorders, confusion

• Sedation

• Respiratory depression

• High doses, fast titration, Benzos

• Urinary retention

PATIENT SAFETY

Patient information should include;

•Risks and adverse effects

• Understand significance of sedation and actions to take if sedated

• No sedatives, no alcohol

• Risks if driving, operating machinery, making decisions

• Cognitive impairment ~ reduced reaction times, reflexes and

coordination, concentration

•Need for safe storage and disposal of unused opioids

• Don’t give to others

• Keep out of reach of children

PATIENT SAFETY CONT..

• Should always have a combination of approaches (incl non-pharm)

• Analgesics alone are of limited clinical benefit

• Long-term use is not supported by evidence

• If opioids, short-term and (both patient and GP to agree “to assist in improved function/rehabilitation only”)

• Opioid agreement/plan

• Judiciously, risk:benefit and clear exit strategy

Start low, Go slow

Keep it short, Keep it low

FENTANYL

NETTIE’S BRUSH WITH FENTANYL• Nettie, 89 yr old lady presented to hospital for mechanical fall

• Targin 5/2.5mg BD, reg paracetamol with minimal Endone 2.5mg breakthrough

• Team changed to Fentanyl 37mcg/hr Patch on Monday

• Tuesday she became drowsy and confused,

• Deceased to 25mcg/hr patch

• Patient still confused and drowsy

• Continue regular paracetamol 1g QID

• Stopped Fentanyl patch

• Changed back to Targin and titrate according to response

NETTIE’S OPIOID CONVERSION GONE WRONG

• Targin 5/2.5mg BD = transdermal fentanyl 5mcg/hr

• Fentanyl patch 37mcg/hr = Oral Oxycodone 74mg/day

• Fentanyl patch 37mcg/hr = Oral Morphine 111mg/day

FENTANYL

• Highly potent; Lowest patch 12mcg = 40mg Morphine

• High lipid solubility, easily crosses BBB

• Patch absorbs into skin, continues to absorb from the skin hours after patch

removal

• Tolerance is quicker

• Sick unwell/weight loss- mobilise saturated fat stores

• Not for chronic pain or acute pain or opioid naïve

• Many deaths reported incl children and pets (unsafe disposable)

• 2 predominate mechanisms of action: MOR agonist NRI

MOR • Very selective to mu receptors• 10 fold more mu affinity then delta or kappa receptors• 44 fold less affinity to MOR then morphine

NRI • Noradrenaline reuptake leads to increase activity in intrinsic

analgesic pathways in central nervous system

• This is important as it has 44 time less affinity to mu then morphine

• AND it doesn't bind to Delta and Kappa opioid receptors (unlike morphine)

Tapentadol

TAPENTADOL

• Mixed nociceptive and neuropathic

• Available in IR and SR

• 250mg BD max dose

• SR 50mg, 100mg, 150mg, 200mg, 250mg

• PBS [SR formulation only]: Chronic severe

disabling pain 28 tabs 0Rpts

• IR 50mg, 75mg, 100mg [NOT on PBS]

• Minimal risk of serotonin syndrome1

• Less addiction potential compared to

oxycodone

• Metabolised by conjugation and inactive

metabolites excreted by kidneys.

• Drug interactions unlikely with CYP

1. Adv Ther 2018; 35:12-30

META-ANALYSIS OF THREE POOLED PHASE III TRIALS- ADVERSE EVENTS

Lange B et al. Adv Ther 2010 & Baron et al Pain Prac 2015.

TAPENTADOL SIDE EFFECTS

•Dizziness, nausea & vomiting, constipation, somnolence,

fatigue, dry mouth, itch, urinary retention, confusion,

hallucinations, visual disturbances, agitation, mood changes,

tremor, headache

OPIOID EQUIANALGESIC TABLES

• Problematic!!

• assumptions: similar potency at mu receptor, and everyone responds

the same to various opioids.

• Equianalgesia is a measure of equivalence of analgesic effect between

two different opioids No exact “cut-off” or threshold in literature

• NOT mu receptor binding equivalent

• Does not account for the polymorphic variations in metabolism, drug-

drug interactions and drug-disease interactions

Search:

“Opioid calculator”

SO… I WANT TO ROTATE SOMEONE FROM OXYCODONE 30MG BD TO TAPENTADOL

• Good for you!!!

• Oxycodone 30mg BD 90mg morphine OD

• Tapentadol 150mg BD 120mg morphine

• So you stop the oxycodone and start tapentadol 150mg BD

• What so think will happen ??????

• You have increased this persons oral morphine equianalgesia by 1/3

• They get sweaty, cant sleep, irritable, low mood, myalgia

• Eventually get put back on oxycodone

• Now firm in the knowledge that this new drug does not work for

them

AN ALTERNATIVE APPROACH

• We slowly reduce the oxycodone: 20mg BD 10mg BD over a

few weeks

• Same time we start low dose tapentadol – 50mg BD

• We prescribe clonidine 50mcg TDS to reduce any sympathetic

mediated discontinuation symptoms

• As we move forward the Tapentadol dose is slowly up titrated –

ideally never reaching the 150mg BD we previously wanted to

start… with superior analgesia and / or safety

SWITCHING FROM A FENTANYL PATCH?

