Pharmacology

Belong to superfamily of G protein-coupled receptors (GPCR).

Extracellular loops are similar in mu, delta and kappa receptors.

Extracellular domains of opioid receptors are considered to be both anchoring points for opioid ligands and gates filtering opioid entry into the binding pocket.

Transmembrane domain forms similar opioid-binding pockets across mu, delta and kappa receptors.

Helix of transmembrane domain is water accessible.

Is coupled to Gi/Go inhibitory proteins.

Involves activating calcium channels.

Involves activation of mitogen-activated protein kinase cascades.

Involves stimulation of G protein-independent signalling pathways.

Will lead to recycling of mu receptors to the cell surface.

Kappa receptor-mediated analgesia is independent from mu and delta receptor-mediated analgesia.

Both mu and delta receptors are recruited in spinal and supraspinal analgesia.

Ablation of delta receptors causes an increase in mechanical nociception and inflammatory pain.

Delta receptor knockout leads to insensitivity to nortriptyline.

Prodynorphin has a biphasic role in control of nociceptive responses.

Opioid receptors are located mostly in superficial dorsal horn.

Opioid binding to receptors is maximally seen with kappa receptors.

Spinally applied morphine can reduce release of substance P and calcitonin G.

Predominant site of spinal opioid action is via presynaptic opioid receptors on the central terminals of nociceptive afferents.

Opioids control dynamic allodynia better than noxious and static allodynia.

Main sites for opioid action are midbrain and brainstem structures.

Nitric oxide is important for 5HT-mediated inhibition of PAG output and reversal of antinociception.

Fibres descending from PAG to dorsal horn of spinal cord are mainly GABAnergic.

Opioids can also interfere with noradrenergic mechanisms.

Tramadol is a weak opioid.

Both static and dynamic allodynia are seen after nerve injury.

Static allodynia is dependent on capsaicin-dependent Aδ fibres.

Morphine blocks static allodynia when administered spinally in nerve injuries.

Large A fibres do not possess opioid receptor.

Nerve injury leads to increased transmitter release via calcium channels.

Is metabolised in liver.

In a dosage of 60 mg, it is a good analgesic by itself.

Is as potent as ibuprofen.

Has a NNT of 8.1.

In a dosage of 30 mg, it improves analgesic efficacy of nonopioids.

Has an oral bioavailability of 80–90%.

Has dose-dependent analgesic efficacy.

Has good efficacy for neuropathic pain.

Has high potential for addiction.

Has a low risk of respiratory depression.

Has an oral bioavailability of 10–45%.

Has active metabolites that contribute to analgesia.

Should be avoided in renal impairment.

Low release formulation has better analgesic profile than immediate release formulation.

Has a NNT of 2.9 for intramuscular route.

Is a semisynthetic derivative of thebaine.

Has less bioavailability than morphine.

Has a better NNT for neuropathic pain than TCAs.

Is only effective for somatic pain.

Has less complications than morphine.

Is a synthetic opioid used in opioid addiction.

Is contraindicated in hepatic and renal impairment.

Steady-state plasma concentration may take 10 days to achieve.

Has a short half-life.

May prolong QTc interval.

Is a racemic mixture of two enantiomers.

Has a higher affinity for delta receptors than morphine.

Has a long half-life.

Has a reduced clearance in acidic urine.

Increases QTc interval.

Is a potent kappa agonist.

Is ideal for transmucosal and transdermal administration.

Has a poor systemic level after transdermal administration.

Is available only for intravenous administration.

Has high risk of abuse.

Bioavailability of fentanyl is higher than morphine via sublingual route.

Intranasal preparations are mainly used for breakthrough pain.

Morphine by inhalation route has a bioavailability of 55%.

Fentanyl iontophoretic patches have technical difficulties in the form of corrosion.

Subcutaneous route is mainly used for cancer pain.

Tolerance to respiratory depression does not occur.

Nausea and vomiting occurs due to direct effect on chemoreceptor trigger zone in area postrema of medulla.

Tolerance to sedation develops quickly.

Both visual and tactile hallucinations can be seen.

Clonazepam is the medication of choice for opioid-induced seizures.

Tolerance develops only on long-term usage.

Physical dependence may be seen on acute administration.

Addiction is not seen with acute/cancer pain management.

Intramuscular route is ideal for post-operative pain relief.

Tramadol is a safe alternative in patients at risk for opioid side effects.

Receptors are located mainly in the dorsal horn of the spinal cord.

Receptors are located only on presynaptic sites.

Receptors mainly modulate visceral pain.

Undergo hepatic metabolism.

Are mainly metabolised by CYP-2D6 and its absence is seen in 50% of white population.

Morphine and methadone achieve steady-state concentration in 24 h.

Methadone is useful in short gut syndrome.

Tolerance to constipation does not develop.

Treatment of opioid-induced constipation is stool softeners and fibre-based bulking agents.

Alvimopan acts as a peripherally acting mu opioid antagonist.

Pruritus is seen more via intravenous/neuraxial route.

Pruritus is because of histamine release.

Fentanyl does not have active metabolites so it causes less sedation.

