Pain is unpleasant sensation which only sufferer casn appraise as such is not capable of any satisfactory objective definitionThe word unpleasant comprises whole range of disagreeable feelings from being merely inconvinienced to misery, anguish, anxiety, depression Because pain is universally accepted as signal of disease it is most common symtom that brings the patient to doctor Thuis this topic is important
Pain can occur without nociception merely by its expectation andNociception does not invariably cause pain
Conduct impulses only in response to noxious stimuli Conduct impulses in response to to thermal and mechanical stimuli
Accompaniment of fast pain: withdrawl reflex, symp response Accompaniment of slow pain: emotional perception, autonomic symptoms, skeletal muscle tone
This system regulates the passage of impulses from the peripheral afferent fibres to the thalamus via transmission neurons originating in the dorsal horn. Neurons in the substantiagelatinosa (SG) of the dorsal horn act to inhibit the transmission pathway. Inhibitory interneurons are activated by descending inhibitory neurons or by non-nociceptive afferent input. They are inhibited by nociceptive C-fibre input, so the persistent C-fibre activity facilitates excitation of the transmission cells by either nociceptive or non-nociceptive inputs. This autofacilitation causes successive bursts of activity in the nociceptive afferents to become increasingly effective in activating transmission neurons
An emotional state characterized by anxiety, depression, or unease.
Opioids excite neurons in the periaqueductal grey matter (PAG) and in the nucleus reticularisparagigantocellularis (NRPG), which in turn project to the rostroventral medulla, which includes the nucleus raphemagnus (NRM). From the NRM, 5-HT- and enkephalin-containing neurons run to the substantiagelatinosa of the dorsal horn, and exert an inhibitory influence on transmission. Opioids also act directly on the dorsal horn, as well as on the peripheral terminals of nociceptive afferent neurons. The locus ceruleus (LC) sends noradrenergic neurons to the dorsal horn, which also inhibit transmission. The pathways shown in this diagram represent a considerable oversimplification but depict the general organisation of the supraspinal control mechanisms. Blue shaded boxes represent areas rich in opioid peptides. DLF, dorsolateralfuniculus; 5-HT, 5-hydroxytryptamine. (For more detailed information, see Fields & Basbaum 1994.)
Elimination is almost complete in 24 hours and morphine is noncumulative. Small amounts may persist due to enterohepatic circulation.
It is accidental,suicidal or seen in drug abusers.
Respiratory support (positive pressure respiration also ↓ pulmonary edema formation) and Maintenance of BP (i.v. fluids, vasoconstrictors). Gastric lavage should be done with pot. permanganate to remove unabsorbed drug.
Infants and the elderlyMore susceptible to respiratory depressionObstetric analgesia, pethidine is preferred Patients with respiratory insufficiency emphysema, pulmonary fibrosis,corpulmonale, sudden deaths have occurred.Bronchial asthma: retains CO2 ↑ intracranial tensionEven therapeutic doses can cause markedrespiratory depression in these patients.Vomiting, miosis and altered mentationproduced by morphine interfere withassessment of progress in head injurycases.morphine can aggravate certain conditionsEg. diverticulitis, biliary colic, pancreatitis. Inflamed appendix may rupture. Morphine can be given after the diagnosis is established.
either by retarding its metabolism or by a pharmacodynamic interaction at the level of central neurotransmitters.
should not be restricted in case of pain of terminal illness(cancer)In other chronic conditions, due consideration must be given to their addicting liabilitiesPrevents neurogenic shock and other autonomic effects of excruciating pain.
It is also indicated to relieve pulmonary edema due to infarction of lung and other causes but not due to irritant gases.
