PAIN MANAGEMENT

Pain assessment
– Intensity: use a simple verbal scale in children over 5 years and adults, and NFCS or FLACC scales in children less
than 5 years.
Self-evaluation scale - Children over 5 years and adults

Observational evaluation scale - Children 2 months-5 years

FLACC scale (Face Limb Activity Cry Consolability)

Observational evaluation scale - Children under 2 months

NFCS scale (Neonatal Facial Coding System)
Nociceptive pain

The WHO classifies analgesics used for this type of pain on a three-step ladder:
– Step 1: non-opioid analgesics such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs).
– Step 2: weak opioid analgesics such as codeine and tramadol. Their combination with one or two Step 1 analgesics
is recommended.
– Step 3: strong opioid analgesics, first and foremost morphine. Their combination with one or two Step 1 analgesics
is recommended.
The treatment of pain is based on a few fundamental concepts:
– Pain can only be treated correctly if it is correctly evaluated. The only person who can evaluate the intensity of pain
is the patient himself. The use of pain assessment scales is invaluable.
– The pain evaluation observations should be recorded in the patient chart in the same fashion as other vital signs.
– Treatment of pain should be as prompt as possible.
– It is recommended to administer analgesics in advance when appropriate (e.g. before painful care procedures).
– Analgesics should be prescribed and administered at fixed time intervals (not on demand).
– Oral forms should be used whenever possible.
– The combination of different analgesic drugs (multimodal analgesia) is advantageous.
– Start with an analgesic from the level presumed most effective: e.g., in the event of a fractured femur, start with a
Step 3 analgesic.
– The treatment and dose chosen are guided by the assessment of pain intensity, but also by the patient’s response
which may vary significantly from one person to another.
Morphine is an effective treatment for many types of severe pain. Its analgesic effect is dosedependent. Its adverse
effects have often been exaggerated and should not be an obstacle to its use.
– The most serious adverse effect of morphine is respiratory depression, which may be fatal. This adverse effect
results from overdose. It is, therefore, important to increase doses gradually. Respiratory depression is preceded by
drowsiness, which is a warning to monitor respiratory rate (RR). 
The RR should remain equal to or greater than the thresholds indicated below:

Respiratory depression must be identified and treated quickly: verbal and physical stimulation of the patient;
administration of oxygen; respiratory support (bag and mask) if necessary. If no improvement,
administer naloxone (antagonist of morphine) in bolus to be repeated every minute until RR normalises and the
excessive drowsiness resolves: 5 micrograms/kg in children and 1 to 3 micrograms/kg in adults.
– Morphine and codeine always cause constipation. A laxative should be prescribed if the opioid treatment
continues more than 48 hours. Lactulose PO is the drug of choice: children < 1 year: 5 ml daily; children 1-6 years: 5
to 10 ml daily; children 7-14 years: 10 to 15 ml daily; adults: 15 to 45 ml daily.
If the patient’s stools are soft, a stimulant laxative (bisacodyl PO: children > 3 years: 5 to 10 mg once daily; adults:
10 to 15 mg once daily) is preferred.
– Nausea and vomiting are common at the beginning of treatment.
Children: ondansetron PO: 0.15 mg/kg (max. 4 mg per dose) up to 3 times daily
Do not use metoclopramide in children.

Adults: haloperidol PO (2 mg/ml oral solution): 1 to 2 mg up to 6 times daily or metoclopramide PO: 5 to 10 mg 3

times daily with an interval of at least 6 hours between each dose
Do not combine haloperidol and metoclopramide.
– For chronic pain in late stage disease (cancer, AIDS etc.), morphine PO is the drug of choice. It may be necessary
to increase doses over time according to pain assessment. Do not hesitate to give sufficient and effective doses.
– Morphine, tramadol and codeine have similar modes of action and should not be combined.
– Buprenorphine, nalbuphine and pentazocine must not be combined with morphine, pethidine, tramadol or
codeine because they have competitive action.
Treatment of nociceptive pain in pregnant and breast-feeding women

Neuropathic pain

Commonly used analgesics are often ineffective in treating this type of pain.
Treatment of neuropathic pain is based on a combination of two centrally acting drugs:
amitriptyline PO
Adults: 25 mg once daily at bedtime (Week 1); 50 mg once daily at bedtime (Week 2); 75 mg once daily at bedtime
(as of Week 3); max.150 mg daily. Reduce the dose by half in elderly patients.
carbamazepine PO
Adults: 200 mg once daily at bedtime (Week 1); 200 mg 2 times daily (Week 2); 200 mg 3 times daily (as of Week 3)
Given its teratogenic risk, carbamazepine should only be used in women of childbearing age when covered
by effective contraception (intrauterine device or injectable progestogen). It is not recommended in pregnant women.

Mixed pain

In mixed pain with a significant component of nociceptive pain, such as in cancer or AIDS, morphine is combined with
antidepressants and antiepileptics.

Chronic pain

In contrast to acute pain, medical treatment alone is not always sufficient in controlling chronic pain. A
multidisciplinary approach including medical treatment, physiotherapy, psychotherapy and nursing is often necessary
to allow good pain relief and encourage patient selfmanagement.
 Co-analgesics

The combination of certain drugs may be useful or even essential in the treatment of pain: antispasmodics, muscle
relaxants, anxiolytics, corticosteroids, local anaesthesia, etc.

PARACETAMOL

Dosage/Direction for Use

Adult : PO 0.5-1 g 4-6 hourly. IV 33-50 kg: 15 mg/kg 4-6 hourly if needed. Max: 3 g/day: >50 kg: 1 g 4-6 hourly if
needed. Rectal As supp: 0.5-1 g 4-6 hourly. Max: 4 g daily.
Dosage Details
Intravenous
Fever, Mild to moderate pain
Adult: 33-50 kg: 15 mg/kg 4-6 hourly if needed. Max: 3 g daily. >50 kg: 1 g 4-6 hourly if needed. Max: 4 g daily. Administer
by infusion over 15 minutes.
Child: Full-term neonates and children <10 kg: 7.5 mg/kg as a single dose, at least 4 hourly. Max: 30 mg/kg/day; 10-33 kg:
15 mg/kg as a single dose, at least 4 hourly. Max: 2 g daily; 33-50 kg: 15 mg/kg as a single dose, at least 4 hourly. Max: 3 g
daily; >50 kg: Same as adult dose.

Oral
Post-immunisation pyrexia
Child: 2-3 months 60 mg as a single dose. May give 2nd dose after 4-6 hours if needed. Max: 4 doses daily.

Oral
Fever, Mild to moderate pain
Adult: 0.5-1 g 4-6 hourly. Max: 4 g daily.
Child: 1-2 months 30-60 mg 8 hourly. Max: 60 mg/kg/day; 3-<6 months 60 mg. 6 months to <2 years 120 mg; 2-<4
years 180 mg; 4-<6 years 240 mg; 6-<8 years 240 or 250 mg; 8-<10 years 360 or 375 mg; 10-<12 years 480 or 500 mg; 12-
16 years 480 or 750mg. Administer 4-6 hourly if necessary. Max: 4 doses in 24 hours.

Rectal
Fever, Mild to moderate pain
Adult: As supp: 0.5-1 g 4-6 hourly. Max: 4 g daily.
Child: 3 months to <1 year 60-125 mg; 1-<5 years 125-250 mg: 5-<12 years 250-500 mg; 12-17 years 500 mg. Given 4-6
hourly if needed. Max: 4 doses/day.

Rectal
Post-immunisation pyrexia
Child: 2-3 months 60 mg as a single dose. May give 2nd dose after 4-6 hours if needed.

Hepatic Impairment
Oral:
Mild to moderate pain; Fever: Dosage reduction may be needed. Recommendation: Max: ≤2-3 g daily.
Intravenous:
Mild or moderate: Max: 3 g daily. Severe: Contraindicated.
Administration
May be taken with or without food.
Reconstitution
IV: Dilute with NaCl 0.9% or glucose 5% to make a concentration of not less than 1 mg/mL.
Incompatibility
Incompatible with acyclovir Na, diazepam, chlorpromazine HCl.
Contraindications
Hypersensitivity. Severe hepatic impairment or active liver disease (IV).
Special Precautions
Patient with known G6PD deficiency, alcohol dependence, chronic malnutrition or dehydration, weight <50 kg; severe
hypovolaemia (IV). Renal and hepatic impairment. Children. Pregnancy and lactation.
Adverse Reactions
Significant: Thrombocytopenia, leucopenia, neutropenia, pancytopenia, methaemoglobinaemia, agranulocytosis,
angioedema, pain and burning sensation at inj site. Rarely, hypotension and tachycardia.
Gastrointestinal disorders: Nausea, vomiting, constipation.
Nervous system disorders: Headache.
Psychiatric disorders: Insomnia.
Skin and subcutaneous tissue disorders: Erythema, flushing, pruritus.
Potentially Fatal: Hepatotoxicity, acute renal tubular necrosis. Rarely, hypersensitivity reactions such as acute generalised
exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).
Pregnancy Category (US FDA)
PO/Rectal: B; IV/Parenteral: C
MonitoringParameters
Assess patient for history of liver disease or alcohol abuse.
Overdosage
Symptoms: Pallor, nausea, vomiting, anorexia, abdominal pain, metabolic acidosis, glucose metabolism abnormalities. After
12-48 hours of ingestion, liver damage may become apparent, which may lead to encephalopathy, haemorrhage,
hypoglycaemia, hypotension, cerebral oedema, cardiac arrhythmia, and pancreatitis. Management: Administer activated
charcoal within 1 hour of ingestion. Determine plasma paracetamol concentration ≥4 hours after ingestion. IV N-
acetylcysteine may be used up to 24 hours after ingestion (most effective if given within 8 hours). As an alternative, oral
methionine can also be used if vomiting is not a problem.
Drug Interactions
Decreased absorption with colestyramine. Decreased serum concentrations with rifampicin and some anticonvulsants (e.g.
phenytoin, phenobarbital, carbamazepine, primidone). Enhances the anticoagulant effect of warfarin and other coumarins
with prolonged use. Increased absorption with metoclopramide and domperidone. Increased serum concentration with
probenecid. May increase serum concentration of chloramphenicol.
Food Interaction
Increased risk of hepatotoxicity with alcohol. Decreased serum concentration with St John’s wort.
Lab Interference
May produce false-positive test results for urinary 5-hydroxyindoleacetic acid.
Action
Description: Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation. It produces
antipyresis by inhibiting the hypothalamic heat-regulating centre. Its weak anti-inflammatory activity is related to
inhibition of prostaglandin synthesis in the CNS.
Synonym: acetaminophen.
Onset: Oral: <1 hour. IV: 5-10 minutes (analgesia); within 30 minutes (antipyretic).
Duration: Oral, IV: 4-6 hours (analgesia). IV: ≥6 hours (antipyretic).
Pharmacokinetics:
Absorption: Well absorbed after oral and rectal administration. Time to peak plasma concentration: Approx 10-60 minutes
(oral); 15 minutes (IV); approx 2-3 hours (rectal).
Distribution: Distributed into most body tissues. Crosses placenta and enters breast milk. Plasma protein binding: Approx
10-25%.
Metabolism: Mainly metabolised in the liver via glucuronic and sulfuric acid conjugation. N-acetyl-p-benzoquinone imine
(NAPQI), a minor metabolite produced by CYP2E1 and CYP3A4, is further metabolised via conjugation with glutathione in
the liver and kidneys.
Excretion: Mainly via urine (<5% as unchanged drug; 60-80% as glucuronide metabolites and 20-30% as sulphate
metabolites). Elimination half-life: Approx 1-3 hours.

