Drugs 15: 387- 392 ( 1978) Cl ADI5 Press 1978
Non-Steroidal Anti·lnflammatory Analgesics: Basic Clinical Pharmacology and Therapeutic Use E.C. Huskisson St . Barth olome w 's Hospital. London
What's new? more drugs- less slde-effects some patients respond and seme don' t
There have been three major advances in the field of non-steroidal anti- inflamm atory analgesics, Firstly, there are now many mor e compounds from wh ich to choose. Secondly, we recognise that differences between patients are more impo rtant than differences between dru gs so that th ere is a best dru g for an individual patient. Third ly. the newer compounds relieve sym ptoms as well as aspirin, but with a majo r reduction in side-effects and a corresponding increase in the numbe r of patients able to continue treatment. The ar t in using dru gs of th is type is to find the right dr ug for the right patient with the right disease. The various non-steroidal anti-inflammatory anal gesics can be conveniently classified under : I) Aspirin and early mimics; phenylbutazon e; oxyphenbutazo ne and indometh acin. 2) Propionic acid derivatives: naproxen: fenoprofen; ibuprofen; ketoprofen. 3) Drugs resembling propionic acid derivatives in their clinical properties: azapropazo ne: sulindac; tolmetin. alclofenac.
Classification of the dru gs is essentia l when there are so man y available, but has become difficult. The propert ies of ibuprofen suggested that this pro pionic acid derivative was clearly different from its predecessors. aspirin, indomethacin and phenylbutazone, T here were 2 major clinical differences. Firstly, there were less side-effects. Secondly, there was so mew hat less anti-inflamm atory effect an d the drug seemed to be more appropriate for less inflam matory conditions like osteoarth ritis rather than acute gout, very active rheumatoid arthritis or ank ylosing spondylitis in whi ch inflammation is prominent. However, the mor e effective propionic acid derivatives like fenoprofen and naproxen are as effective as aspirin and the older anti-inflammatory drugs in all respects. even in acute gout , and it is no longer ju stified to call them 'm inor anti -inflammatories', The major difference whi ch remains between propionic acid der ivatives and the older anti-in flammatory drugs is th e st riking reduction in side-effects: this suggests a differen t order of use and therefore justi fies separate classification. The classification show n above is historical. It was the propionic acid derivatives wh ich first provided ant i-inflammatory th erapy wh ich was safer and
388
Non -S teroid al Anti- Inf lam ma l ory Analgesics
much better tolerated than aspirin and its early mimics. Since then a number of com pounds of other chemica] types have appeared with a sa fety and toleran ce profile com parable with the propionic acid derivatives.
J. Clin ical Pharm acology
1.1 Pharmacokinetic Propert ies All the non-steroidaJ anti-infl ammat ory analgesics are well absorbed from the gastrointestinal tract , except alclofenac which is variably abso rbed, and most have short plasm a half-lives. All are highly bound to plasma pro teins and most have a very low distr ibution volume, wh ich make> such compou nds Ie.g. phenylbutazo ne) capable of displacing other highly albumin boun d drugs such as warfarin. Phenylbutazone can also inhib it the elimination of certain drugs such as tolbutam ide and th is becomes an added mechanism in binding displacement interactions. The plasma half-life appears to bear some relationship to the action since those with longer half-lives like napro xen or su lindac can be given twice daily. The longer elimination half-Jive>of these compoun ds do not appear to lead to a delay in the onset of action. since both naproxen and sulindac are almost fully effective within 24 hours of the sta rt of treatment. All non-steroidal an ti-inflammatory drugs reach their maximal effect with in a few days of the start of treatment or sooner. The effect bears no relationship to plasm a level - responders have sim ilar plasma levels to non-responders and the effect of so me com pounds is apparent long after they have disappeared from the plasma . Most compo unds are eliminated by hepatic metabolism . but some such as azapropazone are mainly elim inated unchanged in the ur ine. Significant amou nts of indomethacin and alclofenac may also be excreted unchanged in the ur ine. necessitating reduction of dosage in renal impairment . Sulindac is particularly interesting because it is a 'pro-drug". The compound is absorbed then converted
to an active sulphide metabolite which appears to accoun t for most of the ant i-inflammatory effect of the drug. at least in animal models. The compou nd itself is not a prostaglandin synt hetase inhibitor an d has very little tendency to cause gastric problems - it may be tha t these 2 propert ies of a compou nd are related. The active sulphide metabolite is a potent prostag landin synthetase inhibitor but its effect on the stom ach is unim portant since the patient doesn't swallow it. Perhaps the perfect anti -inflam matory will be one which is com pletely inactive but is convert ed to an active compound after absor ption.