Natural , 1/6 to 1/10 potency Can be used to control diarrhoeaCough linctusAdverse effect is constipation
but its effect in theupper small intestine is similar to morphineincluding contraction of the sphincter of OddiPethidine attracted attention as a possible analgesic because it caused the tails of laboratory mice to stand erect (Straub phenomenon), a characteristic of morphine-like drugs caused by spasm of the anal sphincter.Pethidine binds to the mu and kappa -receptors; it is effective for moderate or severe pain but its duration of action is shorter than that of morphine. It is effective against pain beyond the reach of codeine.Despite its substantial structural dissimilarity to morphine, pethidine has many similar properties including that of being antagonised by naloxone.Norpethidine retains pharmacological activity and may accumulate dangerously when renal function is impaired. Pethidine causes vomiting about as often as does morphine; it has atropine-like effects, including dry mouth and blurred vision (cycloplegia and sometimes mydriasis, though usually miosis). Overdose or use in renal failure can cause central nervous system stimulation (myoclonus, convulsions) due to norpethidine.There is disagreement on the extent to which pethidine depresses respiration. It is probable that in equianalgesic doses it is as depressant as morphine. Pethidine dependence occurs, with some tolerance, especially to the side-effects, but its psychic effects are less constant and less marked than those of morphine. Pethidine has evident advantages over morphine for pain that is not very intense, and it is widely used. It is usually given orally (50-100 mg) s.c. or i.m. (25-100 mg), when its effects last 2-3 h. Itis widely used in obstetrics because it does not delay labour like morphine; but it enters the fetus and can depress respiration at birth.
Synthetic drug structurally and pharmacologically related to morphine acts on mu receptors Largely metabolized to products that are excreted in urine half life= 8 hrs Causes less dependence than merphine and heoinMetadone in oioidwithdrawl :Occupancy of opioid receptors by methadone reduces the desire for other opioids, and their effects, should any be taken; the slow offset diminishes the severity of the withdrawal. Addicts who are cooperative enough to take oral methadone feel reduced craving and less 'kick/buzz/rush' from i.v. heroin or morphine because their opioid receptors are already occupied by methadone and the i.v. drug must compete.Reports of deaths in addicts entering prescribed methadone substitution programmes have been attributed to the cardiovascular effects of a membrane stabilising action,unlike morphine.
Small doses of opioids given with induction can usefully reduce the dose requirements of drugsused during anaesthesia. Those used are: fentanyl, alfentanil, sufentanylInanalgesic doses it produces fewer few cardiovascular effects, less histamine release Fentanyl is so potent that discarded patches may yet contain sufficient drug to be dangerous.Alfenatil (tl/21.5 h), given i.v., provides maximum analgesia in 90 seconds, which lasts about 5-10 min from a single dose; it is used for brief (painful) operations.Remifentanil is rapidly metabolised, not in the liver but by blood and tissue esterases. Its short duration of action renders it well suited for continuous i.v. infusion without accumulation.
structurally similar to methadone Demethylated metabolite of dextropoxyphene is cardiotoxic and also seizures dangerous in overdose only partly antagonized by nasloxoneAbuse potential similar to coieneBecsause of reported fatalities, no clear advantage of combinations over paracetamol alone such combinations have been withdrawn in uk
Affinity fror mu redceptoris low and kappa and delta is very low, umlike other opioids its inhibnits the reuptake of NA and 5 HT AND ACTIVATES MONOAMINEWRGIC INHIBITION OF PAINANALGESIC ACTION ONLY PARTIALLY REVERSED BY NALOXONEConfusion, convulsions, hallucinations and anaplhylaxis have been reported with its use.
it can also induce psychological and physical dependence (agonist effect), and this can be severe. It has not proved to be the solution to separating the property of analgesiafrom that of producing dependence, as was hoped for initially. Its analgesic efficacy approximates to that of morphine, but its potency (weight for weight) is about one-third of morphine.
a respiratory stimulant(doxapram) may be needed in overdose,ormechanical ventilation.little effect on the cardiovascular system and may spare the sphincter of Oddi from induced spasm. Its tl/2 is 5 h.respiratory depression is only partially reversed by naloxone25 times more potent than morphine With repe3ated use duration of action may increase to 24 hrs
Physiology and pharmacology of pain
Physiology andPharmacology of Pain
“But pain is a perfect misery The worst of evils Excessive overturns All patience” John Milton In Paradise Lost
Objectives• Definition of pain• Nociceptors : Location, types• Types of pain• Pathway of Pain• Opioid analgesics – Mechanism of action – Morphine – Other opioid analgesics
Pain• Unpleasant sensory and emotional experience associated with actual or potential damage• Pain is redefined as a perception instead of a sensation because it is always a psychological state. – Latin word "peona " meaning punishment• Pain is always subjective• It is differently experienced by each individual.
Nociception – Coined by Sherrington – Latin: noxa means injury – it means the ´perception of noxious stimuli´• Mechanism by which noxious peripheral stimuli are transmitted to the central nervous system to elicit a mechanical response .