Much investigation has centered on paracetamol’s inhibition of the COX enzyme because its analgesic and
antipyretic effects are similar to those of aspirin, the archetype NSAID. However, paracetamol does not have
significant anti‐inflammatory activity nor does it inhibit production of the pro‐clotting TXA. Paracetamol antinociception
is through interference with serotonergic descending pain pathways. This mechanism does not refute arguments that
its primary site of action may still be inhibition of PG synthesis.
MORPHINE

Dosage/Direction for Use

Adult : PO Moderate to severe pain As morphine sulfate: As conventional preparation: 5-20 mg 4 hourly. As
extended-release tab/cap: Recommended initial dose: 1 or 2 (10 mg) tab 12-24 hourly. Parenteral Acute pulmonary
oedema; Premedication in surgery As morphine sulfate: Recommended dose: 10 mg 4 hourly if necessary (dose
may vary from 5-20 mg) via SC or IM inj. May also be given via IV infusion at a dose corresponding to ¼ - ½ of the IM
dose not more than 4 hourly. Severe pain As morphine sulfate: Recommended dose: 10-20 mg 4-6 hourly (dose may
vary from 5-20 mg) via SC, IM or IV inj. Severe pain; Severe cancer pain As morphine tartrate: 5-20 mg 4-6 hourly
via SC/IM inj. If rapid onset of action is desired, may give 2.5-15 mg via slow IV inj over 4-5 minutes. As PCA: 1
mg/hour administered with a lockout interval of 6-10 minutes and 0.5 (Max of 1.5 mg) demand
doses. Intravenous Moderate to severe pain; Pain associated with myocardial infarction; Postoperative pain;
Severe cancer pain As morphine sulfate: As PCA: Loading dose: 1-10 mg (Max 15 mg) via IV infusion over 4-5
minutes, then 1 mg on demand with 5-10 minutes lockout time. Rectal Severe pain 10-20 mg 4
hourly. Intraspinal Moderate to severe pain As morphine sulfate: Initial: 5 mg epidural inj, if desired pain relief is not
achieved within 1 hour, incremental doses of 1-2 mg may be given up to 10 mg/24 hour. Postoperative pain As
morphine sulfate liposomal inj: 10-20 mg for lumbar administration only depending on the type of
surgery. Intrathecal Moderate to severe pain As morphine sulfate: 0.2-1 mg as single dose for up to 24 hours. All
dosages are individualised based on the severity of pain, patient response and prior analgesic experience.
Dosage Details
Intraspinal
Moderate to severe pain
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. Initially, 5 mg epidural inj, if desired pain relief is not achieved within 1 hour, incremental doses
of 1-2 mg may be given up to 10 mg/24 hour.

Intraspinal
Postoperative pain
Adult: As morphine sulfate liposomal inj: Dosage is individualised based on the severity of pain, patient response
and prior analgesic experience. 10-20 mg for lumbar administration only depending on the type of surgery. Dose
adjustments may be required according to individual response.

Intrathecal
Moderate to severe pain
Adult: As morphine sulfate: 0.2-1 mg as single dose for up to 24 hours. Dosage is individualised based on the
severity of pain, patient response and prior analgesic experience.

Intravenous
Moderate to severe pain, Pain associated with myocardial infarction, Postoperative pain, Severe cancer pain
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. As Patient-Controlled Analgesia (PCA): Loading dose: 1-10 mg (Max 15 mg) via IV infusion
over 4-5 minutes, then 1 mg on demand with 5-10 minutes lockout time.
Elderly: Dose reduction needed.

Oral
Moderate to severe pain
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. As conventional preparation: 5-20 mg 4 hourly. As extended-release tab/cap: Recommended
initial dose: 1 or 2 (10 mg) tab 12-24 hourly.
Child: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. As conventional preparation: 1-5 years 5 mg 4 hourly (Max: 30 mg daily); 6-12 years 5-10 mg 4
hourly (Max: 60 mg daily); ≥13 years Same as adult dose.

Parenteral
Severe pain
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. Recommended dose: 10-20 mg 4-6 hourly (dose may vary from 5-20 mg) via SC, IM or IV inj.
Elderly: Dose reduction needed.

Parenteral
Acute pulmonary oedema, Premedication in surgery
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. Recommended dose: 10 mg 4 hourly if necessary (dose may vary from 5-20 mg) via SC or IM
inj. May also be given via IV infusion at a dose corresponding to ¼ - ½ of the IM dose not more than 4 hourly.
Elderly: Dose reduction needed.

Parenteral
Severe cancer pain, Severe pain
Adult: As morphine tartrate: 5-20 mg 4-6 hourly via SC/IM inj. If rapid onset of action is desired, may give 2.5-15 mg
via slow IV inj over 4-5 minutes. As IV Patient-controlled analgesia (PCA): 1 mg/hour administered with a lockout
interval of 6-10 minutes and 0.5 (Max of 1.5 mg) demand doses.
Child: As morphine tartrate: 0.1-0.2 mg/kg 4-6 hourly via SC/IM inj. Max dose: 15 mg. If rapid of onset is desired,
0.05-0.1 mg/kg via slow IV inj, may titrate dose incrementally over 5-15 minutes.

Rectal
Severe pain
Adult: As morphine sulfate: Dosage is individualised based on the severity of pain, patient response and prior
analgesic experience. 10-20 mg 4 hourly.
Renal Impairment
Oral
Moderate to severe pain: Dose reduction needed.

Parenteral
Acute pulmonary oedema; Premedication in surgery; Severe pain; Severe cancer pain: Dose reduction
needed.

Intravenous
Moderate to severe pain; Pain associated with myocardial infarction; Postoperative pain; Severe cancer
pain: Dose reduction needed.
Hepatic Impairment
Oral
Moderate to severe pain: Dose reduction needed.

Parenteral
Acute pulmonary oedema; Premedication in surgery; Severe pain; Severe cancer pain: Dose reduction
needed.