1.2 The Drugs and Their Effects All non-steroidal anti -inflam matory analgesics act within a few days of the start of treatment: aJl cause gastric side-effects. usua lly within the first few weeks of treatment. None, not even phenylbutazone, require any part icular ro utine tests to be carr ied out such as blood or urine tests , thoug h these may be required in the event of certain side-effects. The names and doses of a selection of non-steroidal anti-inflammatory dru gs are given in table I. A few have been omitted. The fenamates. mefenamic an d flufenamic acid do not have the same advantages over aspirin as newer compounds . Alclofenac is a mild anti-inflamm atory but causes rashes - its principal interest is in the possibility of an additional penicillam ine-like effect. All these compounds belong with those w hich resemble propionic acid derivatives. Side-effects are the main feature wh ich individualises these compounds. Prop ionic acid derivatives and the compou nds which resemble them cause few. gastr ic side-effects being the most common. They are often m ild and do not normally lead to withdrawa l of treatment. Somet imes they can be avoided by giving the drug with food. before or after food. with antacids or last th ing at night. Otherw ise. one must change to another drug. These drugs rarely cause rashes after a few days of treatment. Tolrnetin occasionally gives rise to headaches.
389
Non-Stero1dal An li -Inflammatory Analgesics
Table I. Some non -ste roid al ant i- inf lam matory analgesics
Drug
Starting dose
Remarks
Propio nic acid derivatives f enoprof en
600mgQds
Reduce w hen effective to 1-2 -1.8g daily
Ibuprofen
400mg tds
Som e patients may req uire up to 2.4g daily
SOmg tds
l00mg at night may help morning stiffn ess
Ketoprofen Naproxen
2SOmgbd
500mg at night for morning stiffness
Drugs rest!Jmbling propionic acid derivetiVt!Js Azapropazone 300mg qds Su~ndac
100m g bd
Up to 400mg da ily in severe cases
Tolmetin
400mg tds
Some require less, some more
Aspirin and earl y mimics Aspirin
900mg Qds
Or equivalen t of otne r formulations
B6noryla te
4g (1Oml)tds
Reduce to minimum effective dose
Phenylbutazone
100mg tds
Same dose for oxyphenbutazone and formulations like Butacote
Indome thacin
25mg tds 75 or 100mg l00mg sta t
Aspirin, indomethacin and phenylbutazone cause gastr ic side-effects more often than the other classes of drugs and may also cause peptic ulcer and bleeding. In addition, phenylbutazone has two rare but serious side-effects. Firstly, it causes aplastic anaemia and agranulocytosis. The mortality rate from these complications has been estimated at 9 per million prescriptions, a very rare event. However, death is unacceptable, even if rare, as the outcome of treatment of a tr ivial condition which could have been treated with safer drugs. Agranulocytosis occurs within the first few months of treatment; aplastic anaemia seldom occurs after less than a year. The second potentially serious problem is precipitation of cardiac failure in elderly patients and those with heart disease, due to the salt and water retaining effect of
Fat chronic lKlministration. Reduce dose in renal fa ilure For pain at night and m orning stiffness Then reducing graduallv for ac ute gout and otbe r sel l -~miting cond itions
phenylbutazone. Indomethacin causes headaches and 'muzziness', which are dose-related; patients who have responded well can often be treated with lower doses or the drug can be given at night when sideeffectsseldom occur. Aspirin has many side-effects of which tinnitus and deafness are the most common. Aspirin and phenylbutazone should not be given with oral anticoagulants, but most other non-steroidal anti-inflammatory analgesicscan be given safely. It is wise to monitor the prothrombin time for the first few weeks of concomitant administration. Phenylbutazone should not be given to patients receiving oral sulphonylurea hypoglycaemic dru gs. It is clear that anaemia is the most important serious adverse effect of non-steroidal anti-inflammatory dr ugs, although it has different causes with
390
Non-$teroKial An ti - lnflammalOo'y Analgesics
different dru gs. Particular atten tion should therefore be paid 10 tbe development of sympto ms suggesting anaem ia.