Pain - Receptors• Specialized naked nerve endings found in almost every tissue of the body.• Activated by stimuli (mechanical, thermal, chemical)• Distinguished from other receptors by – their higher threshold, and – they are normally activated only by stimuli of noxious intensity-sufficient to cause some degree of tissue damage.• Aδ: Myelinated• C: Unmyelinated
Characteristic features of Aδ & C fibresFeature Aδ fibre C fibreNumber Less MoreMyelination Myelinated UnmyelinatedDiameter 2-5 µm 0.4-1.2 µmConduction 12-30 m/s 0.5 -2 m/svelocitySpecific Most sensitive to Most sensitive forstimulus pressure chemical agentsImpulse Fast component of Slow componentconduction pain of pain
Location of nociceptors• Superficial skin layers• Deeper tissues – Periosteum, joints, arterial wall, liver capsule, pleura• Other deeper tissues – Sparse pain nerve endings – But wide spread tissue damage results in pain
Types of Nociceptors• Somatic – Free nerve endings of Aδ & C fibres – Unimodal, polymodal, silent• Visceral – Wide spread inflammation, ischemia, mesentric streching , spasm or dilation of hollow viscera produces pain – Probably strech receptors
Pain stimuli• Mechanical / thermal stimuli – Fast pain: Sharp well localized , pricking type• Chemical stimuli – Slow pain: poorly localized, dull, throbbing – K+, ADP, ATP – Bradykinin, histamine – Serotonin, Prostaglandins – Substance P, CGRP
Clinical types of pain• Somatic• Visceral• Referred pain – Convergence & facilitation theory• Projected pain• Radiating Pain• Hyperalgesia
Analgesics• Drugs which relieve pain due to multiple causes with out causing loss of consciousness• Drugs which relieve pain due to single causes or specific pain syndromes (ergotamine, carbamazepine, nitrates) are not classified as analgesics• Corticosterroids also not classified as analgesics
Analgesics• Opioid analgesics – Morphine and morphine like drugs• Non steroidal anti-inflammatory drugs – Paracetamol, diclofenac, ibuprofen etc
Opioid Receptors• Opioid receptors found in the brain, spinal cord and peripheral nervous system• Mu (μ1 and μ2 )• Kappa (k1 & k3)• Delta (δ)• Nociceptin/Orphanin (N/OFQ)
Opioid Receptors• Inhibitory action; coupled to Go & Gi Structure of the opioid receptor
Mu-Receptor: Two Typesμ1 μ2 – Located outside spinal – Located throughout CNS cord – Responsible for – Higher affinity for • spinal analgesia, morphine • Respiratory – Supraspinal analgesia depression, – Selectively blocked by • constipation naloxone • physical dependence, and euphoria
Kappa Receptor• Only modest analgesia(spinal κ1 and supraspinal κ3)• Little or no respiratory depression• Little or no dependence• Dysphoric effects• Miosis• Reduced GI motility
Delta Receptor• High affinity for Leu/Met enkephalins endogenous ligands.• The δ mediated analgesia is mainly spinal• Affective component of supraspinal analgesia appears to involve δ receptors as these receptors are present in limbic areas—also responsible for dependence and reinforcing actions.• The proconvulsant action is more prominent in δ agonists.
Spinal sites of opioid action. hyperpolarizesecond-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential reduce transmitter release from presynaptic terminals of nociceptive primary afferents
The descending control system, showing the main sites of action of opioids on pain transmission
Efficacy• Morphine is a strong analgesic.• Higher doses can mitigate even severe pain• Degree of analgesia increasing with dose.• Simultaneous action at spinal and supraspinal sites greatly amplifies the analgesic action.
Selectivity• Suppression of pain perception is selective• No affect on other sensations• proportionate generalized CNS depression (contrast general anaesthetics).
Type of pain• Dull, poorly localized visceral pain is relieved better than sharply defined somatic pain• Nociceptive pain arising from stimulation of peripheral pain receptors is relieved better than neuritic pain due to inflammation or damage of neural structures
Mood and subjective effects• Morphine has a calming effect.• The associated reactions to intense pain – apprehension, – fear, – autonomic effects are also depressed.• Perception of pain and reaction to it are both altered so that pain is no longer as unpleasant or distressing, i.e. patient tolerates pain better.
