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International Pain School
Clinical Pharmacology
of Analgesic Medications
& Non-Phramacologcial Treatments
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Contents of this Lecture
(1) Clinical Pharmacology of:
• Paracetamol (Acetaminophen)
• Non-steroidal anti-inflammatory drugs (NSAIDS) /
COX-2 specific inhibitors
• Opioids
• Ketamine
• Drugs used for neuropathic pain
• Local Anaesthetic agents
• Others - Steroids
(2) Non-drug treatments
Clinical Pharmacology includes
• Mechanism of Action
•
•
•
•
Absorption / Elimination of the drug
Indication for use / dosage
Adverse / side effects
Any special precautions that should be taken
Paracetamol
• Paracetamol has been in use for more
than a century
• It has both analgesic and antipyretic action
• However, the exact mechanism of its action is unclear
Absorption / Elimination from the body
•
It is well tolerated when taken orally.
•
On oral administration it is absorbed from the intestine (70%),
stomach and colon (30%)
• The rate of absorption is rapid and depends on the dose
Absorption / Elimination
• The time taken to reach maximum plasma concentration (Tmax)
is 15 - 30 minutes depends on the preparation
• It is available as tablets (adults), suspension
or syrup for children and suppositories
• Tmax is 2 - 3 hours with suppositories
• Bioavailability ranges from 60-90%
Elimination
• Paracetamol is metabolized in the liver and only 2 - 5% is
excreted unchanged
Indications and dosages
• It is used as an analgesic drug for mild to moderate pain
– E.g. Tooth ache / teething pain in children, backpain, joint
and muscle pain, headache, dysmenorrhoea
• Relief of fever in adults and children
Dosage
•
Adults – Up to 1g oral / rectal, every 6 hours ( 4g should not be
exceeded / day
•
Children – Oral / rectal 20 mg / kg – every 6 hours
Side effects
• Paracetamol is well tolerated and has no side effects
at therapeutic doses
• It has good haematological tolerability and does not
alter haemostasis
Caution
• Since it is metabolized in the liver it must be used with
caution / or omitted in the presence of liver
impairment
• In patients with renal impairment, the dose of
paracetamol should be reduced
• Do not exceed 4g/day in adults and 125 mg/ kg in
children
Adverse effects
Hepatotoxicity with an overdose of paracetamol
• This can occur when a patient does not get adequate relief with
paracetamol and decides to take more than the prescribed dose of
a maximum of 4g/day (8 - 10 g / day)
• Intentional overdose (Paracetamol overdose / poisoning is the
leading cause of acute liver failure in the US, UK and Australia)
• Overdose causes acute liver failure, as the elimination pathways
are saturated resulting in elevated levels of toxic metabolites
Adverse Effects
• N-acetylcysteine (NAC) is the antidote for
paracetamol poisoning and it is most effective when
administered within 8 - 10 hours after ingestion
• Renal toxicity – Overdose can cause severe
kidney necrosis
• Allergic reactions are rare
NSAIDs
Non Steroidal Anti-inflammatory Drugs
History of Aspirin
• Salicylate from the bark of the willow tree and was used to
treat fever and rheumatism for centuries
• In the late 19th century, salicylic acid and later
acetylsalicylic acid was synthesized and called aspirin.
• Aspirin was widely used to treat fever and pain till the
availability of other drugs with similar mechanisms of
action. It continues to be used in many parts of the world
Non-Steroidal Anti-inflammatory Drugs
(NSAIDs)
• They are diverse group of compounds which were
later synthesized, with actions similar to that of aspirin
and became known as NSAIDs
• The mechanism of action of aspirin / NSAIDs was
discovered in the 1960’s by Prof Vane, who was
awarded a Nobel prize in Medicine in 1982
Non-steroidal Anti-inflammatory Drugs NSAIDs
• NSAIDs are widely used to treat pain
and inflammation
• They act through inhibition of the two isoforms
of the enzyme cyclooxygenase (COX) – i.e. COX-1
and COX-2
• NSAIDs that act on both the enzymes are known
as non-selective NSAIDs (ns-NSAIDs)
• NSAIDs which act predominantly on the COX-2
enzyme are known as specific COX-2 inhibitors
(also referred to as Coxibs)
The Two Isoforms of COX
• COX-1 is a normal constituent in the body for homeostasis, such
as in:
–
Gastric mucosa – gastric cytoprotection
–
Kidney – Sodium and water balance / renal perfusion
–
Platelets – for aggregation
• COX-2 is induced in the presence of injury and inflammation
• COX-2 is also a normal constituent in the many organs such as:
Kidney, brain, endothelium, ovary and uterus
What happens when there is tissue injury?