Intravenous
Moderate to severe pain; Pain associated with myocardial infarction; Postoperative pain; Severe cancer
pain: Dose reduction needed.
Administration
May be taken with or without food. May be taken w/ meals to reduce GI discomfort.
Incompatibility
Aminophylline, amobarbital, chlorothiazide, phenytoin Na, heparin Na, meperidine HCl, methicillin Na, nitrofurantoin
Na, pentobarbital Na, phenobarbital Na, Na bicarbonate, Na iodide, thiopental Na, Aciclovir Na, doxorubicin,
fluorouracil, furosemide, haloperidol, pethidine HCl, prochloeperazine edisilate, promethazine HCl, ranitidine HCl,
tetracycline.
Contraindications
Hypersensitivity. Respiratory depression, obstructive airway disease, paralytic ileus, acute hepatic disease, acute
alcoholism, head injuries, increased intracranial pressure, excessive bronchial secretions, acute or severe bronchial
asthma, heart failure secondary to chronic lung disease, delayed gastric emptying, GI obstruction, acute abdomen,
circulatory shock. Concomitant use during or within 14 days of MAOI therapy.
Special Precautions
Patient with hypovolaemia, CV disease (including acute MI), circulatory shock, adrenal insufficiency, Addison
disease, biliary tract dysfunction, acute pancreatitis, delirium tremens, prostatic hyperplasia, urinary stricture, toxic
psychosis, myasthenia gravis, mental health conditions (e.g. depression, anxiety, post-traumatic stress disorder),
seizure, thyroid dysfunction, history of drug abuse or acute alcoholism, obese. Renal and severe hepatic impairment.
Pregnancy and lactation.
Adverse Reactions
Significant: CNS depression, orthostatic hypotension, severe hypotension, syncope constipation.
Blood and lymphatic system disorders: Anaemia.
Cardiac disorders: Bradycardia, palpitation, tachycardia.
Eye disorder: Blurred or double vision, miosis.
Gastrointestinal disorders: Abdominal pain, constipation, delayed gastric emptying, diarrhoea, dyspepsia, flatulence,
nausea, vomiting, xerostomia, dry mouth, anorexia.
General disorders and administration site conditions: Asthenic conditions, hyperhidrosis, withdrawal syndrome.
Hepatobiliary disorders: Biliary colic, hypoesthesia, hypokalemia.
Metabolism and nutrition disorders: Anorexia.
Musculoskeletal and connective tissue disorders: Back pain.
Nervous system disorders: Dizziness, headache, paresthesia, paralytic ileus, myoclonus.
Psychiatric disorders: Anxiety, confusion, dependence, insomnia hallucination, euphoria, agitation, mood altered.
Renal and urinary disorders: Bladder spasm, oliguria, urinary retention.
Reproductive system and breast disorders: Decreased libido or potency (long term use).
Respiratory, thoracic and mediastinal disorders: Dyspnea, hypoxia, rigors, bronchospasm, pulmonary oedema.
Skin and subcutaneous tissue disorders: Pruritus, skin rash, urticaria, sweating.
Vascular disorders: Hypertension, facial flushing.
Potentially Fatal: Hypersensitivity. Respiratory depression.
Pregnancy Category (US FDA)
Epidural/IM/IT/IV/Parenteral/PO/Rectal/SC: C (Prolonged use may cause neonatal opioid withdrawal syndrome
(NOWS).)
Patient Counseling Information
This drug may cause CNS depression, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor efficacy of pain control, vital signs, respiratory and mental status. Assess physical and/or psychological
dependence. Monitor signs or symptoms of hypogonadism or hypoadrenalism.
Overdosage
Symptoms: Respiratory depression, pinpoint pupils, hypoxia, hypothermia, severe dizziness, severe drowsiness,
hypotension, bradycardia, circulatory failure pulmonary oedema, severe nervousness or restlessness, hallucinations,
convulsion (especially in infants and children); skeletal muscle flaccidity, cold and clammy skin. Management: Ensure
adequate airway, ventilation and oxygenation. Administration of opioid antagonist e.g. naloxone may be given as an
antidote.
Drug Interactions
Increased depressant effects with other CNS depressants (e.g. sedatives, hypnotics, general anaesthesia,
phenothiazines, tranquilisers). May enhance the neuromuscular blocking action of skeletal muscle relaxants.
Reduced analgesic effect with mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine,
pentazocine). Increased plasma concentrations with cimetidine. Reduced plasma concentration with rifampicin,
ritonavir. Decreased therapeutic effect of diuretics. Increased plasma concentration with cisapride. Increased risk of
orthostatic hypotension with antihypertensive agents. Increased risk of severe constipation and CNS depression with
antidiarrhoeal agents
Potentially Fatal: Enhanced depressant effect with MAOIs.
Food Interaction
Alcohol enhances the CNS depressant effect of morphine. Increased bioavailability with food (oral).
Lab Interference
May interfere with gastric emptying studies and with hepatobiliary imaging using technetium Tc99m diosfenin.
Action
Description: Morphine, an opioid analgesic, is a phenanthrene derivative which acts mainly on the CNS and smooth
muscles. It binds to opiate receptors in the CNS altering pain perception and response by modulating the descending
inhibitory pathways from the brain. Analgesia, euphoria and dependence are thought to be due to its action at the µ-1
receptors while respiratory depression and inhibition of intestinal movements are due to action at the µ-2 receptors.
Spinal analgesia is mediated by morphine agonist action at the κ receptor.
Onset: Approx 30 minutes (conventional tab); 5-10 minutes (IV).
Duration: 3-5 hours (immediate-release); 8-24 hours (extended-release tab/cap); 3-7 hours (supp); Up to 24 hours
(single dose epidural or intrathecal).
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract (oral) and into the blood (SC/IM). Increased bioavailability
with food. Bioavailability: 17-33 % (oral). Time to peak plasma concentration: 1 hour (conventional tab, epidural); 3-4
hours (extended-release tab); 20-60 minutes (supp); 50-90 minutes (SC); 30-60 minutes (IM); 20 minutes (IV).
Distribution: Widely distributed throughout the body mainly in the kidneys, liver, lungs and spleen, with lower
concentrations in the brain and muscles. Crosses the blood-brain barrier and placenta; enters breast milk. Volume of
distribution: 1-6 L/kg. Plasma protein binding: Approx 35%.
Metabolism: Metabolised in the liver and gut via glucuronidation to produce morphine-3-glucoronide and morphine-
6-glucoronide; undergoes extensive first-pass metabolism.
Excretion: Via urine [approx 60% (oral); approx 90% (parenteral)]; faeces (10%, as conjugates). Elimination half-life:
Approx 2 hours (morphine); 2.4-6.7 hours (morphine-3-glucoronide).

ASPIRIN

Dosage/Direction for Use

Adult : PO Mild to moderate pain; Fever Initial: 300-900 mg, repeated 4-6 hrly. Max: 4 g daily. Rheumatic
disorders 4-8 g daily in divided doses for acute disorders. 5.4 g daily in divided doses for chronic conditions. Angina
pectoris; Myocardial Infarction; Acute ischaemic stroke Loading: 150-300 mg. Prophylaxis of cardiovascular
events in high-risk patients Long term: 75-150 mg once daily. Short term: 150-300 mg daily. Rectal  Mild to
moderate pain; Fever As sup: 450-900 mg 4 hrly. Max: 3.6 g daily.
Dosage Details
Oral
Acute ischaemic stroke, Angina pectoris, Myocardial infarction
Adult: For primary prevention: Loading: 150-300 mg.

Oral
Fever, Mild to moderate pain
Adult: Initially, 300-900 mg, repeated 4-6 hourly according to clinical needs. Max: 4 g daily.

Oral
Rheumatic disorders
Adult: 4-8 g daily in divided doses for acute disorders. 5.4 g daily in divided doses for chronic conditions.

Oral
Prophylaxis of cardiovascular events in high-risk patients
Adult: Long term: 75-150 mg once daily. Short term: 150-300 mg daily.

