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Multi Modal Analgesia
Analgesic Drugs and
Pharmacology
Richard Craig R.N. B.N. M. Sci. Med (Pain
Mgmt)
Nurse Consultant
Acute Pain Management Service
Christchurch Hospital
Patients benefit from multi modal analgesia
following surgery.
Combinations of analgesic drugs are used to
improve pain relief, reduce the dose of each
analgesic drug and reduce intensity of side
effects.
Types of pain
Nociceptor pain - Somatic
Structures involved – Skin ,muscle,bones and
tissues.
Quality of painpainEasy to localize,stabbing, boring. movement
dependant
Neuropathic pain.
pain.
Structures involved:
Nociceptic system(peripheral nerves,spinal cord
cerebrum)
Quality of pain:
Shooting, lancing, electric shock like, burning.
Nociceptor pain. VISCERAL
Structures involvedinvolved-Parenchymatous
organs,hollow viscera,peritoneum.
Quality of pain:
Difficult to localize,dull, oppressive,colicky.
Neuropathic pain
Structures involved:
Nociceptic system(peripheral nerves,spinal cord,
cerebrum)
Quality of pain:
Shooting,lacinating,electric shockshock-like,burning
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PARACETAMOL
Classes of pain medications
Paracetamol
Non Steriodal Anti Inflammatories(NSAIDs)
Codeine
Tramadol
Opioids
Neuropathic pain options (TCA,Antiepileptics,NMDA
receptor antagonists.)
Topicals
Dosing
Adults:1 gm oral/rectal 4Adults:
4-6 hrly or 1gm IV
(Perfalgen)
Schoolchildren: 5oomg oral/rectal or 500mg IV
Toddlers250mg rectal
Infants 125mg rectal
(General dose formula for single dose:20mg/kg
body weight)
Mild to moderate pain
Onset 1010-30min, peak 1 hr
Duration of action 44-6hrs
Inexpensive, effective drug
High bio availability,well absorbed with low side effect
profile.
Analgesic, antipyretic, weakly anti inflammatory actions.
Adjunct to opioids in severe pain, (opioid sparing).
Significant central action ??cox 3 inhibitor (animal studies)
4gm/24hr P.O. Adult dose (Regular not PRN).
Overdose / hepatic necrosis (alcohol/malnourishment may
also be predisposing factors for hepatotoxicity).
Adverse effects
In therapeutic doses well tolerated, minimal side effects.
Death from overdose rare but does happen.
Hepatotoxicity with overdose caused by metabolite NNacetyl--p-benzoquinone imine(NAPQI).
acetyl
NAPQI normally inactivated by combination with
glutathione then excreted via kidneys.
Excessive dosing paracetamol may exhaust livers
glutathione stores.
Antidote Parvalax.
NSAIDS (Mechanism of action)
Exhibit a spectrum of analgesic antianti-inflammatory
antiplatlet and antipyretic actions.
Inhibit the enzyme cyclocyclo-oxygenase which metabolizes
arachidonic acid to a large number of eicosanoids,
including prostaglandins,prostacycline and
thromboxane.
This mechanism of action explains the wide range of
adverse effects of NSAIDS as eicosanoids have
protective functions in the intestine mucosa,kidney and
are linked to platelet function
Anti-inflammatory effect is related to reduction
Antiof prostaglandins which act as mediators of
inflammation.
Analgesic effect is result of decreased
prostaglandin synthesis in the periphery leading
to decreased sensitization of nociceptors.
Also cyclocyclo-oxygenase inhibition in the CNS
reduces prostaglandin formation in spinal cord
and brain and thereby central sensitization.
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Non Steroidal Anti Inflammatories
(NSAIDS)
RISKS/ DRAWBACKS
Mild to moderate pain (unsuitable as the sole agent
following major surgery but effective after minor
surgery eg day stay/ gynae /dental. Relatively
contraindicated post tonsillectomy)
Anti inflammatory, anti pyretic,, analgesic.
Reduce inflammation by blockade of prostaglandin
synthesis.
Enhance quality of opioid analgesia, opioid sparing,
decrease opioid side effects.
Especially good in dynamic movement pain.
?? Role in malignancy prevention( eg bowel cancer.)
NSAIDS: Being Sensible
Specifically look for contraindications, eg renal status,
asthma, hx stomach ulcers
Restrict duration of NSAID treatment to 2 to 4 days
post op. (STOP DATE)
If recommended doses fail to achieve pain relief
increasing dose is unlikely to help (ceiling effect)
Increasing doses increases risks of adverse
effects,(recommended doses are already maximal)
If one NSAID fails to achieve pain relief swapping to
another is unlikely to help.(unlike opioid rotation).