1.3 Fo rmulation
4. What to Do with R esponders
Attem pts have been made to overcome the toxic
effects of aspirin and phenylbutazone by using different for mulations. Enteric-coated phenylbuta zone ('Buta cote') and phenylbutazone combi ned with antacids ('8utazolidin-A lka') reduce the incidence of gastric symptoms. There are many alternative aspirin form ulation s, ente ric-coated , microencapsulated and buffe red. These preparations are more expensive and should be used for patients who respo nd but cannot take the dr ug because of gastr ic side-effects.
2. Which Drug First? Does it Malter ? There are 2 possible approaches to the use of th is grou p of fairly similar drugs. Firstly. one can select a drug at random. But it would be preferable 10 have a more rat ional approach and th is is becoming more im portant with the increasin g number of drugs available. T he purpose of the selection process is to find the right drug for a particular patient. The major pr inciple which determ ines the order of use is to give dangerous toxic dr ugs only when safer remedies have been foun d to be inadequat e.
1. If it Matters -
obvious advantages in this respect and they now represent the Iirst line treatment for the non -specific relief of rh eumatic symptoms.
Which Drug First?
Propion ic acid derivatives are now the first line treatment for symptom relief in rheumatic diseases. The message that aspirin is the first line treatment of rheumatoid arthritis is so much part of their dogma that one would imagine it was handed to rheumatologists on tablets of stone. It is no longer tru e. There are now drugs which are just as effective but with stri kingly fewer side-effects - the prop ionic acid derivati ves were the first group of drugs to show
W hichever drug one uses first, there will be, at the end ofa week or two , a group of patients who are better and another gro up who are not. In the responders , one should keep th e dose to the minimum wh ich continues to achieve symptomatic relief, review from time to time th e need for therapy. stop it when it is no longer needed and keep a look-out for adver se effects. The most common adverse effects of anti-Inflam matory dru gs are indigestion. abdominal pain or nausea and these are more common in the first few weeks of treatment. No rou tine tests such as blood coun ts are required in patients receiving non -steroidal an ti· inflammatory dru gs. but as with any other dru g, patients shou ld be warned to repo rt any new symptoms. This is especially important with a compound like phenylbu tazone which causes a small risk of ag ranulocytosis or aplastic anae mia .
5. Wha t to Do with Non-Responders For the group of patients who fail to achieve adequate symptomat ic relief on the first dru g. one must move on to another. It is worth trying al l 4 prop ionic acid derivatives in order to find the best for a particu lar patient and at the end of such a trial . about 60 % of patients with rheumatoid arthritis w ill have achieved adequate symptomatic relief. The remainder must move to other classes of drug and the next logi. cal step is to use compounds with properties like propionic acid deriv atives such as azapropazone or sunndac . Finally, one must use the more toxic dru gs such as indo methacin. aspirin or phenylbutazone . Because of the ris ks. phen ylbu tazone shou ld onl y be given in chro nic conditions when safer dru gs have been tried and failed.
Noo-SterDldal AAli- lnllammatOfY Ana lgesic s
It is important to explain to patients before giving the first dru g that it may be necessary to try a lot more before finding the right one . Co nstant chan ges of dru g. each accompanied by enthusiastic predictions of response or no explanation at all , will lead to loss of confidence by the patient. In non -responders . it is important to cons ider whether the dose was adequate. whether the patient act ually took the pil ls, wh ether they cont inued for a sufficient period of time and w hether the diagnosis was correct and non -steroidal anti -inflammatory thera py appro priate . There are some conditions like tennis elbow for which non -stero idal anti-inflammatory dru gs are not particularly effective and which are better trea ted in other ways. by corticosteroid injection for example.
6. Supplements and Combinations Indomethacin, because of its side-efTeas. is reserved for patients in whom safer dru gs have failed. The re are tw o important exceptions to this - the first is in acute self-limiting cond itions like gout when a sho rt course can be given. The second is the use of indomethacin in a large dose at night for the relief of pain at night. sleep disturbance and morn ing stiffness. A large dose (75 or IOOmg) taken before retiring is nor mally well to lerated, whereas the sa me dose taken in the daytime often causes side-effects. Ot her non steroidal anti- inflammatory dru gs are also effective given in this way and the problem of night pain and morning stiffness may be solved by using a larger dose at night - for example. one can give naproxen 250mg in the morning and 500mg at night. Alternatively. one can combine naproxen in the daytime with indomethacin at night. Apart from the use of an additional an ti-inllammatory dru g at night, there is no evidence that 2 non-steroi dal anti -inflammatory drugs are mor e effective than one . There is no reaso n to give both ibuprofen and naproxen or fenoprofen and aspirin . One is enough.