Cell wall
injury
Releases
Membrane phospholipids
Phospholipase A2
Arachidonic Acid
COX-1 & COX-2 that is induced with
injury and inflammation, cancer
PGH2 (Prostaglandin H2)
PGD2
PGI2
PGE2
PGF2
Prostaglandins- PGE2 as the most significant
TXA2
Thromboxane
Arachidonic Acid Cascade
Phospholipid from cell membrane
Arachidonic Acid
Cyclo-oxygenase
Lipoxygenase
PGH2
Thromboxane
5-HPETE
Prostaglandins
These inflammatory mediators activate the nociceptors on the Aδ
and c fibres and result in pain and sensitization
Leukotrienes
Arachidonic Acid Cascade
Phospholipid from cell membrane
Arachidonic Acid
NSAIDs / COX-2
inhibitors
Cyclo-oxygenase
Lipoxygenase
PGH2
Thromboxane
5-HPETE
Prostaglandins
Reduce Prostaglandins and Thromboxane, resulting in
reduced pain
Leukotrienes
ns-NSAIDs
COX-2 specific
inhibitors (= Coxibs)
Acetylsalicylic acid (aspirin)
Celecoxib
• Tablet, suppository
• Oral capsules
Ibuprofen
Etoricoxib
• Tablet, suspension for children
• Oral tablets
Indomethacin
Parecoxib
• Tablet
• parenteral
Diclofenac
• Oral tablet, suppositories, parenteral
form available
Mefenamic acid
• Oral tablets
Anti-Pyretics / NSAIDs on the WHO essential
drug list :
• Acetylsalicylic acid (Aspirin)
– Tablet 100 mg to 500 mg
– Suppository 50 mg to 150 mg
• Ibuprofen > 3 months in age
– Tablet 200 mg; 400 mg
– Oral liquid: 200 mg / 5 ml
• Paracetamol
– Tablet 100 mg to 500 mg
– Suppository: 100mg, 250 mg
– Oral Liquid: 125 mg / 5 ml
Absorption and Elimination
• When administered orally, aspirin, ns-NSAIDs and
Coxibs are well absorbed and reach therapeutic
levels within 30 to 60 minutes.
Indications
• Both the ns-NSAIDs and Coxibs have the same efficacy in
postoperative analgesia
– Sole analgesia for day surgery
– Along with opioids for major surgery
• Musculo-skeletal pain – e.g. back pain, joints,
muscle sprains etc.
– Osteoarthritis
– Rheumatoid arthritis
• Not indicated for neuropathic pain
Side effects / Adverse effects
Gastrointestinal effects
•The risk of erosions, ulcers and bleeding is higher with
ns-NSAIDs compared to Coxibs.
•This risk with ns-NSAIDs is also variable with some being
less than others.
• Risk is greater
– In elderly patients
– Those who are also taking aspirin
•Risk can be reduced by adding a proton-pump inhibitor (e.g.
omeprazole) to ns-NSAIDs.
– H2 receptor blockers are not very effective.