Rectal
Fever, Mild to moderate pain
Adult: As suppository: 450-900 mg 4 hourly. Max: 3.6 g daily.
Renal Impairment
Severe: Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Administration
Should be taken with food.
Contraindications
Hypersensitivity to aspirin or other NSAIDs. Peptic ulcer, haemorrhagic disease, coagulation disorder (e.g.
haemophilia, thrombocytopenia), gout. Severe hepatic and renal impairment. Children <16 years and recovering from
viral infection. Pregnancy (doses >100 mg daily during 3rd trimester) and lactation. Concomitant use with other
NSAIDs and methotrexate.
Special Precautions
Patient with dyspepsia or lesion of the GI mucosa, asthma or allergic disorders, anaemia, dehydration, menorrhagia,
uncontrolled hypertension, G6PD deficiency, thyrotoxicosis. Patients undergoing surgical procedures. Moderate
hepatic and renal impairment. Pregnancy.
Adverse Reactions
Significant: Salicylate sensitivity, tinnitus.
Blood and lymphatic system disorders: Anaemia, hypoprothrombinaemia, thrombocytopenia.
Gastrointestinal disorders: Dyspepsia, gastric irritation, nausea, vomiting.
Nervous system disorders: Dizziness, confusion.
Respiratory, thoracic and mediastinal disorders: Asthma, bronchospasm, dyspnea, rhinitis.
Skin and subcutaneous tissue disorders:  Rash, urticaria.
Potentially Fatal: Paroxysmal bronchospasm and dyspnoea. Coma, CV collapse, resp failure, severe
hypoglycaemia. Rarely, Reye’s syndrome. Hypersensitivity reactions (e.g. Stevens Johnson syndrome, angioedema),
gastrointestinal bleeding and perforation.
Overdosage
Symptoms: Vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses,
increased respiratory rate, hyperventilation, acid-base disturbance, haematemesis, hyperpyrexia, hypoglycaemia,
hypokalaemia, thrombocytopenia, increased INR/PTR, intravascular coagulation, renal failure, pulmonary oedema,
CNS effects (e.g. confusion, disorientation, coma, convulsion). Management: Administer activated charcoal if patient
presents ingestion of >250 mg/kg within 1 hr. Perform urinary alkalinisation by administration of 1.26% Na
bicarbonate then monitor urine pH. Correct metabolic acidosis with 8.4% Na bicarbonate IV. For severe poisoning
(plasma conc: >700 mg/L), haemodialysis is the treatment of choice.
Drug Interactions
Increased risk of GI bleeding and ulceration with corticosteroids. Increased risk of bleeding with coumarin
anticoagulants (e.g. heparin, warfarin, phenindione) and antiplatelet agents (e.g. clopidogrel, dipyridamole). May
result in severe acidosis and increased CNS toxicity with carbonic anhydrase inhibitors (e.g. acetazolamide).
Increases the hypoglycaemic effect of sulfonylureas. Reduces binding of phenytoin and valproate to serum albumin
leading to increased free concentration of the drugs. Reduces the effect of uricosurics (e.g. probenecid,
sulfinpyrazone). Impairs the renal excretion of lithium and digoxin.
Potentially Fatal: Increased risk of GI bleeding and ulceration with other NSAIDs. Increased risk of haematological
toxicity of methotrexate.
Food Interaction
Increased risk of GI bleeding with alcohol. Reduced GI irritation with admin of food and large quantity of water or milk.
Lab Interference
Interferes with thyroid function, Gerhardt, VMA determination, 5-HIAA, and xylose tolerance tests. False negative
result for glucose oxidase urinary glucose test; false positive in cupric sulfate method.
Action
Description: Aspirin is a salicylate that exhibits analgesic, anti-inflammatory, and antipyretic activities. It is a
selective and irreversible inhibitor of cyclooxygenase-1 (COX-1) enzyme resulting in direct inhibition of the
biosynthesis of prostaglandins and thromboxanes from arachidonic acid. Additionally, it also inhibits platelet
aggregation.
Synonym: acetylsalicylic acid (ASA).
Onset: Platelet inhibition: Within 1 hr (nonenteric-coated); delayed (enteric-coated); 20 minutes (if chewed).
Duration: 4-6 hours (immediate-release); Platelet inhibition: Approx 10 days.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract; less reliable (rectal); absorbed through the skin.
Partially hydrolysed by esterases to salicylate during absorption in the GI tract. Bioavailability: 50-75% (immediate-
release). Time to peak plasma concentration: Approx 1-2 hours (nonenteric-coated); 3-4 hours (enteric-coated);
Approx 2 hours (extended-release cap).
Distribution: Widely and rapidly distributed into most body tissues and fluids. Crosses the placenta and enters
breast milk. Volume of distribution: 170 mL/kg. Plasma protein binding: 80-90%.
Metabolism: Metabolised in the liver into salicyluric acid, salicyl phenolic glucuronide, salicylic acyl glucuronide,
gentisic acid, and gentisuric acid. Undergoes first-pass metabolism.
Excretion: Via urine (75% as salicyluric acid, 10% as salicylic acid). Elimination half-life: 15-20 minutes.
Dosage/Direction for Use
Adult : PO Mild to moderate acute pain As conventional tablet: 50 mg bid-tid. As conventional capsule (acid): 18-35
mg tid. As conventional capsule (K salt): 25 mg qid. As delayed-release tablet: 75-150 mg/day. Osteoarthritis;
Rheumatoid arthritis; Ankylosing spondylitis; Acute musculoskeletal disorders; Pain after accidental trauma; Bursitis;
Sprains; Strains; Tendinitis; Pyrophosphate arthropathy; Acute gout; Pain and inflammation associated with
orthopaedic, dental and other minor surgery As conventional tablet: 50 mg bid-tid. As conventional capsule (acid): 35
mg tid. As delayed-release tablet: 75-150 mg/day in 2-3 divided doses. As extended-release tablet or capsule: 75 mg
once daily - bid or 100 mg/day. Migraine As conventional tablet: 50 mg at 1st signs of attack; if needed, another 50
mg after 2 hours; if still needed, 50 mg 4-6 hourly. Max: 200 mg/day. As powder for oral solution: 50 mg in 30-60 mL
water. Primary dysmenorrhoea As conventional tablet: 50 mg tid. IV Mild to moderate acute pain 37.5 mg as bolus 6
hourly. Postoperative pain Treatment: 75 mg as infusion; may repeat after 4-6 hours. Prophylaxis: After surgery, 25-
50 mg as infusion; then, approx 5 mg hourly. Max: 150 mg/day. Max period: 2 days. IM Acute pain; Osteoarthritis;
Rheumatoid arthritis; Acute gout; Pain after accidental trauma; Postoperative pain 75 mg/day. Renal colic 75 mg;
may repeat after 30 minutes. Max: 150 mg/day. Max period: 2 days. Rectal Acute pain; Osteoarthritis; Rheumatoid
arthritis; Ankylosing spondylitis; Acute musculoskeletal disorders; Pain after accidental trauma; Bursitis; Sprains;
Strains; Tendinitis; Acute gout; Pain and inflammation associated with orthopaedic, dental and other minor surgery As
25, 50 or 100 mg suppository: 75-150 mg/day. Transdermal Acute pain; Pain after accidental trauma; Sprains;
Strains As plaster containing 140 mg diclofenac Na: 1 plaster bid. Max period: 7 days. As patch containing 180 mg
diclofenac epolamine: 1 plaster bid. Topical/Cutaneous Osteoarthritis As 1% diclofenac Na gel: Upper extremities: 2 g
qid up to 8 g/joint/day. Lower extremities: 4 g qid up to 16 g/joint/day. Max: 32 g/day as body dose. As 1.5% solution:
Lower extremities: 40 drops/knee qid. As 2% solution: Lower extremities: 40 mg/knee bid. Local symptomatic relief of
pain and inflammation; Pain after accidental trauma; Sprains; Strains; Osteoarthritis As 1.16% diclofenac
diethylammonium gel: 2-4 g tid-qid. As 2.32% diclofenac diethylammonium gel: 2-4 g bid. Max: 8 g/day. Max period: 7
days. Actinic keratoses As 3% diclofenac Na gel: Apply bid for 60-90 days. Ophthalmic Pain after accidental
trauma As 0.1% solution: 1 drop qid for up to 2 days. Postoperative ocular inflammation 1 drop qid for up to 28
days. Prophylaxis of intra-operative miosis 1 drop 4 times within 2 hours before surgery. Post-photorefractive
keratectomy pain Before surgery, 1 drop twice within an hour. Immediately after surgery, 1 drop twice with 5-minute
interval; then, 1 drop 2-5 hourly while awake for up to 24 hours. Control of inflammation after argon laser
trabeculoplasty Before procedure, 1 drop 4 times within 2 hours; afterwards, 1 drop qid for up to 7 days. Inflammation
and discomfort after strabismus surgery 1 drop qid for week 1, tid for week 2, bid for week 3 and as needed for week
4. Pain and discomfort after radial keratotomy As 0.1% solution: Before surgery, 1 drop; immediately after surgery, 1
drop qid for up to 2 days. Seasonal allergic conjunctivitis 1 drop qid.

DICLOFENAC

Dosage Details
Intramuscular
Renal colic
Adult: 75 mg; if needed, may repeat after 30 minutes. Max: 150 mg daily. Max period: 2 days.

Intramuscular
Acute gout, Acute pain, Osteoarthritis, Pain after accidental trauma, Postoperative pain, Rheumatoid arthritis
Adult: 75 mg once daily by intragluteal inj. Max: 150 mg daily. Max period: 2 days.

Intravenous
Acute pain
Adult: For mild to moderate cases: 37.5 mg as bolus inj 6 hourly as needed. Max: 150 mg daily. Max period: 2
days.

Intravenous
Postoperative pain
Adult: As treatment: 75 mg by IV infusion over 30 minutes to 2 hours or as bolus inj; if needed, may repeat after 4-6
hours. As prophylaxis: After surgery, initially, 25-50 mg by IV infusion over 15 minutes to 1 hour or as bolus inj then, a
continuous infusion approx 5 mg hourly. Max: 150 mg daily. Max period: 2 days.

Ophthalmic
Pain after accidental trauma
Adult: As 0.1% solution: Instill 1 drop into the conjunctival sac of the affected eye(s) 4 times daily for up to 2 days.

Ophthalmic
Postoperative ocular inflammation
Adult: As 0.1% solution: Instill 1 drop into the conjunctival sac of the affected eye(s) 4 times daily for up to 28 days.

Ophthalmic
Post-photorefractive keratectomy pain
Adult: As 0.1% solution: Before surgery, instill 1 drop into the conjunctival sac of the affected eye(s) for 2 doses within
an hour. Immediately after surgery, 1 drop for 2 doses with 5-minute interval; then, 1 drop 2-5 hourly while awake for
up to 24 hours.

Ophthalmic
Prophylaxis of intra-operative miosis
Adult: As 0.1% solution: Instill 1 drop into the conjunctival sac of the affected eye(s) 4 times within 2 hours before
surgery.

Ophthalmic
Inflammation and discomfort after strabismus surgery
Adult: As 0.1% solution: Instill 1 drop into the conjunctival sac of the affected eye(s) 4 times daily for week 1, tid for
week 2, bid for week 3 and as needed for week 4.

Ophthalmic
Control of inflammation after argon laser trabeculoplasty
Adult: As 0.1% solution: Before procedure, instill 1 drop into the conjunctival sac of the affected eye(s) 4 times within
2 hours; afterwards, 1 drop 4 times daily for up to 7 days.

Ophthalmic
Seasonal allergic conjunctivitis
Adult: As 0.1% solution: Instill 1 drop into into the conjunctival sac of the affected eye(s) 4 times daily.

Ophthalmic
Pain and discomfort after radial keratotomy
Adult: As 0.1% solution: Before surgery, instill 1 drop into affected eye(s) then, immediately after surgery, 1 drop into
the conjunctival sac of the affected eye(s) 4 times daily for up to 2 days.

Oral
Acute pain
Adult: For mild to moderate cases: As conventional tablet: 50 mg bid-tid. As conventional capsule in acid form: 18-35
mg tid. As conventional capsule in K salt form: 25 mg 4 times daily. As delayed-release tablet: 75-150 mg daily in 2-3
divided doses.
Child: >14 years As conventional tablet: 25 mg tid or 50 mg bid.

Oral
Primary dysmenorrhoea
Adult: As conventional tablet: 50 mg tid.

Oral
Migraine
Adult: As conventional tablet: Initially, 50 mg at the 1st signs of attack. If symptoms persist after 2 hours, may take
additional dose of 50 mg. If still needed, take 50 mg 4-6 hourly. Max: 200 mg daily. As powder for oral solution: Mix
50 mg with 30-60 mL water. Drink immediately.

Oral
Juvenile chronic arthritis
Child: 1-12 years As delayed-release tablet: 1-3 mg/kg daily in divided doses.

Oral
Fever associated with ear, nose or throat (ENT) infections, Postoperative pain
Child: >9 years ≥35 kg: As delayed-release tablet: 2 mg/kg daily in 3 divided doses.

Oral
Acute gout, Acute musculoskeletal disorders, Ankylosing spondylitis, Bursitis, Osteoarthritis, Pain after accidental
trauma, Pain and inflammation associated with dental surgery, Pain and inflammation associated with minor surgery,
Pain and inflammation associated with orthopaedic surgery, Pyrophosphate arthropathy, Rheumatoid arthritis,
Sprains, Strains, Tendinitis, Tenosynovitis
Adult: As conventional tablet: 50 mg bid-tid. As conventional capsule in acid form: 35 mg tid. As delayed-release
tablet: 75-150 mg daily in 2-3 divided doses. As extended-release tablet or capsule: 75 once daily – bid or 100 mg
once daily. Max: 150 mg daily.
Child: >14 years As conventional tablet: 25 mg tid or 50 mg bid.