7_S pecific Indications / or rarucutar Drugs It seems that certain dru gs are parti cularly effective in certa in conditio ns. For example, indomethacin and phenylbu tazone are particularly effective in ank ylosing spondylitis and more effective than aspirin. In rheumatoid arthritis these 3 dru gs are equa lly effective. Althoug h one can try propionic acid derivatives, many patients wit h an kylosm g spo ndylitis will do better with indomethacin or phenylbutazone. In acute gout, there is no reason to be dissat isfied w ith either indomethacin or phenylbutaz one wh ich are rapidly effective. Indom ethacin is a good choice for other acute self-limiting conditions like pyrophosphate arthropathy, attacks of palindromic rheumatis m and acute calcific periarth ritis. For an the other conditions, rheum atoid arthritis , osteoarth ritis and the rest . one can start with prop ionic acid derivatives and move on if necessary . Non-steroidal anti -inflammatory dru gs must not be used in polymyalgia rheumatica - corticosteroids are required .
8. Other Factors Wh ich Infl uence the Choice ofDrug Child ren must only be given dru gs wh ich have been adequate ly tested over a long period of time. which many of the newer drugs have not . Asp ir in therefore remains the first choice with indomet hacin and ibuprofen as alternatives. Mor e active disease reQuires more potent anti-inflammatory th erapy and drugs like ibuprofen are less successful in very active rheumatoid arthr itis. Patients with peptic ulcers must not be given asp irin, phenylbutazo ne or indom ethac in by mouth. Propionic acid derivatives and drugs like them may be given, as may indomethacin suppos itories. Cost must also be considered. In the unli kely event that 2 dru gs are equal ly effective and equally well tolerated , the cheaper should be chosen. Phenylbutazone and plain aspirin are very cheap - in-
NOIl~Ste,oidal Allti- lllflammato ry An algesic s
Tablell. What you need to kllow about a noe -steeodet allti-iflfla mmatory allalgesic
t.
Features com mo n ro all non -steroidal anti -in llamma/ory drug s al Effective ""';thill a few day s of start of treatment b ) Gastric side- eff ect s most com mo n usually begill wi th ill tha li rst f ew weeks o f treatment c ) No special tests ,equ ;"&d duri llg teeatment
2. Particular feature s 01 each drug (see also secron '.21 a) Name b) Dose (see table II c} Side -effects aod what to do about t hem
domethacin and the propionic acid derivatives are much more expensive and some of the newer drugs cost even more. Sophisticated aspirin preparations. enteric coated or microencapsulated, cost much more than plain aspirin but a bit less than propionic acid derivatives.
9. S imple R utes f or Using Non-Steroidal An ti -Inflammatory Analgesics The use of non-steroidal anti-inflammatory drugs is not difficult Although it is best to have some philosophy. what really matters is that each patient eventually finds a drug which suits. Some simple rules are summarised below: I . Start with the safest drug 2. Give it for I or 2 weeks 3. If it hasn't worked , change it
392
4. Use toxic drugs only in patients who have failed to respond to safer compounds 5. Keep the dose as low as possible 6. Stop when treatmen t is no longer required 7. Ask the patient to report any adverse effects.
10. Whal You Need 10 Know Bef ore Using a Non -S teroidal Anti -Inflammato ry Analgesic Quite a small amount of informa tion is sufficient to enable the clinician to use any of these compounds. There are a number of properties which apply to all drugs of this class and in addition it is necessary to know the name, dose and particular side-effects of any compound . Information required is summarised in table II and section 1.2.
I I . Conclusions Non-steroidal anti-inflammatory analgesics are very useful for relief of symptoms in a wide range of rheumatic diseases. A few simple rules will ensure their best use. The new generation of compounds should be used first because they are as effective as the old but safer and better tolerated. The clinician must be prepared to use all the available drugs if he is (0 satisfy the maximum number of patients.
Author's address, Dr Ed...ard C. Hus~ iss(J/', 51 Bartholomew's Hospital, L""d"" ECJA JBE (England).