Patients at high risk
TRAMADOL
Analgesic with minimal sedation, G.I. disturbance, resp.
depression or abuse potential.(Caution still indicated in
pts with Hx drug abuse.)
Weak Mu opioid agonist.(Oagonist.(O-desmethyl Tramadol
metabolite)
Also has spinal and CNS effects via noradrenergic and
serotoninergic pathways.
Therefore both opioid and non opioid analgesic.
Safer than other opioids in higher doses.(although still
possible to cause sedation, resp. depression)
Less constipating than other opioids.
Association with G. I. Ulceration and bleeding (cox 1)
May cause renal dysfunction (extreme caution with elderly)
Asthma in susceptible patients.
Ceiling dose.
Large and individual variation in minimal effective dose,
toxic dose and ceiling dose.
Cox 2s all under a cloud ( no platelet inhibition, increased
risk of stroke M.I. with chronic use).
May cause headache, constipation,cognitive impairment in
elderly.
Expensive.
Aged under 65 yrs and 2 risk factors.
Aged over 65 yrs and one risk factor
Risk Factors.
Hx of peptic ulcer
Hx of GI bleeding
Concomitant use of meds eg anti coags, steriods.
Significant coco-morbidities eg CVD, cirrhosis
Prolonged and high dose NSAID use.
Tramadol Dosing
Can be up to 600mg daily but usually 400mg
maintenance dose (50(50-100mg 44-6hrly)
50mg tramadol approx equal to 60mg codeine
for pain relief.
Onset 1 hour after oral dose.
Peak 22-4 hrs after oral dose.
Duration of analgesia 9 hrs (approx)
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Elderly Patients
DISADVANTAGES
High affinity with nausea.(“Start low and go slow”
may avoid this eg 50mg t.d.s.t.d.s.-100mg qid.)
Parental tramadol produces less analgesia than
equivalent morphine in severe post op pain.
Contraindicated for pts taking SSRIs.
Expensive.
Adverse Effects
Common- nausea, vomiting,
Commontremor,headache,rash,sweating.
More serious reactionsreactionsconfusion,hallucinations,convulsions,serotonin
syndrome,hypertension,hepatic reactions,
warfarin interactions.
Serotonin Syndrome
Diagnosis of Serotonin Syndrome
Requires 3 of the following.
changes in mental state.
agitation.
hyperflexia.
Sweating.
Tremor.
diarrohoea.
Fever.
incoordination.
Over 75 yrs recommended daily max is
300mg/day
50 mg doses may be preferable
Some centres do not favour Tramadol in the
elderly.
Tramadol may cause serotonin syndrome.
Particularly at high doses or in conjunction with
serotonin enhancing agents including
anyidepressants,ondansetron,L dopa, lithium,
and some illegal drugs such as
amphetamines,cocaine,LSD,ecstacy.
Seizures
Tramadol lowers the seizure threshold.
Risk increases with excessive dosing.
Caution in patients with hx of
epilepsy,combination of other drugs which
lower the seizure threshold
(SSRI,opioids,antihistamines).
Other seizure risks eg head injury, alcohol
withdrawl,CNS infections.
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OPIOIDS
NARCOTICS
TERMINOLOGY:
OPIOIDS are drugs which bind to opioid receptors,
this includes agonists such as morphine, pethidine and
fentanyl as well as antagonists such as naloxone.
OPIATES are drugs derived from opium, mostly
morphine, codeine and their families. However it is
commonly, but incorrectly, used to include other opioid
agonists such as pethidine and methadone.
OPIOIDS
CODEINE
Cornerstone of post op pain management for
moderate to severe nociceptive pain. Effective and
inexpensive.
Produce sense of wellbeing and promote sleep.
Act at supraspinal level (brain stem), spinal cord
level(greatest density of opioid receptors around c
fibre terminals in lamina 1 and in substansia
gelatinosa, (70%Mu, 24% delta, 6% kappa)
Peripherally
Oxycodone
OxyNorm=Immediate release tablets.
Full dose absorbed in first 1010-15 mins with peak
effect in 3030-60 mins.
Usually dosed every 44-6 hrs.
OxyContin=Controlled release capsule.
Initial burst release of 40% of dose in first hour.
Remaining 60% of dose releases slowly giving it
a 12 hour duration of action.
Term was originally used for drugs that produced
sleep like state (narcosis), then for drugs (usually
from opium) that both produced pain relief and
sleep like state, it is no longer a medically useful
term because it has been hi jacked into legal circles
and is now often used to include many other drugs
used illegally such as cannabanoids, amphetamines,
etc that have nothing to do with opium.