Renal effects
• Both COX-1 & 2 are constituent enzymes in the kidney
– Maintain renal perfusion and sodium/water balance
• Both ns-NSAIDs and Coxibs can cause
– Hypertension, odema
– Decrease in creatinine clearance that may be
significant in patients with impaired renal function or
transient hypotension / hypovolaemia in the
postoperative period
Cardiovascular effects
• Some studies have shown that there was a higher risk
of thrombotic cardiovascular events (stroke, heart attack)
when on Coxibs when compared to ns-NSAIDs such
as naproxen
• Other studies have shown that the cardiovascular
events are similar
• Nevertheless, current recommendations are that Coxibs
should not be used in patients with active cardiovascular
disease and a known thrombotic condition
Effect on platelets
• ns-NSAIDs are able to prevent platelet aggregation as
platelets do not have COX-2. There is therefore a potential
for bleeding with ns-NSAIDs
• Coxibs do not prevent platelet aggregation
• ns-NSAIDs should be used with caution in patients who
are already on aspirin
Others
• Some ns-NSAIDs can precipitate asthma is aspirin
sensitive asthmatic patients.
• Coxibs are well tolerated by patients who have aspirin
sensitive asthma
Summary (cont.)
NS-NSAIDs / Coxibs
• Both drugs are effective in providing pain relief for
moderate pain
• The mechanism of action of both groups of drugs is by
inhibiting the COX-2 enzyme that is induced with injury,
inflammation and cancer
• Gastrointestinal side effects are less with coxibs
Summary
NS-NSAIDs / Coxibs
• Coxibs have no effect on platelet aggregation
• Both drugs should be used with caution in patients with
renal impairment and in the elderly
• Coxibs should not be used in patients with active
cardiovascular disease or known thrombotic effects
• Coxibs can be given to patients with aspirin
sensitive asthma
• Both drugs should be used for the shortest period of time
at the lowest dosage
Opioids
Opioids
• Opium alkaloids derived from the opium
poppy has been used for pain relief for centuries
• Morphine was isolated by Sertuner in 1813
• The glass syringe was introduced in 1844
• Since then morphine has been the mainstay in the
management of severe pain
• The term “opioid” is referred to any drug, either natural,
semi-synthetic or fully synthetic, which has actions similar
to morphine
Available Opioids
Natural
• Morphine
• Codeine
Semi-Synthetic
• Hydromorphone
• Oxycodone
• Diacetylmorphine
(heroin)
• Naloxone
(antagonist)
Opioids on the WHO essential drug list
• Morphine
• Codeine
• Tramadol
Fully Synthetic
• Pethidine
(meperidine)
• Tramadol
• Nalbuphine
• Methadone
• Pentazocine
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil
Opioids can be classified as:
• Strong opioids used for severe pain
– Morphine, Oxycodone, Pethidine, Fentanyl
• Weak Opioids used for moderate pain
– Codeine, Tramadol
The analgesic ladder for acute pain
management
Strong opioids
Weak opioids
Mechanism of Action
• Opioids act by binding to opioid receptors
(complex proteins embedded within the cell
membrane of neurons)
There are three different
opioid receptors - µ, δ, κ
µ - most relevant as all
clinically used opioids exert
their action via the
µ -opioid receptor
Opioid receptors are found in the brain
and in the dorsal horn of the spinal cord
Mechanism of Action
• Opioids bind to opioid receptors
• Activate intracellular signaling events
• Leading to reduction in excitability of neurons and
inhibition of pain signals
• Resulting in reduction of pain perception
Opioids can be administered via several
routes
Opioids produce potent analgesia when administered:
• Systemically – oral, Intravenous, intramuscular,
subcutaneous, transcutaneous, per rectal
• Spinally – epidural, intrathecal, intraventricular
Time to peak action and duration of action depends on
the route and dose of the drug
Morphine
• Is the most widely used opioid for the control
of severe pain
• It can be given by all the routes that was described in the
previous slide.
• It is well absorbed when given orally and has a
bio-availability of around 30-35%.
• Bio-availability means the amount of drug that is
available in the systemic circulation after an oral dose
is given.
Oral morphine
Immediate release morphine
• Aqueous / liquid morphine (usually prepared
as 1-2 mg / ml)
• Tablet morphine (10 mg)
• Need to be given every four hours for continuous relief of
severe pain
Sustained Release (SR) Morphine Tablets
• Morphine is released slowly over 12 hours
• 10 mg, 30 mg, 60 mg
• These tablets are given twice a day
Parenteral morphine (10 mg / I ml ampoule)
Intramuscular / subcutaneous morphine
• Onset of Analgesia 15 - 20 min
• Peak action
45 - 90 min
• Duration of action 4 hours
Intravenous route is chosen when rapid control of
severe pain is desired.