Non-Steroidal Anti·lnflammatory Analgesics: Basic Clinical Pharmacology and Therapeutic Use E.C. Huskisson St . Barth olome w 's Hospital. London
What's new? more drugs- less slde-effects some patients respond and seme don' t
There have been three major advances in the field of non-steroidal anti- inflamm atory analgesics, Firstly, there are now many mor e compounds from wh ich to choose. Secondly, we recognise that differences between patients are more impo rtant than differences between dru gs so that th ere is a best dru g for an individual patient. Third ly. the newer compounds relieve sym ptoms as well as aspirin, but with a majo r reduction in side-effects and a corresponding increase in the numbe r of patients able to continue treatment. The ar t in using dru gs of th is type is to find the right dr ug for the right patient with the right disease. The various non-steroidal anti-inflammatory anal gesics can be conveniently classified under : I) Aspirin and early mimics; phenylbutazon e; oxyphenbutazo ne and indometh acin. 2) Propionic acid derivatives: naproxen: fenoprofen; ibuprofen; ketoprofen. 3) Drugs resembling propionic acid derivatives in their clinical properties: azapropazo ne: sulindac; tolmetin. alclofenac.
Classification of the dru gs is essentia l when there are so man y available, but has become difficult. The propert ies of ibuprofen suggested that this pro pionic acid derivative was clearly different from its predecessors. aspirin, indomethacin and phenylbutazone, T here were 2 major clinical differences. Firstly, there were less side-effects. Secondly, there was so mew hat less anti-inflamm atory effect an d the drug seemed to be more appropriate for less inflam matory conditions like osteoarth ritis rather than acute gout, very active rheumatoid arthritis or ank ylosing spondylitis in whi ch inflammation is prominent. However, the mor e effective propionic acid derivatives like fenoprofen and naproxen are as effective as aspirin and the older anti-inflammatory drugs in all respects. even in acute gout , and it is no longer ju stified to call them 'm inor anti -inflammatories', The major difference whi ch remains between propionic acid der ivatives and the older anti-in flammatory drugs is th e st riking reduction in side-effects: this suggests a differen t order of use and therefore justi fies separate classification. The classification show n above is historical. It was the propionic acid derivatives wh ich first provided ant i-inflammatory th erapy wh ich was safer and
388
Non -S teroid al Anti- Inf lam ma l ory Analgesics
much better tolerated than aspirin and its early mimics. Since then a number of com pounds of other chemica] types have appeared with a sa fety and toleran ce profile com parable with the propionic acid derivatives.
J. Clin ical Pharm acology
1.1 Pharmacokinetic Propert ies All the non-steroidaJ anti-infl ammat ory analgesics are well absorbed from the gastrointestinal tract , except alclofenac which is variably abso rbed, and most have short plasm a half-lives. All are highly bound to plasma pro teins and most have a very low distr ibution volume, wh ich make> such compou nds Ie.g. phenylbutazo ne) capable of displacing other highly albumin boun d drugs such as warfarin. Phenylbutazone can also inhib it the elimination of certain drugs such as tolbutam ide and th is becomes an added mechanism in binding displacement interactions. The plasma half-life appears to bear some relationship to the action since those with longer half-lives like napro xen or su lindac can be given twice daily. The longer elimination half-Jive>of these compoun ds do not appear to lead to a delay in the onset of action. since both naproxen and sulindac are almost fully effective within 24 hours of the sta rt of treatment. All non-steroidal an ti-inflammatory drugs reach their maximal effect with in a few days of the start of treatment or sooner. The effect bears no relationship to plasm a level - responders have sim ilar plasma levels to non-responders and the effect of so me com pounds is apparent long after they have disappeared from the plasma . Most compo unds are eliminated by hepatic metabolism . but some such as azapropazone are mainly elim inated unchanged in the ur ine. Significant amou nts of indomethacin and alclofenac may also be excreted unchanged in the ur ine. necessitating reduction of dosage in renal impairment . Sulindac is particularly interesting because it is a 'pro-drug". The compound is absorbed then converted
to an active sulphide metabolite which appears to accoun t for most of the ant i-inflammatory effect of the drug. at least in animal models. The compou nd itself is not a prostaglandin synt hetase inhibitor an d has very little tendency to cause gastric problems - it may be tha t these 2 propert ies of a compou nd are related. The active sulphide metabolite is a potent prostag landin synthetase inhibitor but its effect on the stom ach is unim portant since the patient doesn't swallow it. Perhaps the perfect anti -inflam matory will be one which is com pletely inactive but is convert ed to an active compound after absor ption.