Respiratory depression may be delayed for as much as 12 h after neuraxial administration.

Naloxone administration can cause congestive heart failure with seizures.

Cause reduction in immune function.

Cause sexual dysfunction only in men.

Has no effect on sleep architecture.

Tolerance involves NMDA receptors.

Tolerance can be treated by opioid rotation.

Noradrenergic neurons within locus coeruleus are implicated in the maintenance of dependence.

Addiction is mediated by ventral tegmental dopaminergic area and orbitofrontal glutaminergic projections to nucleus accumbens.

Alpha2 agonists and beta-agonists can attenuate many of the symptoms of opioid withdrawal.

Withdrawal symptoms usually last for 1 month.

Clonidine can help in weaning from opioids.

Is similar in affinity for mu opioid receptors as is morphine.

Is converted to morphine by O-demethylation.

Major enzyme for conversion to morphine is CYP2D6.

NNT of codeine (60 mg) is 17.

Works more effectively in combination.

Paracetamol (active metabolite of phenacetin) has fewer side effects.

Works by inhibiting prostaglandin formation.

Causes central analgesic effects due to decrease in beta-endorphins.

Is metabolised mostly by renal pathway.

Toxicity is increased with low glutathione levels.

Causes depletion of glutathione stores.

Is seen with dosages increasing 1 g.

Can be seen within daily normal dosages in the form of increased alanine transaminase levels.

Is increased by concomitant usage of alcohol.

Can cause hypertension.

Has central analgesic properties.

Mainly involves mu receptors and effects are fully antagonised by naloxone.

Has equal bioavailabilities for both extended release and immediate release formulations.

Has maximum bioavailability via rectal route.

Has more side effects with extended release formulation.

Exert analgesic effects through strong anti-inflammatory actions.

Are readily absorbed through gastrointestinal tract.

Have bone fractures as main side effects.

May have a role in chemotherapy-induced peripheral neuropathy.

Are of benefit in disc interruptions.

NNT for steroids is more for acute pain than chronic pain.

Topical ketoprofen has the best analgesic profile of all topical NSAIDs.

Lidocaine patches work by binding to and blocking the sodium channels.

TRPV1 receptors are only activated by capsaicin.

Menthol provides analgesia only by its calcium-blocking actions.

Five percent lidocaine patch is as effective as pregabalin in postherpetic neuralgia.

Five percent lidocaine has no role in postherpetic neuralgia.

Eight percent capsaicin patch has efficacy in postherpetic neuralgia and painful HIV neuropathy.

Topical flurbiprofen has greater pain reduction than topical diclofenac.

Topical diclofenac has similar efficacy as oral diclofenac.

Convert arachidonic acid into prostaglandin G2 and H2.

COX-1 is induced only in response to inflammatory stimuli.

COX-2 inhibition may increase the risk of hypertension and increase cardiovascular risk.

Aspiring/acetylsalicylic acid permanently inhibits COX inhibitors.

COX-3 is present in humans.

Prostaglandins act on voltage-gated sodium channels.

Thermal hyperalgesia in inflammatory diseases is mediated by cyclooxygenases.

Prostaglandins increase the excitability of nociceptive nerve fibres.

Intrathecal ketorolac can reduce spinal PGE2 levels.

Inhibition of platelet aggregation is mediated by prostaglandins.

Blockade of COX-2 reduces tissue concentration of prostanoids and also increases endocannabinoids.

Indomethacin has analgesic effect due to increase in spinal endocannabinoids.

Anti-inflammatory action of aspirin-triggered lipoxins is mediated by COX-2 inhibitors.

Non-acidic compounds have high lipophilicity and can enter the CNS.

Ibuprofen is used as an S enantiomer.

Diclofenac works equally well on COX-1 and COX-2.

Galenic formulation of the drug increases absorption of diclofenac.

Diclofenac has significant first-pass metabolism.

Liver toxicity is not seen with diclofenac.

Post-operative bleeding may be seen with ketorolac.

Inactivates both COX enzymes permanently.

Has no effect on thrombocytes.

In a low dose, it has no effect on endothelial cells outside the gut.

Has been used for pain management in paediatric population.

Has no side effect in pregnancy and young children.

Is an indirect inhibitor of COX.

In doses more than 4 grams per day, it may cause liver damage.

May cause increase in blood pressure and CVS events.

Is safe in pregnancy.

Requires N-acetylcysteine for overdosage.

Paracetamol has good anti-inflammatory action.

Etoricoxib has shown maximum benefit in arthritis.

NSAID intake can cause acute renal failure in patients with >10% perioperative blood loss.

NSAID use can cause congestive heart failure in elderly population.

Long-term use of proton pump inhibitors used in conjunction with NSAIDs can increase the risk of osteoporotic fractures.

Have three independent folding units.

Both COX-1 and COX-2 are located on chromosome 9.

TATA box is present in both enzymes.

COX-2 induction is done by IL-1β.

COX-2 inhibitors that penetrate blood brain barrier are better analgesics.

Effect of NSAIDs is related to its level in affected synovial fluid.