Metabolism
The principle pathway of metabolism is conjugation with
glucuronic acid in hepatic and extra-hepatic (kidney) sites
• Morphine -3 and morphine -6 glucuronides that are
excreted mainly by the kidneys
• Morphine should be used with caution in patients with
hepatic and renal impairment
Codeine phosphate – Weak opioid
• Oral tablet 15mg; 30 mg
• Is well absorbed and there is no first pass metabolism
in the liver
• Codeine is metabolized to morphine; which accounts for
its analgesic effect
• 60 mg of codeine has an equi-analgesic effect
of 650 mg aspirin
• Has an anti-tussive effect and is often used in cough mixtures
• Is available in combination with paracetamol
• Cause minimal sedation, nausea, vomiting and constipation
Tramadol – Weak opioid
•
This is also known as an “atypical opioid”
•
It has a dual mechanism of action:
– weak opioid receptor binding properties
– Inhibits the reuptake of serotonin and noradrenaline at the
descending inhibitory pathway
• It is available
– Oral capsule (50 mg)
– Injection – 50 mg / ml – in 2 ml ampoules
• Due to its weak opioid activity it is not placed in the same
schedule as the strong opioids such as morphine
Tramadol
• It is well absorbed when given orally
• Time to effect is around 30 minutes and can last
5 - 6 hours
• Sedation is minimal
• Can cause nausea, vomiting, dizziness
• Abuse potential is minimal
• Is used as a weak opioid, however as it has a dual
mechanism of action – its analgesic efficacy is superior to
codeine – Maximum daily dose is 400 mg
Metabolism
• Tramadol is metabolized by the liver and excreted
by the kidneys
• Tramadol has an active metabolite
(O-desmethyltramadol) – that is also excreted
by the kidney
• The daily dose should be reduced in the presence of
chronic renal failure
Opioid related side effects
• Gastrointestinal
– Nausea and vomiting
– Constipation
• Sedation
• Respiratory depression in overdose
• Pruritus
• Cough suppression (anti-tussive)
Opioid related side effects
• On initiation of opioid therapy, patients frequently report
acute side effects of sedation, dizziness,
nausea and vomiting
• After a few days these symptoms subside except
for constipation
• This is noted in patients with cancer pain
Opioids and Tolerance
Patients can develop tolerance when opioids are used
for an extended period
• E.g. cancer pain; intensive care units
Tolerance is defined as reduction of the pharmacological
effect of an opioid:
• When the same dose produces a lesser effect
• Increasing doses of drug is required to produce
the same effect
• The mechanisms of the development of tolerance
are complex
Physical Dependence and Addiction
Physical dependence is a state of adaptation by the body
with extended use of an opioid
• It is manifested by withdrawal symptoms with abrupt
cessation of the opioid, rapid dose reduction or
administration of an opioid antagonist
Addiction to opioids is drug seeking behaviour where the
person is looking for opioids for its euphoric action rather
than pain relief alone
Ketamine – is on the WHO essential drug list
• It is a phencyclidine derivative
• It has been used to provide anaesthesia for many years
– The side effect of hallucinations has limited its use as
an anaesthetic agent
– Ketamine causes an increase in blood pressure and
heart rate, hence it is used as an induction agent when
a patient is in shock
• It has multiple mechanisms of action
– The main mechanism of action is that of a noncompetitive antagonist at the NMDA receptors
Ketamine
• Routes of administration
– Intravenous
– Intramuscular / Subcutaneous (onset – 10 - 15 min)
– Oral (bioavailability 20%) /
sublingual (30%) / rectal (30%)
• Metabolized by the liver
– Metabolites are about 1/5th as potent as ketamine
Ketamine has potent analgesic properties
• Analgesia
• Low dose ketamine – 0.1 - 0.5 mg / kg / hr can provide
excellent analgesia
– It can reduce opioid requirements in the postoperative
period
– It can be used for the management of neuropathic pain
such as in patients with complex regional pain
syndrome
– As an adjunct for the relief of cancer pain, particularly
for the neuropathic component
Ketamine
• 5mg / kg – IM can be used for painful dressing
change in children
• An anti-sialagogue should be added as it causes salivary
secretions that can cause coughing / laryngospasm
Side effects of ketamine
• Dizziness
• Hallucinations
• Emergence delirium when larger doses are used
– Benzodiazepines can reduce these side effects
• Salivary secretions
– Anti-sialagogues should be used with ketamine
Ketamine and drug abuse
• In recent years, ketamine has been known to be
abused for its “euphoric” effects
• Long term use can lead to cognitive impairment
and memory loss
Drugs for Neuropathic Pain
Neuropathic pain
• Is defined as pain that arises as a result of injury
or disease of the somatosensory system
• Neuropathic pain is not responsive to ns-NSAIDs.