Rectal
Acute gout, Acute musculoskeletal disorders, Acute pain, Ankylosing spondylitis, Bursitis, Osteoarthritis, Pain after
accidental trauma, Pain and inflammation associated with dental surgery, Pain and inflammation associated with
minor surgery, Pain and inflammation associated with orthopaedic surgery, Rheumatoid arthritis, Sprains, Strains,
Tendinitis
Adult: As 25, 50 or 100 mg suppository: 75-150 mg daily in divided doses.

Rectal
Postoperative pain
Child: ≥6 years As 12.5 or 25 mg supp: 1-2 mg/kg daily in divided doses. Max period: 4 days.

Rectal
Juvenile chronic arthritis
Child: 1-12 years As 12.5 or 25 mg supp: 1-3 mg/kg daily in 2-3 divided doses.

Topical/Cutaneous
Actinic keratoses
Adult: As 3% diclofenac Na gel: Apply on affected area bid for 60-90 days.

Topical/Cutaneous
Osteoarthritis
Adult: As 1% diclofenac Na gel: Upper extremities: Apply 2 g onto affected area 4 times daily. Max dose: 8 g per joint
daily. Lower extremities: Apply 4 g onto affected area 4 times daily. Max dose: 16 g per joint daily. Max: 32 g daily as
body dose. As 1.5% solution: Lower extremities: 40 drops per knee 4 times daily. As 2% solution: Lower extremities:
40 mg per knee bid.

Topical/Cutaneous
Local symptomatic relief of pain and inflammation, Osteoarthritis, Pain after accidental trauma, Sprains, Strains
Adult: As 1.16% diclofenac diethylammonium gel: Apply 2-4 g onto affected area 3-4 times daily. As 2.32% diclofenac
diethylammonium gel: Apply 2-4 g onto affected area bid. Max: 8 g daily. Max duration of treatment: 7 days.
Child: ≥14 years Same as adult dose.

Transdermal
Acute pain, Pain after accidental trauma, Sprains, Strains
Adult: As plaster containing 140 mg diclofenac Na: 1 plaster bid. Max duration of treatment period: 7 days. As patch
containing 180 mg diclofenac epolamine: 1 plaster bid.
Child: ≥16 years As plaster containing 140 mg diclofenac Na: Same as adult dose.
Renal Impairment
Oral/IV/IM/Rectal:
Severe: Contraindicated.
Hepatic Impairment
Oral/IV/IM/Rectal:
Severe: Contraindicated.
Administration
Should be taken with food. Take immediately after meals.
Reconstitution
IV infusion: Dilute with 100-500 mL of NaCl 0.9% or glucose 5% solution (buffered with 0.5 mL of 8.4% or 1 mL of
4.2% of Na bicarbonate solution).
Contraindications
Hypersensitivity to diclofenac or other NSAIDs. Aspirin-sensitive asthma, risk factors for volume depletion (inj).
Moderate to severe heart failure, ischaemic heart disease, peripheral arterial disease, cerebrovascular disease,
gastrointestinal ulceration, perforation or haemorrhage, proctitis (rectal). Treatment in the setting of CABG.
Concomitant use of other NSAIDs, antiplatelets, anticoagulants. Severe hepatic or renal impairment. Pregnancy (3rd
trimester).
Special Precautions
Patient with history of gastrointestinal bleeding or peptic ulceration, coagulopathy, current or risk factors for CV
disease (e.g. CHF, ischaemic heart disease, CVA, hypertension, oedema, hyperlipidaemia, diabetes mellitus),
dehydration, hypovolemia, asthma, rhinitis, COPD, respiratory tract infections, SLE, mixed connective tissue
disorders, porphyria, ocular disease including infections (ophthalmic). Hepatic and renal impairment. Children.
Pregnancy (1st-2nd trimester) and lactation. Smokers. Avoid prolonged use for migraine (powder for oral solution).
Adverse Reactions
Significant: Na and fluid retention, oedema, HTN, liver function abnormalities (e.g. increased liver, transaminase,
enzyme levels), anaemia, rare severe blood dyscrasias (e.g. agranulocytosis, thrombocytopenia, aplastic anaemia),
risk of hyperkalaemia; keratitis (ophthalmic).
Cardiac disorders: Chest pain.
Ear and labyrinth disorders: Tinnitus.
Eye disorders: Blurred vision; transient burning or stinging of the eyes, lacrimation, increased intraocular pressure
(ophthalmic).
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, dyspepsia, flatulence, abdominal pain.
General disorders and administration site conditions: Injection site reactions (e.g. pain), application site reactions
(e.g. irritation, erythema, itchiness, dryness, oedema, pyrexia.
Infections and infestations: Influenza.
Metabolism and nutrition disorders: Anorexia.
Musculoskeletal and connective tissue disorders: Arthralgia, osteoarthritis, back pain, limb pain.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia, somnolence.
Renal and urinary disorders: UTI, renal function abnormality, haematuria.
Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection, nasopharyngitis, sinusitis,
bronchitis, cough.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Vascular disorders: Hypotension.
Potentially Fatal: Anaphylaxis reaction, CV thrombotic events (e.g. MI, stroke), gastrointestinal ulceration, perforation
or haemorrhage, bronchospasm; rarely, hepatotoxicity (e.g. fulminant hepatitis, hepatic necrosis or failure), Stevens-
Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis.
Pregnancy Category (US FDA)
Topical: C (FDA Pregnancy Category B for 3% topical gel); IV/Parenteral/PO/Rectal: C (prior to 30 weeks gestation);
Ophth: C; IV/Parenteral/PO/Rectal/Topical: D (starting at 30 weeks gestation)
Patient Counseling Information
This drug may cause dizziness, drowsiness or blurred vision, if affected, do not drive or operate machinery. Avoid
excessive exposure of affected area to sunlight (transdermal or topical/cutaneous). Remove contact lenses prior to
administration and reinsert after 15 minutes (ophthalmic).
MonitoringParameters
Monitor CBC, blood pressure (at baseline and during therapy), K levels, LFTs (including ALT/AST levels), renal
function (including urine output, BUN, serum creatinine), occult blood loss, oedema, weight gain; signs and symptoms
of gastrointestinal ulceration, perforation or haemorrhage; mental confusion, disorientation, bleeding, bruising.
Overdosage
Symptoms: Lethargy, tinnitus, headache, drowsiness, nausea, vomiting, diarrhoea, dizziness, disorientation,
excitation, epigastric pain, gastrointestinal bleeding, convulsions; rarely, anaphylactoid reactions, hypertension,
respiratory depression, acute renal failure, coma. Management: Symptomatic and supportive treatment. Maintain a
clear airway. Administration of activated charcoal within 1 hour of ingestion or perform gastric lavage. May perform
osmotic cathartic within 4 hours of ingestion.
Drug Interactions
Increased risk of gastrointestinal ulceration, perforation or haemorrhage with other corticosteroids, SSRIs. Increased
risk CV-related adverse reactions with cardiac glycosides. Increased risk of hyperkalaemia and renal toxicity with
ACE inhibitors, diuretics, ciclosporin, tacrolimus. Increased risk of haematological toxicity with zidovudine. Increased
levels and risk of toxicity with digoxin, lithium, methotrexate, pemetrexed, phenytoin. Decreased effect with colestipol,
cholestyramine. Decrease effect of mifepristone. Increased peak plasma concentration with CYP2C9 inhibitors e.g.
voriconazole.
Potentially Fatal: Increased risk of gastrointestinal ulceration, perforation or haemorrhage with other NSAIDs (e.g.
aspirin), antiplatelets, anticoagulants (e.g. warfarin).
Food Interaction
Decreased absorption with food. Avoid alcohol.
Lab Interference
May cause false-positive aldosterone/renin ratio.
Action
Description: Diclofenac, an NSAID derived from phenylacetic acid, has analgesic, anti-inflammatory and antipyretic
properties. It reversibly inhibits cyclooxygenase-1 and 2 thereby, also inhibiting prostaglandin synthesis.
Pharmacokinetics:
Absorption: Absorbed from the gastrointestinal tract, skin. Decreased absorption rate with food. Bioavailability: 55%.
Time to peak plasma concentration (under fasted conditions): Approx 1 hour (conventional tablet or capsule,
suppositories); 2-3 hours (delayed-release tablet); approx 4-5 hours (extended-release tablet or capsule); approx
0.25 hour (powder for oral solution); approx 5 minutes (IV); approx 20 minutes (IM); 10-20 hours (transdermal).
Distribution: Crosses the placenta and enters breastmilk. Volume of distribution: Approx 1.3-1.4 L/kg. Plasma protein
binding: >99% mainly to albumin.
Metabolism: Undergoes first-pass metabolism in the liver via hydroxylation and methoxylation into metabolites
including 4'-hydroxydiclofenac (major), 3'-hydroxydiclofenac, 5-hydroxydiclofenac, 4',5-dihydroxydiclofenac and 3'-
hydroxy-4’-methoxydiclofenac; further metabolised via glucuronidation.
Excretion: Mainly via urine (approx 60% as metabolites including glucuronide conjugates; <1% as unchanged drug);
bile (approx 35%). Terminal elimination half-life: Approx 1-2 hours (tablet, capsule, inj, suppositories); approx 12
hours (transdermal patch).