Analgesic for mild to moderate pain.
Limited use in the management of severe pain.
Undergoes less “first pass” metabolism than oral
morphine.(60% effective orally as parentally)
Once absorbed 10% of codeine is metabolised by
liver to morphine. (CYP(CYP-2D6)
10% of adult population lack this ability therefore
codeine will be ineffective for them.
Probably the most constipating opioid.
Abuse potential.
Oxycodone
What is the difference between
Oxycodone, oxynorm and oxycontin?
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OPIOID RECEPTORS
Opioid drugs act as agonists at opioid receptors located in brain
spinal cord, urinary and G.I.tracts, lung and peripheral nerve
endings.
Three principal types of opioid receptor
Mu, Kappa,Delta.(op3, op2, op1 new classification)
endogenous agonists are BB-endorphins, encaphalins and
dynorphins respectively.
Receptor Actions
Naloxone
Pure opioid antagonist.
Rapidly reverses opioid induced analgesia and
repiratory depression.
Short half life (lasts 11-2 hrs
May require further doses (close monitoring)
Precipitates withdrawal symptoms in opioid
dependant patients.
MuMu- analgesia, resp depression,euphoria,
bradycardia,pruritis, miosis, n+v, physical
dependence,inhibition gut.
Delta-- analgesia
Delta
Kappa-- analgesia,sedation,dysphoria, diuresis
Kappa
Morphine
Gold standard
Mu selective agonist
Least lipid soluble,metabolised by liver, excreted
kidneys.
Can be given IM, IV, SC, oral, transmucosal,
rectal epidural, intrathecal.
Metabolic Toxicity
Oral morphine loses 40% of potency to “first
pass” effect.
Potency of oral morphine to IV is about 3:1
IV provides rapid titration, shortest duration
of action, complete systemic absorption.
Morphine is metabolised by the liver to
morphine--3-glucuronide (M3G) and morphinemorphine
morphine6-glucuronide (M6G)
With impaired renal function M6G may
accumulate and contribute to analgesia and
prolonged sedation.
With high dose morphine administration M3G
may antagonise the action of morphine causing
myoclonic jerks and hyperalgesia.
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Morphine (cont)
Dose required to control pain depends on
many factors, and not related to any one
parameter.
There is no “ceiling dose” or “normal range”
Right dose is that which controls the pain
with fewest side effects.
Breakthrough Doses
Should be short acting and immediate release.
Dose should be appoximately1/6 of daily dose.
Eg MorphineSR 30mg bd Breakthrough
Morphine IR 10mg IR every hour as needed.
The rule of 3! If 3 or more breakthrough doses
are needed in 24 hrs for 3 or more days the SR
dose should be increased.
Pethidine
Mu selective agonist, weak affinity for NMDA
receptor.
Administer IV, IM,oral, rectal, transmucosal,
epidural, intrathecal, (Not SC)
Myocardial depression with larger doses
Metabolised liver, excreted kidneys,
contraindicated if taking MOIs.
Pethidine
Active metabolite norpethidine
Accumulation of norpethidine associated with seizures and
death.
Toxicity will occur in approx 19% of cases where doses exceed
10mg/kg/day OR therapy exceeds 3 days.
Impaired renal function increases half life of norpethidine.
Naloxone does not reverse (and may aggravate) norpethidine
toxicity.
Norpethidine Effects
Agitation
Irritability
Nervousness
Tremors
Twitches
Seizures
Fentanyl
Highly lipid soluble Mu selective agonist
Rapid onset, (peak IV 15 mins)short duration of
action (IV 3030-60mins)
Inactive metabolites so good choice in renal
impairment.
IV, epidural, intrathecal, oral transmucosal
(“lollipop”), transdermal (usually not in acute
pain and caution in elderly)
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Dose Intervals
DOSING
Dosing schedule for opioids needs to be
individualised. (large variation between individuals
5-7 fold.)
Response determined in relation to both efficacy
AND side effects.
Opioid titration (small IV doses) best method for
estimating optimal starting dose. In adult patient.
In adults AGE rather than weight has been shown
to be a better predictor of opioid requirement.
Elderly patients require lower doses of opioids to
achieve an equivalent analgesic effect and effect is
often longer due to age related increase in terminal
elimination half life of opioids.
Speed of onset of opioid will be influenced by
route and lipid solubility.
Time to max blood concentration depends
primarily on administration route.
Time to maximum effect then depends upon the
rate at which the drug crosses to CNS and
opioid receptors.
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