1.2 The Drugs and Their Effects All non-steroidal anti -inflam matory analgesics act within a few days of the start of treatment: aJl cause gastric side-effects. usua lly within the first few weeks of treatment. None, not even phenylbutazone, require any part icular ro utine tests to be carr ied out such as blood or urine tests , thoug h these may be required in the event of certain side-effects. The names and doses of a selection of non-steroidal anti-inflammatory dru gs are given in table I. A few have been omitted. The fenamates. mefenamic an d flufenamic acid do not have the same advantages over aspirin as newer compounds . Alclofenac is a mild anti-inflamm atory but causes rashes - its principal interest is in the possibility of an additional penicillam ine-like effect. All these compounds belong with those w hich resemble propionic acid derivatives. Side-effects are the main feature wh ich individualises these compounds. Prop ionic acid derivatives and the compou nds which resemble them cause few. gastr ic side-effects being the most common. They are often m ild and do not normally lead to withdrawa l of treatment. Somet imes they can be avoided by giving the drug with food. before or after food. with antacids or last th ing at night. Otherw ise. one must change to another drug. These drugs rarely cause rashes after a few days of treatment. Tolrnetin occasionally gives rise to headaches.
389
Non-Stero1dal An li -Inflammatory Analgesics
Table I. Some non -ste roid al ant i- inf lam matory analgesics
Drug
Starting dose
Remarks
Propio nic acid derivatives f enoprof en
600mgQds
Reduce w hen effective to 1-2 -1.8g daily
Ibuprofen
400mg tds
Som e patients may req uire up to 2.4g daily
SOmg tds
l00mg at night may help morning stiffn ess
Ketoprofen Naproxen
2SOmgbd
500mg at night for morning stiffness
Drugs rest!Jmbling propionic acid derivetiVt!Js Azapropazone 300mg qds Su~ndac
100m g bd
Up to 400mg da ily in severe cases
Tolmetin
400mg tds
Some require less, some more
Aspirin and earl y mimics Aspirin
900mg Qds
Or equivalen t of otne r formulations
B6noryla te
4g (1Oml)tds
Reduce to minimum effective dose
Phenylbutazone
100mg tds
Same dose for oxyphenbutazone and formulations like Butacote
Indome thacin
25mg tds 75 or 100mg l00mg sta t
Aspirin, indomethacin and phenylbutazone cause gastr ic side-effects more often than the other classes of drugs and may also cause peptic ulcer and bleeding. In addition, phenylbutazone has two rare but serious side-effects. Firstly, it causes aplastic anaemia and agranulocytosis. The mortality rate from these complications has been estimated at 9 per million prescriptions, a very rare event. However, death is unacceptable, even if rare, as the outcome of treatment of a tr ivial condition which could have been treated with safer drugs. Agranulocytosis occurs within the first few months of treatment; aplastic anaemia seldom occurs after less than a year. The second potentially serious problem is precipitation of cardiac failure in elderly patients and those with heart disease, due to the salt and water retaining effect of
Fat chronic lKlministration. Reduce dose in renal fa ilure For pain at night and m orning stiffness Then reducing graduallv for ac ute gout and otbe r sel l -~miting cond itions
phenylbutazone. Indomethacin causes headaches and 'muzziness', which are dose-related; patients who have responded well can often be treated with lower doses or the drug can be given at night when sideeffectsseldom occur. Aspirin has many side-effects of which tinnitus and deafness are the most common. Aspirin and phenylbutazone should not be given with oral anticoagulants, but most other non-steroidal anti-inflammatory analgesicscan be given safely. It is wise to monitor the prothrombin time for the first few weeks of concomitant administration. Phenylbutazone should not be given to patients receiving oral sulphonylurea hypoglycaemic dru gs. It is clear that anaemia is the most important serious adverse effect of non-steroidal anti-inflammatory dr ugs, although it has different causes with
390
Non-$teroKial An ti - lnflammalOo'y Analgesics
different dru gs. Particular atten tion should therefore be paid 10 tbe development of sympto ms suggesting anaem ia.