IBUPROFEN

Dosage/Direction for Use

Adult : PO Mild to moderate pain; Dysmenorrhoea As conventional tab or cap: 200-400 mg 4-6 hourly as needed.
Max: 1.2 (OTC) or 3.2 g/day. Max duration: 10 days (OTC). As modified-release tab or cap: Up to 1.6 g once daily
(evening). If needed, may further increase to 2.4 g/day in 2 divided doses. Fever 200-400 mg 4-6 hourly. Max: 1.2
(OTC) or 3.2 g/day. Max duration: 3 days (OTC). Osteoarthritis; Rheumatoid arthritis As conventional tab or cap:
400-800 mg 3-4 times/day. Max: 3.2 g/day. As modified-release tab or cap: Up to 1.6 g/day (evening). If needed, may
further increase to 2.4 g/day in 2 divided doses. IV Mild to moderate pain 400-800 mg 6 hourly, as needed. Max: 3.2
g/day. Fever Initial: 400 mg then, 400 mg 4-6 hourly or 100-200 mg 4 hourly, as needed. Max: 3.2
g/day. Topical/Cutaneous Pain and inflammation associated with musculoskeletal and joint disorders As 5%
gel, foam, spray solution or 10% gel: Apply onto affected area as directed. As 200 mg plaster: 1 plaster/day.
Dosage Details
Intravenous
Fever
Adult: Initially, 400 mg then, 400 mg 4-6 hourly or 100-200 mg 4 hourly, as needed. Max: 3.2 g daily.
Child: 6 months to <12 years 10 mg/kg over 10 minutes 4-6 hourly, as needed; 12-17 years 400 mg over 10 minutes
4-6 hourly. Max: 2.4 g daily (Max 400 mg/dose).

Intravenous
Mild to moderate pain
Adult: 400-800 mg 6 hourly, as needed. Max: 3.2 g daily.
Child: 6 months to <12 years 10 mg/kg over 10 minutes 4-6 hourly, as needed. 12-17 years 400 mg over 10 minutes
4-6 hourly. Max: 2.4 g daily (Max 400 mg/dose).

Intravenous
Closure of patent ductus arteriosus
Child: Initially, 10 mg/kg infused over 15 minutes then, 2 doses of 5 mg/kg after 24 and 48 hours. Dosage should be
based on birth weight.

Oral
Juvenile rheumatoid arthritis
Child: As conventional tab or cap: 30-40 mg/kg daily in 3-4 divided doses. Max: 2.4 g daily. As modified-release tab
or cap: ≥12 years Same as adult dosage.

Oral
Dysmenorrhoea
Adult: As conventional tab or cap: 200-400 mg 4-6 hourly. Max: 3.2 g daily. As modified-release tab or cap: Up to 1.6
g once daily (evening). If needed, may further increase to 2.4 g daily in 2 divided doses.

Oral
Fever
Adult: 200-400 mg 4-6 hourly. Max: 1.2 (OTC) or 3.2 g daily. Max duration: 3 days (OTC).
Child: ≥6 months 5-10 mg/kg 6-8 hourly. Max: 40 mg/kg daily (Max 400 mg/dose).

Oral
Osteoarthritis, Rheumatoid arthritis
Adult: As conventional tab or cap: 400-800 mg 3-4 times daily. Max: 3.2 g daily. As modified-release tab or cap: Up
to 1.6 g once daily (evening). If needed, may further increase to 2.4 g daily in 2 divided doses.

Oral
Mild to moderate pain
Adult: As conventional tab or cap: 200-400 mg 4-6 hourly as needed. Max: 1.2 (OTC) or 3.2 g daily. Max duration: 10
days (OTC). As modified-release tab or cap: Up to 1.6 g once daily (evening). If needed, may further increase to 2.4 g
daily in 2 divided doses.
Child: As conventional tab or cap: ≥6 months 4-10 mg/kg daily 6-8 hourly. Max: 400 mg/dose, 40 mg/kg daily. As
modified-release tab or cap: ≥12 years Same as adult dosage.

Rectal
Fever, Mild to moderate pain
Child: As 60 or 125 mg suppository: ≥3-9 months weighing 6-8 kg: 60 mg 6-8 hourly up to 3 doses daily; >9 months
to 2 years weighing 8-12.5 kg: 60 mg 6 hourly up to 4 doses daily; >2-4 years weighing 12.5-17 kg: 125 mg 6-8
hourly up to 3 doses daily; >4-6 years weighing 17-20.5 kg: 125 mg 6 hourly up to 4 doses daily. As 75 mg
suppository: ≥8-12 months weighing 7.5-10 kg: 75 mg up to 3 times daily; >12 months to 3 years weighing 10-15 kg:
75 mg up to 4 times daily.

Topical/Cutaneous
Pain and inflammation associated with musculoskeletal and joint disorders
Adult: As 5% gel, foam, spray solution or 10% gel: Apply onto affected area as directed. As 200 mg plaster: 1 plaster
daily.
Child: As 5% gel, foam, spray solution or 10% gel: ≥12 years Same as adult dosage. As 200 mg plaster: ≥16 years 1
plaster daily.
Administration
Should be taken with food.
Contraindications
Hypersensitivity (including asthma) to ibuprofen or other NSAIDs. History of gastrointestinal bleeding, perforation, or
ulceration related to NSAID therapy. Gastrointestinal ulceration, perforation or haemorrhage. Severe cardiac failure or
patients undergoing coronary artery bypass graft surgery. Severe renal or hepatic impairment. Pregnancy (3rd
trimester).
Special Precautions
Patient with CV disease or risk factors of (e.g. CHF, ischaemic heart disease, CVA, hypertension, hyperlipidaemia,
diabetes mellitus), bleeding disorders, SLE, mixed connective tissue disorders, porphyria. Surgery. Hepatic and renal
impairment. Elderly, children (especially premature neonates with risk factors for infection and infants with increased
bilirubin levels). Pregnancy (1st-2nd trimester) and lactation. Concomitant use of other NSAIDs, antiplatelets,
anticoagulants. Not for prolonged usage.
Adverse Reactions
Significant: Anaphylactoid reactions, risk of hyperkalaemia, oedema, HTN, liver function abnormalities, anaemia,
blurred vision, scotomata, changes in colour vision. Rarely, severe blood dyscrasias (e.g. agranulocytosis,
thrombocytopenia, aplastic anaemia).
Ear and labyrinth disorders: Tinnitus.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, heartburn, abdominal
pain; enterocolitis (IV).
General disorders and administration site conditions: Fluid retention.
Infections and infestations: Sepsis (IV).
Injury, poisoning and procedural complications: Injection site reactions.
Investigations: Increased BUN (IV).
Metabolism and nutrition disorders: Decreased appetite; hypoalbuminemia, hypoglycaemia, hypocalcaemia,
hypokalaemia, hypernatraemia, adrenal insufficiency (IV).
Nervous system disorders: Headache, dizziness; intraventricular haemorrhage (IV).
Psychiatric disorders: Nervousness.
Renal and urinary disorders: Haematuria, UTI.
Respiratory, thoracic and mediastinal disorders: Apnoea, cough, respiratory infection.
Skin and subcutaneous tissue disorders: Rashes, pruritus; skin irritation (IV).
Potentially Fatal: CV thrombotic events (e.g. MI, stroke), gastrointestinal ulceration, perforation or haemorrhage;
rarely, hepatotoxicity (e.g. fulminant hepatitis, hepatic necrosis or failure), Stevens-Johnson syndrome, exfoliative
dermatitis, toxic epidermal necrolysis.
Patient Counseling Information
This drug may cause dizziness, drowsiness or blurred vision, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor CBC, occult blood loss, K levels, LFTs and renal function; signs and symptoms of ophthalmic-related
reactions.
Overdosage
Symptoms: Headache, drowsiness, CNS depression, seizures, tinnitus, nausea, vomiting, abdominal pain,
hypotension, bradycardia, tachycardia, atrial fibrillation, apnoea, respiratory failure, hyperkalaemia, acute renal
failure, lethargy, metabolic acidosis, coma. Management: Supportive and symptomatic treatment. Induce emesis with
syrup of ipecac or perform gastric lavage. Administer activated charcoal to reduce absorption and reabsorption.
Forced alkaline diuresis might be beneficial. Management of hypotension, gastrointestinal bleeding and acidosis may
also be necessary.
Drug Interactions
Increased risk of gastrointestinal ulceration, perforation or haemorrhage with other NSAIDs (e.g. aspirin),
antiplatelets, anticoagulants (e.g. warfarin), corticosteroids, SSRIs. Increased risk of hyperkalaemia and renal toxicity
with ciclosporin, tacrolimus. Increased levels and risk of toxicity with lithium, methotrexate. May decrease
antihypertensive effect of ACE inhibitors, angiotensin II receptor antagonist; natriuretic effect of diuretics.
Food Interaction
Food intake decreases absorption rate. Avoid alcohol.
Action
Description: Ibuprofen, an NSAID, has analgesic, anti-inflammatory and antipyretic properties. It inhibits
cyclooxygenase-1 and 2 thereby, also inhibiting prostaglandin synthesis.
Onset: Analgesic: 30-60 minutes. Anti-inflammatory: ≤7 days (oral).
Duration: 4-6 hours (oral).
Pharmacokinetics:
Absorption: Absorbed from the gastrointestinal tract, partially into the skin, and almost completely absorbed after
rectal administration. Food intake decreases absorption rate. Time to peak plasma concentration: 1-2 hours (oral);
0.75 hours (rectal).
Distribution: Enters breast milk. Plasma protein binding: 90-99%.
Metabolism: Metabolised in the liver via oxidation.
Excretion: Mainly via urine (45-80% as metabolites, approx 1% as unchanged drug); faeces. Elimination half-life:
Approx 2 hours.

Classification & Chemistry

The term opioid describes all compounds that work at opioid

receptors. The term opiate specifically describes the naturally

occurring alkaloids: morphine, codeine, thebaine, and papaverine.

In contrast, narcotic was originally used to describe sleep-inducing

medications, but in the United States, its usage has shifted into a

legal term.