Mood and subjective effects• Other effects include – feeling of detachment, – Lack of initiative, – limbs feel heavy and body warm, – mental clouding and inability to concentrate.• In normal people, in the absence of pain or apprehension, these are generally appreciated as unpleasant
Mood and subjective effects• Patients in pain or anxiety and addicts – specially perceive it as pleasurable – Refer it as high.• Rapid IV injection by addicts - gives them a kick or rush which is intense, pleasurable—akin to orgasm.• Thus one has to learn to perceive the euphoric effect of morphine.
Mood and subjective effectsIn patients - Pain relief In normal persons Dependence and No addiction Addiction
Other pharmacological actionsGastrointestinal system : – Increase in tone , – reduced motility , – contraction of sphincters , – decrease of G.I. secretions – leading to constipation .( , k , receptors ).
Other effectsRespiratory centre• Morphine depresses respiratory centre in a dose dependent manner• Rate and tidal volume are both decreased• Death in poisoning is due to respiratory failure• Neurogenic, hypercapnoeic and later hypoxic drives are suppressed in succession
Other effects• C.V.S. : – Vasodilatation due to direct decrease of tone of blood vessels – Shift of blood from pulmonary to systemic circuit – histamine release and – depression of vasomotor centre• Urinary bladder – Detrusor contraction leading to urgency . – Sphincter contraction leading to retention of urine
Other effects• Bronchoconstriction – due to histamine release by morphine .• Uterus may be relaxed .• Mild hyperglycemia due to central sympathetic stimulation .• It has weak anticholinesterase action .
Other effects• Endocrine – Growth hormone and prolactin and ADH levels are increased . – FSH ,LH and ACTH levels are decreased .
Pharmacokinetic features• Oral absorption is unreliable• Metabolized by glucuronide conjugation.• Morphine-6-glucuronide is an active metabolite (more potent than morphine)• freely crosses placenta• t1/2of morphine averages 2-3 hours• Effect of a parenteral dose lasts 4-6 hours
ADVERSE EFFECTS• The toxic effects of morphine are an extension of their pharmacological effects• Idiosyncrasy and allergy – Urticaria, itch,swelling of lips. – A local reaction at injection site may occur due to histamine release.• Allergy is uncommon and anaphylactoid reaction is rare.
ADVERSE EFFECTS• Apnoea This may occur in new born when morphine is given to mother during labour.• The BBB of foetus is undeveloped, morphine attains higher concentration in foetal brain• Naloxone 10 µg/kg injected in chord is the treatment of choice.
ToleranceOnset• Tolerance to morphine develops rapidly and can be detected within 12 – 14 hours of morphine administration• within 3 days the equianalgesic dose is increased 5 fold .
Tolerance - effects• Tolerance extends to most actions of morphine – analgesia , – euphoria , – respiratory depression• not to the constipation miosis and convulsions• Cross tolerance occurs between drugs acting at the same receptor , but not drugs acting on different receptor
Tolerance - Mechanism• The tolerance is not pharmacokinetic but due to the true cellular adaptive response• Two proposed mechanisms – upregulation of cAMP system – Downregulation of μ receptors• Recent research suggests tolerance results due to uncoupling between μ receptor and G proteins• Leading to reversal of second messenger (cAMP) and ion channel system
Tolerance - Mechanism• Recently the NMDA antagonists and nitric oxide synthase inhibitors have been found to block morphine tolerance and dependence in animals.• Thus, analgesic action of morphine can be dissociated from tolerance and dependence which contribute to its abuse by – NMDA receptor antagonists – Agents that recouple μ receptor and G proteins
DependenceDependence comprises two components• Physical dependence - associated with the withdrawal syndrome, lasting for a few days• Psychological dependence - associated with craving, lasting for months or years.
Withdrawal symptoms• Withdrawal of the drug causes significant distress to cause a drug seeking behavior manifested by – sweating ,lacrimation, dehydration,fear – anxiety , restlessness , mydriasis , tremor , colic – hypertension , tachycardia and weight loss .• Weak long acting receptor agonist methadone used to relieve withdrawal syndrome.