Renal excretion is the main pathway.

Haemodialysis leads to increased excretion.

Aspirin metabolism follows first-order and zero-order kinetics.

Ketorolac has better efficacy through intranasal route.

Unlike other NSAIDs, diclofenac has a higher first-pass metabolism.

Ibuprofen antagonises the irreversible platelet inhibition induced by aspirin.

Efficacy of ketoprofen patch is because of lower plasma levels.

Naproxen is safe in pregnancy.

Meloxicam should not be used in renal failure.

Etoricoxib has significantly less risk of GI events as compared to other NSAIDs.

Potentiate the effect of warfarin.

COX-2 inhibitors increase the risk of myocardial infarction.

Maximum cardiovascular effect is seen with meloxicam.

COX-2 inhibitors may impair spinal fusion.

Sodium channel blockade may contribute to its effect.

Amitriptyline is first-line medication for postherpetic neuralgia.

Does not have any role in fibromyalgia.

Selective serotonin reuptake inhibitors may have beneficial effect in fibromyalgia.

Nausea is a side effect of duloxetine.

High voltage-activated calcium channels include L, P/Q and T channels.

T channels are involved with absence seizures.

N-type channels are associated with release of neurotransmitter at synaptic junctions.

P/Q channels are mainly found in the cerebellum.

L-type channels are only found in skeletal muscle.

Binds to α2δ subunit of L-type voltage-gated sodium channels.

Is effective in pain of multiple sclerosis.

Along with other analgesics in combination, it is more effective in diabetic neuropathy.

Gastroretentive formulation is more effective in postherpetic neuralgia.

Enacarbil salt is effective in restless legs syndrome.

Works by a similar mechanism as gabapentin.

Is approved for spinal cord injury pain.

Has no increased side effect in renal failure.

Helps in regulating sleep.

Should be tapered gradually over a 1-week period.

Has a peptidic structure.

Blocks calcium influx into T-type calcium channels.

Causes early tolerance.

Is contraindicated in patients with psychosis.

Has a poor side effect profile.

Can cycle open and close rapidly causing seizures.

Nav1.2 is expressed in sensory neurons.

Mutations may cause long QT syndrome.

Have no role in acute pain.

Phenytoin blocks both fast current and persistent current channels.

Are expressed on nociceptive sensory neurons only.

Mutations lead to decrease in pain.

Anticonvulsants interact and bind with alpha subunit of channels.

Mutations can cause migraine.

Gabapentin only binds to δ1 and δ2 fractions.

Is used in postherpetic neuralgia only.

Side effects can be limited by slow titration.

Has a lower NNT for trigeminal neuralgia.

Decreases hyperalgesia in diabetes mellitus.

Has no major side effect on long-term usage.

Blocks sodium channels in actively firing nerves.

Increases concentration of glutamate.

Has a short half-life.

Has no role in lumbar radicular pain.

Can be given for all neuropathies.

All are expressed on nociceptive sensory neurons.

Mutations lead to decrease in pain.

Anticonvulsants interact and bind with α subunit of channel.

Mutations can cause migraine.

Gabapentin only binds to α2δ1 and α2δ2 genes.

Carbamazepine is the drug of choice for trigeminal neuralgia.

Oxcarbazepine has no effect on sodium channels.

Lamotrigine has been effective in HIV neuropathy.

Lacosamide is a functionalised amino acid.

Pregabalin has less efficacy than gabapentin.

Levetiracetam works on sodium channels.

Retigabine works on potassium channels.

Topiramate acts on multiple receptors.

Valproate acts on multiple receptors.

Perampanel is a selective AMPA-glutamate receptor antagonist.

Work on one receptor only.

CB1 receptors cause membrane hyperpolarisation and inhibit release of neurotransmitters.

CB2 receptors causes positive coupling to adenylate cyclase.

CB1 and CB2 are restricted to neurons only.

CB1 receptors are present in presynaptic terminals of gabanergic and glutaminergic neurons, Aδ and C fibres.

Anandamide is the only preparation known.

Synthesis is seen in neurons.

Anandamide causes inhibition of adenyl cyclase to cause effect.

Anandamide is degraded by fatty acid amide hydrolase (FAAH).

2-AG is a full agonist at CB1 receptors.

Can cause sedation and vasodepression when given in analgesic doses.

Tizanidine is effective in myofascial and neuropathic pain.

Mechanism of action involves activation of postsynaptic receptors.

Activation leads to analgesic properties.

Adrenoceptor agonism is responsible for action of clonidine.

Cause analgesic reaction by blockade of glutamate action.

Ketamine supresses central sensitisation.

Agents acting on glycine co-agonist site on the NMDA receptor complex may have less side effects.

Methadone is the only opioid drug to have actions at NMDA receptors.

Memantine is effective in diabetic neuropathy.

Cause depression of postsynaptic reflexes within the dorsal horn.

Cyclobenzaprine has no drug interactions.

Orphenadrine is contraindicated in neuromuscular junction defects.

Diazepam works with GABA-mediated presynaptic inhibition.

Baclofen can be administered intrathecally.