PHARMACOTHERAPY - WRITE UP

Dr. KHAJA JAVED KHAN

INTRODUCTION

Pharmacotherapy alone is rarely optimal therapy for chronic pain. Analgesic pharmacotherapy
often is appropriate alone for acute pain.Chronic malignant and non malignant pain usually
responds better to multimodal treatment.

CLASSIFICATION

DRUGS IN PAIN MANAGEMENT

Analgesics - NSAID, Paracetamol , Opioids.

Co analgesics -

Anti convulsants

Anti Depressants
Local Anaesthetics
Steroid
Muscle Relaxants
Botulinum toxin
NMDA receptor antagonist
Alpha 2 agonist
Calcium chanel blockers.

Individual drugs :

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.The time taken to reach maximum plasma
concentration (Tmax) is 15 - 30 minutes depending on the preparation.Available as tablets (adults),
suspension or syrup for children and suppositories.Tmax is 2 - 3 hours with suppositories.
Bioavailability ranges from 60-90%. Paracetamol is metabolized in the liver and only 2 - 5% is
excreted unchanged.
INDICATIONS
Used as an analgesic drug for mild to moderate pain.Toothache/teething pain in children, back
pain, joint and muscle pain, headache, dysmenorrhoea.Relief of fever in adults and children.

DOSE
Adults – Up to 1g oral / rectal, every 6 hours ( 4g should not be exceeded / day).
Children – Oral / rectal 20 mg / kg – every 6 hour.

SIDE EFFECTS
• Paracetamol is well tolerated and has no side effects at therapeutic doses.It has good
haematological tolerability and does not alter haemostasis

ADVERSE EFFECTS
• Overdose can lead to Hepatotoxicity , acute liver failure.
• N-acetylcysteine (NAC) is an 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

HISTORY OF ASPIRIN
• Salicylate obtained 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 ,pain till the availability of other drugs with similar
mechanisms of action. It is continued to be used in many parts of the world.
• NSAIDs are diverse group of compounds which were later synthesized, with actions similar to
that of aspirin and became known as 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-2NSAIDs 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).

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.

NSAIDs

Acetylsalicylic acid (aspirin)

Tablet, suppository
Ibuprofen
Tablet, suspension for children
Indomethacin
Tablet
Diclofenac
Oral tablet, suppositories, parenteral form available
Mefenamic acid
Oral tablets
etc

COX 2 SELECTIVE INHIBITORS

Celecoxib
Oral capsules
Etoricoxib
Oral tablets
Parecoxib
parenteral

ABSORPTION & ELIMINATION

• When administered orally, aspirin, ns-NSAIDs and Coxibs are well absorbed and reach
therapeutic levels within 30 to 60 minutes.
• They are eliminated by the renal mechanism.

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

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.
EFFECTS 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
•
• Other Effects –
• Some ns-NSAIDs can precipitate asthma is aspirin sensitive asthmatic patients.
• Coxibs are well tolerated by patients who have aspirin sensitive asthma

ns-NSAIDs. Vs. 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
• 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

HISTORY

• 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
CLASSIFIACTION

• Natural
• Morphine
• Codeine

• Semi-Synthetic
• Hydromorphone
• Oxycodone
• Diacetylmorphine
(heroin)
• Buprenorphine (partial agonist)
• Naloxone (antagonist)

Fully Synthetic

Pethidine (meperidine)
Tramadol
Nalbuphine
Methadone
Pentazocine
Fentanyl
Alfentanil
Sufentanil
Remifentanil

• Strong opioids used for severe pain

• Morphine, Oxycodone, Pethidine, Fentanyl

• Weak Opioids used for moderate pain

• Codeine, Tramadol

MECHANISM
• Opioids act by binding to opioid receptors (complex proteins embedded within the cell
membrane of neurons) .
• Opioid receptors are found in the brain and in the dorsal horn of the spinal cord
• 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

ROUTES OF ADMINISTRATION
• 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.