Psychological dependence• Opioids facilitate DA transmission in mesolimbic /mesocortical pathways and activate endogenous reward pathways in brain.• Important in intiating and mantaining drug seeking behaviour• Psychological dependence rarely occurs in patients being given opioids as analgesics
Acute morphine poisoning• 50 mg morphine i.m. produces serious toxicity.• lethal dose : 250 mg.• Manifestations are extension of pharm. action.• Stupor, flaccidity, shallow breathing, cyanosis, miosis, ↓BP & shock. Convulsions, pulmonary edema,coma occur at terminal stages• Death is due to respiratory failure.
Treatment• Respiratory support• Maintenance of BP• Gastric lavage with pot. Permanganate• Naloxone 0.4-0.8 mg i.v. repeated every 2-3 min till respiration picks up. Repeat every 1- 4 hrs later on, according to response.• preferred specific antagonist : does not have any agonistic action and resp. depression
Precautions and C/I• Infants and the elderly• Patients with respiratory insufficiency• Bronchial asthma• Head injury• Hypotensive states and hypovolemia• Undiagnosed acute abdominal pain• Elderly male• Hypothyroidism, liver and kidney disease• Unstable personalities
Drug interactions• Drugs which poteniate morphine – Phenothiazines, TCA, MAO inhibitors, – Amphetamine and Neostigmine• Morphine retards absorption of many orally administered drugs by delaying gastric emptying..
Dose• 10-50 mg oral,• 10-15 mg i.m. or s.c. or• 2-6 mg i.v.• 2-3 mg epidural/intrathecal;• children 0.1-0.2 mg/kg
Therapeutic uses• Morphine / parenteral congeners indicated as analgesic in – traumatic, visceral, ischaemic (myocardial infarction), – postoperative, burns, cancer pain.• Relieves anxiety and apprehension in serious and frightening disease accompanied by pain: myocardial infarction,
Therapeutic usesAcute left ventricular failure (cardiac asthma)• Morphine rapid i.v. affords dramatic relief by – ↓ preload and peripheral pooling of blood. – shift blood from pulmonary to systemic circuit – relieves pulmonary congestion and edema. – Allays air hunger by depressing respiratory centre. – Cuts down sympathetic stimulation by calming the patient, reduces cardiac work.
Epidural and intrathecal injection of Morphine• It is being used for – analgesia in abdominal, lower limb and pelvic surgeries – labour, postoperative, cancer and other intractable pain. – Preanaesthetic medication• produces segmental analgesia for 12 hour without affecting sensory, motor or autonomic modalities.• Resp. depression occurs after delay due to ascent through subarachnoid space to the resp. centre.
Codiene (Methyl Morphine)• low-efficacy opioid a prodrug (t1/2 3 h).• lacks efficacy for severe pain• most of its actions 1/10th those of morphine.• Large doses cause excitement.• Dependence much less than with morphine.• principal use: mild to moderate pain & cough• 60 mg coeine = 600 mg aspirin
Pethidine• Pethidine differs from morphine in that it:• does not usefully suppress cough• less likely to constipate• less likely to cause urinary retention & prolong childbirth• little hypnotic effect• shorter duration of analgesia (2-3 h).• Dose: 50-100mg SC or IM
Methadone• principal feature of methadone is long duration, analgesia may last for 24 h.• If used for chronic pain in palliative care (12- hourly) an opioid of short t ½ should be provided for breakthrough pain rather than an extra dose of methadone.• Also used in opioid withdrawal• Dose: 2.5 mg to 10 mg oral or IM
Fentanyl• Pethidine congener 80-100 times potent than morphine in analgesia and resp. depression• High lipid solubility peak effect in 5 min• Duration of action 30-40 min• Injectable form exclusively used in anaesthesia• Transdermal patch available used in cancer or other types of chronic pain• Dose: 25-75 µg /hr acts for 72 hours
Patient controlled analgesia (PCA)• An attractive technique of postoperative pain control• patient himself regulates the rate of i.v. fentanyl infusion according to intensity of pain felt.• Transdermal fentanyl is a suitable option for chronic cancer and other terminal illness pain
Dextropropoxyphene• Less analgesic, antitussive, and less dependence• Its analgesic usefulness equal to codeine.• Commonly combined with paracetamol• Dextropropoxyphene interacts with warfarin, enhancing its anticoagulant effect.• Dose= 60-120 mg
Tramadol• Relieves pain by opioid as well as other mechanisms• 100 mg IV Tramadol = 100 mg IM morphine• Dose: 50-100 mg TDS• Less respiratory depression, sedation, constipation, urinary retention, ↑intrabiliary pressure & dependence than morphine• As effective as pethidine for postoperative pain and as morphine for moderate chronic pain.