Fentanyl patch 50mcg 72hourly

• Decrease patch by 12mcg/hr/1-2weekly

• At the same time add 50mg Tapentadol TWICE daily

• Increase Tapentadol every 1-2 weeks,

• Clonidine 50mcg TDS

even slower for some patients

NEUROPATHIC PAIN AND ITS TREATMENTS

• Australian and international guidelines recommend four first-line

medicines for the treatment of neuropathic pain:

• amitriptyline

• duloxetine

• gabapentin

• pregabalin

Finnerup et al. Lancet Neurol 2015; 162–73

eTG-Neurology

UK NICE guidelines

AMITRIPTYLINE NNT=3.6

• TCAs most documented analgesics

• Old and very small studies may lead to overestimation of NNTs

• Amitriptyline mostly investigated

• Nortriptyline less AEs

• Start low doses, effect needs time!

• Indicated & TGA approved for depression & nocturnal enuresis

• Starting dose 10 - 25mg daily

• Increase every 7 days usually to 75mg

• PBS unrestricted [off-label for pain but accepted]

MONITORING ~ AMITRIPTYLINE

• Trial for 2 months (may notice some benefit after 1-2 weeks)

• Anticholinergic-side effects

• Orthostatic hypotension-risk of falls

• Drowsiness

• Confusion

• May precipitate delirium in elderly patients

• Dry mouth

• Constipation

• Urinary retention

SNRI ~ DULOXETINE (NNT=6.4)

• Indicated for (TGA approved)

• Major depressive disorder;

• generalised anxiety disorder; diabetic peripheral neuropathic pain

• PBS-Restricted benefit- Major depressive disorders

• Dose- start 30mg MAX 60mg (pain indications)

• Side effects; nausea, dry mouth, constipation, fatigue

Ref:

Lunn MPT etal. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of

Systematic Reviews 2014, Issue 1

Finnerup etal. Lancet Neurol. 2015 Feb;14(2):162-73

ANTICONVULSANTS

PREGABALIN

GABAPENTIN

GABAPENTIN NNT=6.3• Indicated for (TGA) : Neuropathic pain & partial seizures

• PBS Authority(streamlined) Partial seizures (100caps 5Rpt)

• Repatriation – (phone approval) refractory neuropathic pain

• Dose: 100 mg or 300 mg nocte

• Max of 2400 mg, <3600mg

• BD, TDS

• Use lower doses in elderly

• Renally cleared

• CrCl <30mls/min max dose 300-600mg daily

• CrCl <10mls/min ESRF require only 300mg alt days

PREGABALIN NNT= 7.7 • Indicated for: Neuropathic pain

• PBS restricted for neuropathic pain (streamlined) [The condition must be refractory to treatment with other drugs]

• 56 caps 5Rpt

• Dose: Initial 75mg ONCE nocte [25mg?]

• Twice daily dosing

• 300mg-600mg daily (2 dd doses)

• Renally cleared

• Peak effect can be seen after 2-4 weeks

• Anxiety related pain

MONITORING – GABAPENTIN AND PREGABALIN

• Adverse effects:

• Vertigo, fatigue, sedation, dizziness, tremor, diplopia,

weight gain, myoclonic jerks, ataxia/unsteady gait,

memory problems, impaired concentration, word finding

problems (anomic aphasia), balance problems, elevated

LFTs (longer term)

PREGABALIN IN THE FIRST YEAR

• 294,274 PBS/RPBS patients treated with PBS

subsidised pregabalin

• The PBS/ RPBS expenditure was $60.7 million.

• 2016-2017 PBS/RPBS expenditure was $159 616 588

• Position 8 of top ten drugs by cost to government

• Australian prescriber Dec 2017

https://www.nps.org.au

FURTHER READING…..

NONSTEROIDAL ANTI-INFLAMMATORY MEDICINES

Cox 1 Cox 2

Ibuprofen Celecoxib

Naproxen Meloxicam

Diclofenac

Caution in select patientsElderlyCKDLiver impairment/cirrhosisHTNHFHistory of or active gastric ulcers/bleeding/erosions COPD & Asthma

NSAIDS - MAJOR ADRSSystem Adverse effects Comments

Cardiovascular Rise HTN, Fluid retention, MI, Stroke, CVA death

Use with caution

Gastrointestinal Upper abdo pain,Gastric erosions, ulcers, bleeding(gastric, oesophageal, small bowel)

Risk varies between NSAIDs and doseOTC lower riskLower risk with Celecoxib (not with low dose aspirin)

Renal Renal impairment Risk with elderly, dehydration, ACEI ARB, existing HF, CKD, diuretics other nephrotoxic meds

eTherapeutic Guidelines

2017

ANALGESICS- NON STEROIDAL ANTI-INFLAMMATORY (PRECISION TRIAL)

• Analgesic, antipyretic and anti-inflammatory actions

• Optimum duration is unclear, no intermittent dosing strategy trials

• Long-term not favourable GI, Cardiovasc, renal, platelet function (non-selective and

Coxibs)

• GI adverse effects may be reduced if taken with a PPI?

• Naproxen may have a lower risk of CVA than other nonselective NSAIDs but still has GI

effects (Level1) ?still inconclusive (PRESCISION Trial)

•Bally et al. BMJ 2017;357:j1909

•Bayesian Meta-analysis of individual patient data

•All NSAIDs (higher doses) increased risk of MI (<Rofecoxib)

•Onset of risk occurred in the first week and was greatest in the first month

•Risk did not increase after one month

NSAIDS- UPDATE

Questions?