• 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
• 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

• 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

• This is also known as an “atypical opioid”

• It has a :
• 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
• 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)

• 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

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

HYPERALGESIA

• The process of increased sensitivity to pain with the short term and long-term use of opioids
is termed opioid-induced hyperalgesia .
• Decreasing the opioid dose (40% to 50%) and adding adjuvants or a low dose of
methadone can be used to treat
• Ketamine, a NMDA receptor antagonist is another option for the management of this
condition.
• In cases of failure of opioid therapy, OIH must be considered in the differential
diagnosis .

KETAMINE

• It is a phencyclidine derivative
• It has multiple mechanisms of action
• The main mechanism of action is that of a non-competitive antagonist at the NMDA
receptors
• 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

• Analgesic Effects -

• 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 .
• It can be used in Intravenous Infusions for the management of chronic pain
conditions like Fibromyalgia

SIDE EFFECTS

• Dizziness
• Hallucinations
• Emergence delirium when larger doses are used -
Benzodiazepines can reduce these side effects
• Salivary secretions -
Anti-sialagogues should be used with ketamine

ANTICONVULSANTS

FIRST GENERATION
Benzodiazepines
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin
Primidone
Valproic acid

SECOND GENERATION

Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam

Oxcar- bazepine
Pregabalin
Topiramate
Vigabatrin
ANTIDEPRESSANTS

TRICYCLIC ANTIDEPRESSANTS

• Alter monoamine transmitter activity at the synapse by blocking the reuptake of serotonin
and norepinephrine.
• Clinically demonstrable improvement in the patient's pain complaints requires 2 to 3 weeks
of treatment.
• Long elimination half-lives of 1 to 4 days
• Side effect urinary retention, orthostatic hypotension, decrease gastric acid
• Amitriptyline, Desipramine ( better in elderly ) and nortriptyline

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

• Lack of side effects relative to the TCAs

• Good choice for patients with pain who cannot or will not tolerate the side effects of the
TCAs
• Block the reuptake of serotonin by blocking the sodium/potassium adenosine
triphosphate pump. The result is an increased level of serotonin at the synaptic cleft
• The SSRIs are well absorbed orally.
• Fluoxetine, Sertraline, Escitalopram( MDD,PSTD,Anxiety)

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS

• Duloxetine and venlafaxine are antidepressants with effectiveness for neuropathic pain.
MUSCLE RELAXANTS

Sedatives : Chlorzoxazone, Methocarbamol .

TCA-like : Cyclobenzaprine

Central alpha-2 agonists : Tizanidine

GABA-agonists : Baclofen , BDZ

GABA-antagonist : Thiocolchicoside

Piperidine derivative : Tolperisone

DRUGS USED IN INTERVENTIONS

• Commonly used drugs in Interventions include :-

• Corticosteroids.
• Local Anaesthetics.
• Contrast agents.
CORTICOSTEROIDS

• Reduce inflammation: inhibit phospholipase A2

• Blocks transmission of nociceptive C fiber input thus suppresses ongoing and ectopic neural
discharge
• Suppress the action of nuclear factor KB, which induces many inflammatory
cytokines.
• Also have weak membrane stabilizing & local anaesthetic action
• Drugs -
• Triamcinolone
• Methyl prednisolone 40mg/ml vial, particulate ( depo-medrol )
• Other corticosteroids include :-
• Betamethasone
• Dexamethasone
• Deflazacort
• Dose for Depot steroids ( 40mg/10mg /ml )

3 mg/kg/year

6 mg/kg/lifetime

LOCAL ANAESTHETICS
• Lignocaine and bupivacaine for nerve block

• Systemic Lignocaine for central desensitization.

• 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.

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

CONTRAST AGENTS

• Ionic contrast agents- highly osmolar, toxic.

• Non-ionic contrast agents- hydrophilic, less osmolar, less toxic. Contains organic iodine.
Commonly used agent is iohexol (omnipaque).
• Each ml contains- 300mg.
• Maximum daily dose is 3g.

Miscellaneous Drugs :-

Botulinum Toxin.
Transdermal patches - Ex : Fentanyl, Diclofenac, Buprenorphine, Lidocaine.

Conclusion

• An adequate understanding of the basic pharmacology of drugs is very essential.

• The different class of drugs with varying pharmacology pose a challenge to the Pain
Physician.

• Sufficient knowledge of side effects is essential to avoid any untoward harm to the patient.