1.3 Fo rmulation
4. What to Do with R esponders
Attem pts have been made to overcome the toxic
effects of aspirin and phenylbutazone by using different for mulations. Enteric-coated phenylbuta zone ('Buta cote') and phenylbutazone combi ned with antacids ('8utazolidin-A lka') reduce the incidence of gastric symptoms. There are many alternative aspirin form ulation s, ente ric-coated , microencapsulated and buffe red. These preparations are more expensive and should be used for patients who respo nd but cannot take the dr ug because of gastr ic side-effects.
2. Which Drug First? Does it Malter ? There are 2 possible approaches to the use of th is grou p of fairly similar drugs. Firstly. one can select a drug at random. But it would be preferable 10 have a more rat ional approach and th is is becoming more im portant with the increasin g number of drugs available. T he purpose of the selection process is to find the right drug for a particular patient. The major pr inciple which determ ines the order of use is to give dangerous toxic dr ugs only when safer remedies have been foun d to be inadequat e.
1. If it Matters -
obvious advantages in this respect and they now represent the Iirst line treatment for the non -specific relief of rh eumatic symptoms.
Which Drug First?
Propion ic acid derivatives are now the first line treatment for symptom relief in rheumatic diseases. The message that aspirin is the first line treatment of rheumatoid arthritis is so much part of their dogma that one would imagine it was handed to rheumatologists on tablets of stone. It is no longer tru e. There are now drugs which are just as effective but with stri kingly fewer side-effects - the prop ionic acid derivati ves were the first group of drugs to show
W hichever drug one uses first, there will be, at the end ofa week or two , a group of patients who are better and another gro up who are not. In the responders , one should keep th e dose to the minimum wh ich continues to achieve symptomatic relief, review from time to time th e need for therapy. stop it when it is no longer needed and keep a look-out for adver se effects. The most common adverse effects of anti-Inflam matory dru gs are indigestion. abdominal pain or nausea and these are more common in the first few weeks of treatment. No rou tine tests such as blood coun ts are required in patients receiving non -steroidal an ti· inflammatory dru gs. but as with any other dru g, patients shou ld be warned to repo rt any new symptoms. This is especially important with a compound like phenylbu tazone which causes a small risk of ag ranulocytosis or aplastic anae mia .
5. Wha t to Do with Non-Responders For the group of patients who fail to achieve adequate symptomat ic relief on the first dru g. one must move on to another. It is worth trying al l 4 prop ionic acid derivatives in order to find the best for a particu lar patient and at the end of such a trial . about 60 % of patients with rheumatoid arthritis w ill have achieved adequate symptomatic relief. The remainder must move to other classes of drug and the next logi. cal step is to use compounds with properties like propionic acid deriv atives such as azapropazone or sunndac . Finally, one must use the more toxic dru gs such as indo methacin. aspirin or phenylbutazone . Because of the ris ks. phen ylbu tazone shou ld onl y be given in chro nic conditions when safer dru gs have been tried and failed.
Noo-SterDldal AAli- lnllammatOfY Ana lgesic s
It is important to explain to patients before giving the first dru g that it may be necessary to try a lot more before finding the right one . Co nstant chan ges of dru g. each accompanied by enthusiastic predictions of response or no explanation at all , will lead to loss of confidence by the patient. In non -responders . it is important to cons ider whether the dose was adequate. whether the patient act ually took the pil ls, wh ether they cont inued for a sufficient period of time and w hether the diagnosis was correct and non -steroidal anti -inflammatory thera py appro priate . There are some conditions like tennis elbow for which non -stero idal anti-inflammatory dru gs are not particularly effective and which are better trea ted in other ways. by corticosteroid injection for example.
6. Supplements and Combinations Indomethacin, because of its side-efTeas. is reserved for patients in whom safer dru gs have failed. The re are tw o important exceptions to this - the first is in acute self-limiting cond itions like gout when a sho rt course can be given. The second is the use of indomethacin in a large dose at night for the relief of pain at night. sleep disturbance and morn ing stiffness. A large dose (75 or IOOmg) taken before retiring is nor mally well to lerated, whereas the sa me dose taken in the daytime often causes side-effects. Ot her non steroidal anti- inflammatory dru gs are also effective given in this way and the problem of night pain and morning stiffness may be solved by using a larger dose at night - for example. one can give naproxen 250mg in the morning and 500mg at night. Alternatively. one can combine naproxen in the daytime with indomethacin at night. Apart from the use of an additional an ti-inllammatory dru g at night, there is no evidence that 2 non-steroi dal anti -inflammatory drugs are mor e effective than one . There is no reaso n to give both ibuprofen and naproxen or fenoprofen and aspirin . One is enough.