Opioid drugs include full agonists, partial agonists, and antag

onists–measures of intrinsic activity or efficacy. Morphine is a full

agonist at the μ (mu)-opioid receptor, the major analgesic opioid

receptor (Table 31–1). Opioids may also differ in receptor binding

affinity. For example, morphine exhibits a greater binding affinity

at the μ-opioid receptor than does codeine. Other opioid receptor

subtypes include c (delta) and j (kappa) nociception/opioid

receptor-like subtype 1 (ORL-1) receptors. Simple substitution

of an allyl group on the nitrogen of the full agonist morphine plus

addition of a single hydroxyl group results in naloxone, a strong

μ-receptor antagonist. The structures of some of these compounds

are shown later in this chapter. Some opioids, eg, nalbuphine, a

mixed agonist-antagonist, are capable of producing an agonist

(or partial agonist) effect at one opioid receptor subtype and

an antagonist effect at another. The receptor-activating proper

ties and affinities of opioid analgesics can be manipulated by

pharmaceutical chemistry; in addition, certain opioid analgesics

are modified in the liver, resulting in compounds with greater

analgesic action. Chemically, the opioids derived from opium are phenanthrene derivatives and include four or more fused
rings,
while most of the synthetic opioids are simpler molecules.

Endogenous Opioid Peptides

Opioid alkaloids (eg, morphine) produce analgesia through

actions at central nervous system (CNS) receptors that also

respond to certain endogenous peptides with opioid-like phar

macologic properties. The general term currently used for these

endogenous substances is endogenous opioid peptides.

Three families of endogenous opioid peptides have been

described: the endorphins, the pentapeptide enkephalins

(methionine-enkephalin [met-enkephalin] and leucine-enkeph

alin [leu-enkephalin]), and the dynorphins. These three families

of endogenous opioid peptides have overlapping affinities for

opioid receptors (Table 31–1).

The endogenous opioid peptides are derived from three precur

sor proteins: prepro-opiomelanocortin (POMC), preproenkepha

lin (proenkephalin A), and preprodynorphin (proenkephalin B).

POMC contains the met-enkephalin sequence, β-endorphin, and

several nonopioid peptides, including adrenocorticotropic hormone

(ACTH), β-lipotropin, and melanocyte-stimulating hormone.

Preproenkephalin contains six copies of met-enkephalin and one

copy of leu-enkephalin. Leu- and met-enkephalin have slightly

higher affinity for the δ (delta) than for the μ-opioid receptor

(Table 31–1). Preprodynorphin yields several active opioid peptides

that contain the leu-enkephalin sequence. These are dynorphin A,

dynorphin B, and α and β neoendorphins. Painful stimuli can

evoke release of endogenous opioid peptides under the stress associ

ated with pain or the anticipation of pain, and they diminish the

perception of pain.

In contrast to the analgesic role of leu- and met-enkephalin,

an analgesic action of dynorphin A—through its binding to

κ-opioid receptors—remains controversial. Dynorphin A is also

found in the dorsal horn of the spinal cord. Increased levels of

dynorphin occur in the dorsal horn after tissue injury and inflam

mation. This elevated dynorphin level is proposed to increase pain

and induce a state of long-lasting sensitization and hyperalgesia.

The pronociceptive action of dynorphin in the spinal cord appears

to be independent of the opioid receptor system. Beyond their

role in pain, κ-opioid receptor agonists can also function as

antipruritic agents.

The principal receptor for this novel system is the G protein

coupled orphanin opioid-receptor-like subtype 1 (ORL1). Its

endogenous ligand has been termed nociceptin by one group of

investigators and orphanin FQ by another group. This ligand

receptor system is currently known as the N/OFQ system. Noci

ceptin is structurally similar to dynorphin except for the absence

of an N-terminal tyrosine; it acts only at the ORL1 receptor,

now known as NOP. The N/OFQ system is widely expressed in

the CNS and periphery, reflecting its equally diverse biology and

pharmacology. As a result of experiments using highly selective

NOP receptor ligands, the N/OFQ system has been implicated in

both pro- and anti-nociceptive activity as well as in the modula

tion of drug reward, learning, mood, anxiety, and cough processes,

and of parkinsonism.
STRONG AGONISTS
Phenanthrenes
Morphine, hydromorphone, and oxymorphone are strong ago

nists useful in treating severe pain.

Heroin (diamorphine, diacetylmorphine) is potent and fast

acting, but its use is prohibited in the USA and Canada. In recent

years, there has been considerable agitation to revive its use.

However, double-blind studies have not supported the claim that

heroin is more effective than morphine in relieving severe chronic

pain, at least when given by the intramuscular route.

Phenylheptylamines
Methadone has undergone a dramatic revival as a potent and

clinically useful analgesic. It can be administered by the oral, intra

venous, subcutaneous, spinal, and rectal routes. It is well absorbed

from the gastrointestinal tract, and its bioavailability far exceeds

that of oral morphine.

Methadone is not only a potent μ-receptor agonist but its

racemic mixture of d- and l-methadone isomers can also block

both NMDA receptors and monoaminergic reuptake transporters.

These nonopioid receptor properties may help explain its ability

to relieve difficult-to-treat pain (neuropathic, cancer pain), espe

cially when a previous trial of morphine has failed. In this regard,

when analgesic tolerance or intolerable side effects have developed

with the use of increasing doses of morphine or hydromorphone,

“opioid rotation” to methadone has provided superior analgesia at

10–20% of the morphine-equivalent daily dose. In contrast to its

use in suppressing symptoms of opioid withdrawal, use of metha

done as an analgesic typically requires administration at intervals

of no more than 8 hours. However, given methadone’s highly

variable pharmacokinetics and long half-life (25–52 hours), initial

administration should be closely monitored to avoid potentially

harmful adverse effects, especially respiratory depression. Because

methadone is metabolized by CYP2B6 and CYP3A4 isoforms in

the liver, inhibition of its metabolic pathway or hepatic dysfunc

tion has also been associated with overdose effects, including

respiratory depression or, more rarely, prolonged QT-based cardiac

arrhythmias.

Methadone is widely used in the treatment of opioid misuse.

Tolerance and physical dependence develop more slowly with

methadone than with morphine. The withdrawal signs and symp

toms occurring after abrupt discontinuance of methadone are

milder, although more prolonged, than those of morphine. These

properties make methadone a useful drug for detoxification and

for maintenance of the chronic relapsing heroin addict.

For detoxification of a heroin-dependent addict, low doses of

methadone (5–10 mg orally) are given two or three times daily for

2 or 3 days. Upon discontinuing methadone, most addicts experi

ence a mild but endurable withdrawal syndrome.

For maintenance therapy of the opioid recidivist, tolerance to

50–100 mg/d of oral methadone may be deliberately produced; in

this state, the addict experiences cross-tolerance to heroin, which

prevents most of the addiction-reinforcing effects of heroin. One

rationale of maintenance programs is that blocking the reinforce

ment obtained from misuse of illicit opioids removes the drive to

obtain them, thereby reducing criminal activity and making the

addict more amenable to psychiatric and rehabilitative therapy.

The pharmacologic basis for the use of methadone in maintenance

programs is sound and the sociologic basis is rational, but some

methadone programs fail because nonpharmacologic management

is inadequate.

The concurrent administration of methadone to heroin addicts

known to be recidivists has been questioned because of the

increased risk of overdose death secondary to respiratory arrest. As

the number of patients prescribed methadone for persistent pain

has increased, so, too, has the incidence of accidental overdose

and complications related to respiratory depression. Variability

in methadone metabolism, protein binding, distribution, and

nonlinear opioid dose conversion all play a role in adverse events.

Buprenorphine, a partial μ-receptor agonist with long-acting

properties, has been found to be effective in opioid detoxification

and maintenance programs and is presumably associated with a

lower risk of such overdose fatalities.

Phenylpiperidines
Fentanyl is one of the most widely used agents in the family

of synthetic opioids. The fentanyl subgroup now includes suf

entanil, alfentanil, and remifentanil in addition to the parent

compound, fentanyl. An extremely potent analog, carfentanil,

is used in veterinary medicine for sedating large mammals, eg,

elephants. Adulteration of street heroin with carfentanil has been

responsible for many deaths in humans

These opioids differ mainly in their potency and biodisposi

tion. Sufentanil is five to seven times more potent than fentanyl.

Alfentanil is considerably less potent than fentanyl, but acts more

rapidly and has a markedly shorter duration of action. Remifen

tanil is metabolized very rapidly by blood and nonspecific tissue

esterases, making its pharmacokinetic and pharmacodynamic

half-lives extremely short. Such properties are useful when these

compounds are used in anesthesia practice. Although fentanyl

is now the predominant analgesic in the phenylpiperidine class,

meperidine continues to be used. This older opioid has signifi

cant antimuscarinic effects, which may be a contraindication if

tachycardia would be a problem. Meperidine is also reported to

have a negative inotropic action on the heart. In addition, it has

the potential for producing seizures secondary to accumulation

of its metabolite, normeperidine, in patients receiving high doses

or with concurrent renal failure. Given this undesirable profile,

use of meperidine as a first-line analgesic is becoming increas

ingly rare.

Morphinans
Levorphanol is a synthetic opioid analgesic closely resembling

morphine that has μ-, δ-, and κ-opioid agonist actions, serotonin

norepinephrine reuptake inhibition, and NMDA receptor antago

nist properties.

MILD TO MODERATE AGONISTS

Phenanthrenes
Codeine, dihydrocodeine, and hydrocodone have lower

binding affinity to μ-opioid receptors than morphine and often

have adverse effects that limit the maximum tolerated dose

when one attempts to achieve analgesia comparable to that of

morphine.

Oxycodone is more potent and is prescribed alone in higher

doses as immediate-release or controlled-release forms for the

treatment of moderate to severe pain. Combinations of hydro

codone or oxycodone with acetaminophen are the predominant

formulations of orally administered analgesics in the United States

for the treatment of mild to moderate pain. However, there has

been a large increase in the use of controlled-release oxycodone at

the highest dose range. An intravenous formulation of oxycodone

is available outside the United States.

Phenylheptylamines
Propoxyphene is chemically related to methadone but has

extremely low analgesic activity. Its low efficacy makes it unsuit

able, even in combination with aspirin, for severe pain. The

increasing incidence of deaths associated with its use and misuse

caused it to be withdrawn in the United States.