• Poorly responsive to Opioids
Drugs used for treating neuropathic pain
• Amitriptyline
• Carbamazepine
• Sodium valproate
• Gabapentinoids (not on the WHO essential drug list)
Amitriptyline
• Is a tri-cyclic anti-depressant drug
• Used more for the management of neuropathic pain than for
symptoms of depression
• Low dose amitryptyline is a first line drug for
neuropathic pain
• Mechanism of action
– Inhibits the reuptake of noradrenaline and serotonin (thus
increasing these two neurotransmitters) at the descending
inhibitory pathway
– The descending inhibitory tract influences the output of the
neurons in the dorsal horn of the spinal cord
Absorption / Elimination
• Amitriptyline is well absorbed on oral administration
– Bioavailability 30 - 60%
– Effects last 2 - 12 hours
• Metabolized in the liver (de-methylation) and excreted in
the urine
Adverse effects
• Common ones
– Dry mouth, disturbances of visual accommodation
– Constipation and urinary retention
– Light-headedness, drowsiness
• Less common effects
– Cardiac Arrhythmias
It should be used cautiously in the elderly and in those
with a history of cardiovascular disease
Carbamazepine
• Is an antiepileptic drug
• It is currently the drug of choice for the management of
pain in patients with trigeminal neuralgia
• Mechanism of action
– It blocks the frequency and use of the voltage-gated
neuronal sodium channels
– Limits repetitive firing action of action potentials
– There is a proliferation of sodium channels when there
is nerve injury – thus the efficacy of carbamazepine in
patients with neuropathic pain
Side effects
• The most common side effects are neurotoxic and doserelated. They include:
– Drowsiness, diplopia, headache, ataxia, nausea
– Vomiting, dizziness
– These side effects tend to occur within a week of initiation
or dosage increase.
• In chronic therapy, they typically are noticeable
3 - 4 hours after a dose (associated with peak serum
concentrations)
• Systemic effects
– Abdominal pain, diarrhea, hyponatraemia in the elderly
Serious side effects
• Agranulocytosis and aplastic anaemia
• Skin eruptions and life threatening Steven-Johnson’s
syndrome
• Blood tests should be done early in the course of therapy
and patients should be asked to report easy bruising.
Interaction with other drugs
• Carbamazepine is an inducer of CYP450 in the liver
– Efficacy of other drugs are reduced notably e.g.
• Warfarin
• Phenytoin
• Valproic acid
• Some drugs reduce the metabolism of carbamazepine and
therefore increase its plasma level
– Erythromycin
– Cimetidine
– Calcium channel blockers
Local Anaesthetics (LA)
• Lignocaine (short acting) – 0.5%, 1.0%, 2.0% solutions
• Bupivacaine (long acting) – 0.5%
• Both belong to the amide group of LA drugs
• Mechanism of action
– LA drugs act by producing a reversible block to the
transmission of peripheral nerve impulses
– i.e. they block membrane depolarization of all excitable
tissue, in particular the nerves
– This action is on the sodium channels of the peripheral
nerves.