Pentazocine• Weak µ antagonist action and marked κ agonist action• Analgesia is primarily spinal (K1)• can cause a withdrawal syndrome in addicts• Dose= 30-60 mg IM OR 50 -100 mg oral• shorter duration of pain relief 4-6 hrs,• less dependence, sedation & resp. depression• Use: post operative, moderately severe burns
Butorphanol• K analgesic like pentazocine but more potent• Psychomimetic effects less marked• Neither substitute nor antagonize morphine• Dose: 1-4 mg IM / IV• Use: – Post operative – Short lasting painful conditions (renal colic)
Buprenorphine• High-efficacy partial agonist of µ receptor and an antagonist of the K-receptor.• Less liability to induce dependence and respiratory depression than pure agonists• Duration of action = 6-8hrs• Dose: 0.3-0.6 mg IM, SC, 0.2 -0.4 mg SL• Use: cancer, MI, Post Operative, morphine dependence Contraindiacted In labour pain
Benefits due to PG Synthesis inhibition• Analgesia: prevention of pain nerve ending sensitization• Antipyretic• Anti-inflammatory• Antithrombotic• Closure of ductus arteriosus
Toxicities due to PG synthesis inhibition• Gastric mucosal damage• Bleeding: inhibition of platelet function• Limitation of renal blood flow : Na and water retention• Delay/prolongation of labour• Asthma and anaphylactoid reactions in susceptible individuals
Adverse effects of NSAIDsGastrointestinal-• Gastric irritation, erosions, peptic ulceration, gastric bleeding/perforation, esophagttisRenal• Na and water retention, chronic renal failure, interstitial nephritis, papillary necrosis (rare)Hepatic• Raised transaminases, hepatic failure (rare)
USES• Analgesic- headache, backache, myalgia, joint pain, dysmenorrhoea;• Antipyretic-fever of any origin; paracetamol being safer.• Acute rheumatic fever- the first drug to be used
• Rheumatoid arthritis - Aspirin in a dose of 3-5 g/day is effective in most cases; produces relief of pain, swelling and morning stiffness.• Osteoarthritis - It affords symptomatic relief only; paracetamol is the first choice analgesic• Post myocardial infarction and post stroke patients By inhibiting platelet aggregation it lowers the incidence of reinfarction.
Other uses are:• Pregnancy induced hypertension and pre eclampsia.• To delay labour• Patent ductus arteriosus
• Better tolerated than aspirin.• The analgesic, antipyretic and antiinflammatory efficacy is lower than high dose of aspirin.• All inhibit PG synthesis- naproxen being most potent;• They inhibit platelet aggregation and prolong bleeding time.
IndomethacinPotent antiinflammatory drug comparable to phenylbutazone.Potent and promptly acting anti-pyretic.Analgesic action is better than phenylbutazone, but it relieves only inflammatory or tissue injury related pain.highly potent inhibitor of PG synthesis and suppresses neutrophil motility.
Uses• Rheumatoid arthritis not controlled by aspirin;• Ankylosing spondylitis, acute exacerbations of destructive arthropathies and psoriatic arthritis.• It acts rapidly in acute gout.• Malignancy associated fever refractory to other antipyretics.• Medical closure of patent ductus arteriosus
MEPHENAMIC ACID• Analgesic, Antipyretic and Anti-inflammatory drug which inhibits COX & antagonizes actions of PGs.• Exerts peripheral & central analgesic action.
Uses• analgesic in muscle, joint and soft tissue pain - strong anti-inflammatory action is not needed.• It is quite effective in dysmcnorrhoea.• useful in some cases of rheumatoid and osteoarthritis
DICLOFENAC SODIUM• An analgesic-antipyretic-antiinflammatory drug similar in efficacy to naproxen.• short lasting antiplatelet action.• Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced.
USE• most extensively used in rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis, dysmenorrhoea, post-traumatic and postoperative inflammatory conditions— affords quick relief of pain and wound edema.