7_S pecific Indications / or rarucutar Drugs It seems that certain dru gs are parti cularly effective in certa in conditio ns. For example, indomethacin and phenylbu tazone are particularly effective in ank ylosing spondylitis and more effective than aspirin. In rheumatoid arthritis these 3 dru gs are equa lly effective. Althoug h one can try propionic acid derivatives, many patients wit h an kylosm g spo ndylitis will do better with indomethacin or phenylbutazone. In acute gout, there is no reason to be dissat isfied w ith either indomethacin or phenylbutaz one wh ich are rapidly effective. Indom ethacin is a good choice for other acute self-limiting conditions like pyrophosphate arthropathy, attacks of palindromic rheumatis m and acute calcific periarth ritis. For an the other conditions, rheum atoid arthritis , osteoarth ritis and the rest . one can start with prop ionic acid derivatives and move on if necessary . Non-steroidal anti -inflammatory dru gs must not be used in polymyalgia rheumatica - corticosteroids are required .
8. Other Factors Wh ich Infl uence the Choice ofDrug Child ren must only be given dru gs wh ich have been adequate ly tested over a long period of time. which many of the newer drugs have not . Asp ir in therefore remains the first choice with indomet hacin and ibuprofen as alternatives. Mor e active disease reQuires more potent anti-inflammatory th erapy and drugs like ibuprofen are less successful in very active rheumatoid arthr itis. Patients with peptic ulcers must not be given asp irin, phenylbutazo ne or indom ethac in by mouth. Propionic acid derivatives and drugs like them may be given, as may indomethacin suppos itories. Cost must also be considered. In the unli kely event that 2 dru gs are equal ly effective and equally well tolerated , the cheaper should be chosen. Phenylbutazone and plain aspirin are very cheap - in-
NOIl~Ste,oidal Allti- lllflammato ry An algesic s
Tablell. What you need to kllow about a noe -steeodet allti-iflfla mmatory allalgesic
t.
Features com mo n ro all non -steroidal anti -in llamma/ory drug s al Effective ""';thill a few day s of start of treatment b ) Gastric side- eff ect s most com mo n usually begill wi th ill tha li rst f ew weeks o f treatment c ) No special tests ,equ ;"&d duri llg teeatment
2. Particular feature s 01 each drug (see also secron '.21 a) Name b) Dose (see table II c} Side -effects aod what to do about t hem
domethacin and the propionic acid derivatives are much more expensive and some of the newer drugs cost even more. Sophisticated aspirin preparations. enteric coated or microencapsulated, cost much more than plain aspirin but a bit less than propionic acid derivatives.
9. S imple R utes f or Using Non-Steroidal An ti -Inflammatory Analgesics The use of non-steroidal anti-inflammatory drugs is not difficult Although it is best to have some philosophy. what really matters is that each patient eventually finds a drug which suits. Some simple rules are summarised below: I . Start with the safest drug 2. Give it for I or 2 weeks 3. If it hasn't worked , change it
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4. Use toxic drugs only in patients who have failed to respond to safer compounds 5. Keep the dose as low as possible 6. Stop when treatmen t is no longer required 7. Ask the patient to report any adverse effects.
10. Whal You Need 10 Know Bef ore Using a Non -S teroidal Anti -Inflammato ry Analgesic Quite a small amount of informa tion is sufficient to enable the clinician to use any of these compounds. There are a number of properties which apply to all drugs of this class and in addition it is necessary to know the name, dose and particular side-effects of any compound . Information required is summarised in table II and section 1.2.
I I . Conclusions Non-steroidal anti-inflammatory analgesics are very useful for relief of symptoms in a wide range of rheumatic diseases. A few simple rules will ensure their best use. The new generation of compounds should be used first because they are as effective as the old but safer and better tolerated. The clinician must be prepared to use all the available drugs if he is (0 satisfy the maximum number of patients.
Author's address, Dr Ed...ard C. Hus~ iss(J/', 51 Bartholomew's Hospital, L""d"" ECJA JBE (England).