Phenylpiperidines
Diphenoxylate and its metabolite, difenoxin, are not used for

analgesia but for the treatment of diarrhea. They are scheduled

for minimal control (difenoxin is Schedule IV, diphenoxylate

Schedule V; see inside front cover) because the likelihood of their

misuse is remote. The poor solubility of the compounds limits

their use for parenteral injection. As antidiarrheal drugs, they are

used in combination with atropine. The atropine is added in a

concentration too low to have a significant antidiarrheal effect but

is presumed to further reduce the likelihood of misuse.

Loperamide is a phenylpiperidine derivative used to control

diarrhea. Due to action on peripheral μ-opioid receptors and

lack of effect on CNS receptors, investigations are ongoing as to

whether it could be an effective analgesic. Its potential for misuse

is considered very low because of its limited access to the brain. It

is therefore available without a prescription.

The usual dose with all of these antidiarrheal agents is two

tablets to start and then one tablet after each diarrheal stool.

OPIOIDS WITH MIXED RECEPTOR

ACTIONS
Care should be taken not to administer any partial agonist or drug

with mixed opioid receptor actions to patients receiving pure ago

nist drugs because of the unpredictability of both drugs’ effects;

reduction of analgesia or precipitation of an explosive abstinence

syndrome may result.

Phenanthrenes
As noted above, buprenorphine is a potent and long-acting

phenanthrene derivative that is a partial μ-receptor agonist

(low intrinsic activity) and an antagonist at the δ and κ recep

tors and is therefore referred to as a mixed agonist-antagonist.

Although buprenorphine is used as an analgesic, it can antago

nize the action of more potent μ agonists such as morphine.

Buprenorphine also binds to ORL1, the orphanin receptor.

Whether this property also participates in opposing μ recep

tor function is under study. Administration by the sublingual

route is preferred to avoid significant first-pass effect. Buprenor

phine’s long duration of action is due to its slow dissociation

from μ receptors. This property renders its effects resistant to

naloxone reversal. Buprenorphine was approved by the FDA in

2002 for the management of opioid dependence, and studies

suggest it is as effective as methadone for the management of

opioid withdrawal and detoxification in programs that include

counseling, psychosocial support, and direction by physicians

qualified under the Drug Addiction Treatment Act. In the USA,

a special Drug Enforcement Administration (DEA) license and

training are needed to legally prescribe buprenorphine for addic

tion. In contrast to methadone, high-dose administration of

buprenorphine results in a μ-opioid antagonist action, limiting

its properties of analgesia and respiratory depression. However,

buprenorphine formulations can still cause serious respiratory

depression and death, particularly when extracted and injected

intravenously in combination with benzodiazepines or used with

other CNS depressants (ie, sedatives, antipsychotics, or alcohol).

Buprenorphine is also available combined with naloxone, a pure

μ-opioid antagonist (as Suboxone), to help prevent its diversion

for illicit intravenous misuse. A slow-release transdermal patch

preparation that releases drug over a 1-week period is also avail

able (Butrans). Most recently, the FDA approved an implanted

buprenorphine rod (Probuphine) that lasts for 6 months and is

meant to deter misuse. Psychotomimetic effects, with hallucina

tions, nightmares, and anxiety, have been reported after use of

drugs with mixed agonist-antagonist actions.

Pentazocine (a benzomorphan) and nalbuphine are other

examples of opioid analgesics with mixed agonist-antagonist

properties. Nalbuphine is a strong κ-receptor agonist and a partial

μ-receptor antagonist; it is given parenterally. At higher doses there

seems to be a definite ceiling—not noted with morphine—to

the respiratory depressant effect. Unfortunately, when respiratory

depression does occur, it may be relatively resistant to naloxone

reversal due to its greater affinity for the receptor than naloxone.

Nalbuphine is equipotent to morphine for analgesia and, at lower

doses, can be effective for pruritus for opioid and nonopioid

etiologies.

Morphinans
Butorphanol produces analgesia equivalent to nalbuphine but

appears to produce more sedation at equianalgesic doses. Butor

phanol is considered to be predominantly a κ agonist. However,

it may also act as a partial agonist or antagonist at the μ receptor.

Benzomorphans
Pentazocine is a κ agonist with weak μ-antagonist or partial

agonist properties. It is the oldest mixed agent available. It may

be used orally or parenterally. However, because of its irritant

properties, the injection of pentazocine subcutaneously is not

recommended.

MISCELLANEOUS
Tramadol is a centrally acting analgesic whose mechanism of

action is complex and dependent on ability of the parent drug

and its metabolites to block serotonin and norepinephrine

reuptake. Because its analgesic effect is only partially antagonized

by naloxone, it is thought to depend less on its low-affinity

binding to the μ receptor for therapeutic activity. The recom

mended dosage is 50–100 mg orally four times daily; however,

its systemic concentration and analgesic effect are dependent

on the enzymatic activity of CYP2D6 polymorphisms. Toxicity

includes association with seizures; the drug is relatively contra

indicated in patients with a history of epilepsy and for use with

other drugs that lower the seizure threshold. Another serious risk

is the development of serotonin syndrome, especially if selective

serotonin reuptake inhibitor antidepressants are being adminis

tered (see Chapter 16). Other adverse effects include nausea and

dizziness, but these symptoms typically abate after several days

of therapy. No clinically significant effects on respiration or the

cardiovascular system have thus far been reported when used as

monotherapy. Given the fact that the analgesic action of tramadol

is largely independent of μ-receptor action, tramadol may serve as

an adjunct with pure opioid agonists in the treatment of chronic

neuropathic pain.

Tapentadol is an analgesic with modest μ-opioid recep

tor affinity and significant norepinephrine reuptake-inhibiting

action. In animal models, its analgesic effects were only

moderately reduced by naloxone but strongly reduced by an

α2-adrenoceptor antagonist. Furthermore, its binding to the

norepinephrine transporter (NET, see Chapter 6) was stronger

than that of tramadol, whereas its binding to the serotonin

transporter (SERT) was less than that of tramadol. Tapentadol

was approved in 2008 and has been shown to be as effective as

oxycodone in the treatment of moderate to severe pain but with

a reduced profile of gastrointestinal complaints such as nausea.

Tapentadol carries risk for seizures in patients with seizure

disorders and for the development of serotonin syndrome. It is

unknown how tapentadol compares in clinical utility to trama

dol or other analgesics whose mechanism of action is not based

primarily on opioid receptor pharmacology.

ANTITUSSIVES
The opioid analgesics are among the most effective drugs avail

able for the suppression of cough. This effect is often achieved at

doses below those necessary to produce analgesia. The receptors

involved in the antitussive effect appear to differ from those associ

ated with the other actions of opioids. For example, the antitussive

effect is also produced by stereoisomers of opioid molecules that

are devoid of analgesic effects and addiction liability (see below).

The physiologic mechanism of cough is complex, and little

is known about the specific mechanism of action of the opioid

antitussive drugs. It appears likely that both central and peripheral

effects play a role.

The opioid derivatives most commonly used as antitus

sives are dextromethorphan, codeine, levopropoxyphene, and

noscapine (levopropoxyphene and noscapine are not available

in the USA). They should be used with caution in patients tak

ing monoamine oxidase inhibitors (Table 31–5). Antitussive

preparations usually also contain expectorants to thin and liquefy

respiratory secretions. Importantly, due to increasing reports of

death in young children taking dextromethorphan in formula

tions of over-the-counter “cold/cough” medications, its use

in children younger than 6 years of age has been banned by

the FDA. Moreover, because of variations in the metabolism

of codeine, its use for any purpose in young children is being

reconsidered.

Dextromethorphan is the dextrorotatory stereoisomer of a

methylated derivative of levorphanol. It is purported to be free

of addictive properties and produces less constipation than

codeine. The usual antitussive dose is 15–30 mg three or four

times daily. It is available in many over-the-counter products.

Dextromethorphan has also been found to enhance the anal

gesic action of morphine and presumably other μ-receptor

agonists. However, misuse of its purified (powdered) form

has been reported to lead to serious adverse events including

death.

Codeine, as noted, has a useful antitussive action at doses lower

than those required for analgesia. Thus, 15 mg is usually sufficient

to relieve cough.

Levopropoxyphene is the stereoisomer of the weak opioid ago

nist dextropropoxyphene. It is devoid of opioid effects, although

sedation has been described as a side effect. The usual antitussive

dose is 50–100 mg every 4 hours.

THE OPIOID ANTAGONISTS

Pharmacokinetics
Naloxone is usually given by injection and has a short duration

of action (1–2 hours) when given by this route. Metabolic dis

position is chiefly by glucuronide conjugation like that of the

agonist opioids with free hydroxyl groups. Naltrexone is well

absorbed after oral administration but may undergo rapid first

pass metabolism. It has a half-life of 10 hours, and a single oral

dose of 100 mg blocks the effects of injected heroin for up to

48 hours. Nalmefene, the newest of these agents, is a derivative

of naltrexone but is available only for intravenous administration.

Like naloxone, nalmefene is used for opioid overdose but has a

longer half-life (8–10 hours).

Pharmacodynamics
When given in the absence of an agonist drug, these antagonists

are almost inert at doses that produce marked antagonism of ago

nist opioid effects.

When given intravenously to a morphine-treated subject, the

antagonist completely and dramatically reverses the opioid effects

within 1–3 minutes. In individuals who are acutely depressed by

an overdose of an opioid, the antagonist effectively normalizes

respiration, level of consciousness, pupil size, bowel activity, and

awareness of pain. In dependent subjects who appear normal

while taking opioids, naloxone or naltrexone almost instanta

neously precipitates an abstinence syndrome.

There is no tolerance to the antagonistic action of these agents,

nor does withdrawal after chronic administration precipitate an

abstinence syndrome.