LA drugs
• Can provide both surgical anaesthesia and analgesia
– Depends on the site of administration
– Concentration of the drug used
• Common routes of administration:
– Local infiltration
– Individual nerve block
– Plexus block
– Epidural administration
Absorption / Elimination
• LA drugs are absorbed into the systemic circulation from
the site of administration
– Rate of absorption depends on the site
– Addition of adrenaline can delay absorption
– After absorption, they are distributed rapidly and taken
up by organs
• Metabolized in the liver and excreted by the kidney
• LA cross the placenta, but their effects are of minimal
significance
Systemic toxicity
• If significant amounts of LA drugs are absorbed they can
cause toxicity :
– Nervous system:
• Numbness and tingling over the circumoral area
• Anxiety, Light-headedness, tinnitus
• Loss of consciousness and convulsions
– Heart
• Direct myocardial depression and hypotension
• Vasodilatation
• Cardiac arrest
Systemic toxicity can occur due to:
• Inadvertent intravenous administration of LA drugs
• Overdose if the following limits are exceeded:
– Lignocaine plain – 4 mg / kg
– Lignocaine with adrenaline – 7 mg / kg
– Bupivacaine – 2 mg / kg
Other Drugs (Miscellaneous category)
• Steroids
– Dexamethasone , Prednisone
Dexamethasone
• Is a potent synthetic member of the glucocorticoid
class of steroid drugs
• It acts as anti-inflammatory
• Immunosuppresant
• Can be taken orally and is more potent than the naturally
occurring hormone ‘cortisol’
• Used to reduce pain and inflammation in
– Rheumatoid arthritis
Non-pharmacological treatments
• Both physical and psychological factors affect our
perception of pain. Treatments include:
• Physical
– Rest, Ice (cold), Compression, Elevation of injuries
– Surgery (e.g. draining an abscess / fixing fractures)
– Acupuncture, massage, physiotherapy
– Ultrasound therapy
– Transcutaneous electrical nerve stimulation (TENS)
Psychological treatments
• Adequate explanation
• Reassurance that their pain will be addressed
• Counseling
– Individual
– Family
• This is particularly important when dealing with patients
with cancer pain
• Cognitive Behavioural Therapy (CBT) – for chronic
non-cancer pain
Conclusion –
Adequate control of pain requires:
• An understanding the mechanisms of pain:
– Nociceptive or neuropathic pain
• An understanding of the drugs that help to control it:
– Mechanism of action
– Pharmacokinetics (Absorption and time to onset and peak
action and elimination)
– Side effect profile
This talk was originally prepared by:
Ramani Vijayan, M.D.
Kuala Lumpur, Malaysia
International Pain School
Talks in the International Pain School include the following:
Physiology and pathophysiology of pain
Nilesh Patel, PhD, Kenya
Assessment of pain & taking a pain history
Yohannes Woubished, M.D, Addis Ababa,
Ethiopia
Clinical pharmacology of analgesics
and non-pharmacological treatments
Ramani Vijayan, M.D. Kuala Lumpur, Malaysia
Postoperative – low technology treatment methods
Dominique Fletcher, M.D, Garches & Xavier
Lassalle, RN, MSF, Paris, France
Postoperative– high treatment technology methods
Narinder Rawal, M.D. PhD, FRCA(Hon), Orebro,
Sweden
Cancer pain– low technology treatment methods
Barbara Kleinmann, MD, Freiburg, Germany
Cancer pain– high technology treatment methods
Jamie Laubisch MD, Justin Baker MD, Doralina
Anghelescu MD, Memphis, USA
Palliative Care
Jamie Laubisch MD, Justin Baker MD,
Memphis, USA
Neuropathic pain - low technology treatment methods
Maija Haanpää, MD, Helsinki & Aki Hietaharju,
Tampere, Finland
Neuropathic pain – high technology treatment methods
Maija Haanpää, M.D., Helsinki & Aki Hietaharju,
M.D., Tampere, Finland
Psychological aspects of managing pain
Etleva Gjoni, Germany
Special Management Challenges
Debra Gordon, RN, DNP, FAAN, Seattle, USA
International Pain School
The project is supported by these organizations: