Training module

Recent Advances And Technique In Anaesthesia For Ss/Js In Raj. State Health System.

INDEX

SESSION/ minute

SERIAL NO.

TOPIC PAGE NO.

1. PROGRAMME 3 2. AIMS AND OBJECTIVE 4 DAY1-a A . ANAESTHESIA MACHINE, EQUIPMENT AND TECHNIQUES 1a-30m 3. EXPERIENCE WITH THE GLOSVENT ANAESTHETIC

MACHINE 5-7

1b-30m 4. VAPORISERS 8 1c-30m 5. POSITIONING ON THE OPERARING TABLE 9-12 DAY1-b B .PHARMACOLOGY 2a-45m 6. NITRIC OXIDE AND PROPOFOL 13-15 2b-45m 7. LEVOBUPIVACAINE 16-18 3-90m 8. ACUTE OXYGEN TREATMENT 19-26 4a-45m 9. A NEW MANDATE FOR THE ANAESTHESIOLOGIST-

CANCER PAIN SPECIALIST:EXPERTISE IN PRESCRIBING ANALGESICS.

27-32

4b-45m 10 EMERGENCY DRUGS IN ANAESTHESIOLOGY AND CRITICAL CARE MEDICINE

33-34

DAY2 C . ANAESTHESIA IN PATIENTS ASSOCIATED WITH COMORBID CONDITIONS

1-90m 20 MONITERING DURING CAESAREAN SECTION 35-38 2a-45m 11. THR PATIENT WITH HEART DISEASE 39-42 2b-45m 12. ANAESTHESIA AND CHRONIC RENAL FAILURE 43-45 3a-45m 13 ANESTHESIA AND LIVER DISEASE 46-48 4-90m 14 CLINICAL MANAGEMENT OF DIABETES MELLITUS

DURING ANAESTHESIA AND SURGERY 49-56

3b-45m 15 ANAESTHESIA FOR THE PATIENT WITH RESPIRATORY DISEASE

57-58

DAY3 D .ANAESTHESIA- SPECIAL COSIDERATION

1a-30m 16 A MOBILE ANAESTHESIA SERVICE 59 1b-60m 17 A PRACTICAL APPROACH TO EMERGENCY EYE

ANAESTHESIA 60-64

2-90m 18 ANAESTHESIA FOR ELDERLY PATIENT 65-69 3-90m 19 ANAESTHESIA FOR THE PATIENT REQUIRING

EMERGENCY ABDOMINAL SURGERY 70-83

4-90m 20 INDUCTION OF ANAESTHESIA IN PAEDIATRIC PATIENTS

84-88

DAY4 F. REGIONAL ANAESTHESIA AND PAIN

1a-30m 21 INTRAVENOUS REGIONAL ANAESTHESIA-BIERBLOCK

89-90

1b-60m 22 NERVE BLOCKS FOR ANAESTHESIA AND ANALGESIA OF THE LOWER LIMB

91-98

2-90m 23 POSTOPERATIVE ANALGESIA IN PAEDIATRIC DAY CASE SURGRRY

99-102

3-90m 24 THE PHARMACOLOGICAL MANAGEMENT OF NEUROPATHIC PAIN

103-105

4-90m 25 PAIN RELIEF IN LABOUR 106-109

PROGRAMME DURATION- 4 Days TRANIES- NOT MORE THAN 5. SESSIONS /DURATIONS

DAY-1

2 SESSIONS EACH FOR 90 MINUTES

2 SESSION EACH FOR 90 MINUTES

ANAESTHESIA MACHINE, EQUIPMENT AND TECHNIQUES PHARMACOLOGY

DAY -2

4 SESSION EACH FOR 90 MINUTES

. ANAESTHESIA IN PATIENTS ASSOCIATED WITH COMORBID CONDITIONS

DAY-3

4 SESSION EACH FOR 90 MINUTES

ANAESTHESIA-SPECIAL COSIDERATION

DAY-4

4 SESSION EACH FOR 90 MINUTES

REGIONAL ANAESTHESIA AND PAIN

TEACHING/TEACHINGS AIDS-

LECTURES

POWER- POINT AND OHP PRESENTATIONS

DEMONSTRATIONS

VIDEO/LAPTOP- CD PRESENTATIONS

SKILLS

ON MANIKINS/DUMMIES

HANDS ON EXPERIENCES

OPERATION THEATERS

FURTHER READINGS- 1. ANAESTHESIA UPDATES 2. BRITISH JOURNAL OF ANAESTHESIA 3. INDIAN JOURNAL OF ANAESTHESIA 4 . ANNUAL CMES OF ISA .

AIMS AND OBJECTIVES Sr . Topics Objectives 1 ANAESTHESIA

MACHINE, EQUIPMENT AND TECHNIQUES

To introduce a new machine be re l iab le, easy to understand and operate, economical to run, require min imal servicing which can be carr ied out local ly , and be versati le , so that the same machine can be used in a l l pat ients both as an anaesthet ic machine in the operating room and as a vent i la tor in a recovery room

To provide basic knowledge of recent vaporisers. To upgrade the basic ideology of posit ion ing of patient in

theaters,to avoid var ious complications with convent ional posi t ion.

2. PHARMACOLOGY

To provide in format ions of newer drugs usefu l l a t 30 to 100 beded hospita ls l ike,propofol , n i t r ic oxides and levobupivacaine.

To know about the impor tance of acute oxygen treatment in cr i t ica l si tuations in theater as wel l in recovery room.

To make fami ler with recent analgesics usefu l l in the management of pain for the patients suffer ing from var iety of cancers at d istr ic t level and provide pal l ia tive treatment,to reduce the burden over the ter tery centers.

3 . ANAESTHESIA IN PATIENTS ASSOCIATED WITH COMORBID CONDITIONS

TO STRENGTHEN THE KNOWLEDGE OF ANAESTHESIST AT DISTRICT AND LESS AFFULENT HOSPITALS TO PROVIDE ANAESTHESIA IN PATIENTS AT HIGH RISK VIZ. HEART DISEASE,HYPERTENSION,DIABETES MELLITUS,RENAL FAILURE AND LIVER DISEASES,THUS TO CURTAIL THE NUMBER OF REFERRAL TO THE TERTERY CENTERS.

4. ANAESTHESIA-SPECIAL COSIDERATION

To provide anaesthesia in mobi le surgica l camps. To manage the patient of abdominal trauma very common in

RTA at d istr ic t levels inc luding eye trauma. To introduce cer ta in newer aspects of GERIATRICS

anaesthesia, s ince no. of patients requir ing anaesthesia of age>70 years increasing, specia lly in v i l lage populations.

5. REGIONAL ANAESTHESIA AND PAIN

To provide impitus for regional anaesthesia so that frequency . o f GA as wel las i ts complicat ions can bereduced.

To provide knowledge of nerve b locks To provide analgesia in ch i ldren postoperatively which is

d i ff icu l t and of i ts immense impotance. TO START A NEW ERA OF PAINLESS DELIVERY.

EXPERIENCE WITH THE GLOSTAVENT ANAESTHETIC MACHINE In many parts of the wor ld, anaesthet is ts have to work in di ff icu l t or iso lated s i tuations where medical suppl ies are erratic and servic ing faci l it ies are poor or non-existent. Most modern anaesthetic machines, however, are not designed to be used in these condit ions, as they requi re h igh levels of maintenance and serv ic ing by trained engineers and are dependent on continuous suppl ies of compressed gases and electr ici ty . Consequent ly, when condi t ions are unfavorable, they are l iab le to mal function or even fai l complete ly. An anaesthet is t working in such di ff icu l t condit ions requires an anaesthet ic machine which has been specif ical ly designed to overcome these problems. It should therefore be re l iab le, easy to understand and operate, economical to run, requi re min imal serv ic ing which can be carr ied out local ly , and be versati le , so that the same machine can be used in a l l pat ients both as an anaesthet ic machine in the operating room and as a venti la tor in a recovery room or I.C.U. Most important of a l l , i t must cont inue to function i f ei ther the electr ic i ty or oxygen suppl ies fa i l , s i tuations that are al l too common in parts of the developing wor ld and that have been responsible for many tragedies. The Glostavent anaesthet ic machine has been designed to fu l f i l l these requirements precise ly. In the development of the Glostavent, four separate components have been incorporated, each of which has, in i ts own r ight, al ready proved valuable in d i ff icul t environments. These are the draw-over anaesthesia system, the oxygen concentrator , the Manley Mul tivent venti la tor , and the a ir compressor.

1. The Draw-Over Anaesthesia System Atmospher ic a ir is used as the carr ier gas, which is drawn over a low resistance vapor iser , in th is case, the Oxford Miniature Vapor iser (O.M.V.) , e i ther by the negat ive pressure created dur ing inspiration in spontaneously breath ing pat ients, or by the act ion of bel lows when breath ing is contro l led. IT CAN THEREFORE BE COMPLETELY INDEPENDENT OF THE SUPPLY OF COMPRESSED GASES. Oxygen from a cyl inder or a concentrator can be added upstream of the vapor iser , to increase the inspired oxygen concentration. 2. Oxygen Concentrator This is an e lectr ical ly powered device which produces a cont inuous supply of oxygen from atmospher ic a ir , by f i rs t compressing the a ir and then d irect ing i t through canisters conta in ing zeol i te granules where the n i t rogen is absorbed and the residual oxygen del ivered to the pat ient. The zeol i te granules are continual ly being re-activated and do not require changing. 3. Manley Mult ivent Venti lator This is a pneumatica l ly dr iven vers ion of the Oxford in fla t ing bel lows. It can be dr iven ei ther by compressed ai r or oxygen and only requires a volume of dr iv ing gas equal to 1/10 of the patient 's minute volume. When oxygen is used for dr iving the vent i la tor , i t is automatica lly co l lected and returned to the breathing c ircu it . In other words the same oxygen is used twice, f i rs t to dr ive the vent i la tor and then for the patient to breathe. The bel lows of the Mult ivent can also be operated manual ly . 4 . A ir Compressor This is an integra l par t o f the oxygen concentrator , which has been modif ied to a l low some of the compressed a ir generated by the concentrator to be d iver ted for use as dr iv ing gas for the venti la tor , so that the concentrator provides both the dr iv ing gas for the venti la tor and oxygen for the patient. In the design of the Glostavent, the four components are mounted on a s ingle tro l ley, together with 2 reserve oxygen cyl inders ( f igures 1 & 2) . It was in i t ia l ly descr ibed under i ts or iginal name of Oxyvent1 and subsequently as the Glostavent2. Al though i t has now been in regular use in several hospita ls throughout the wor ld for the past 6 years3 & 4, del iver ing anaesthesia safe ly to thousands of pat ients, few reports of i ts use have so far been publ ished5, and a fu l l descr ip tion of i ts operation i l lustrat ing i ts many advantages is not avai lab le. Its potentia l as a safe, re l iable and cost effective anaesthet ic machine has been recognised by the Association of Anaesthetis ts of Great Br i tain &

Ire land, the Wor ld Federation of Societ ies of Anaesthesio logy and the Department for In ternational Development, a l l o f whom have contr ibuted to i ts development. However, anesthetists pract ic ing in d i ff icu l t s i tuations or in iso lation need to be conf ident that i t wi l l per form predictably and rel iably in the i r own envi ronments, so that i t can be used safe ly when monitor ing faci l i ties are l imited or to ta l ly absent. Paediatr ic Use The use of the draw over technique is not recommended in smal l ch i ldren breath ing spontaneously, because of the resistance of the c ircu it and the deadspace of the valves6. For th is reason, in chi ldren under 25kg, the Glostavent was conver ted for continuous flow use. This was achieved s imply by occluding the open end of the reservoir tube wi th a bung, in order to a l low the gas f low to bui ld up suff icient pressure to pass through the vapor iser . A Mapleson E ci rcu it was then attached to the common gas out let, as with any standard cont inuous f low anaesthetic machine and oxygen administered at a f low rate of 4L/Min from ei ther the cyl inder of the concentrator . The O.M.V was shown to funct ion equal ly satis factor i ly for cont inuous flow and draw over anaesthesia, so that no change of vapor iser was requi red. Using the Glostavent An important feature of the Glostavent is i ts s impl ic i ty , enabling f i rs t t ime users to master i t quick ly and easi ly. The same circu it is used for both I.P.P.V. and spontaneous respiration. Conversion from one to the other s imply involves turn ing the venti lator of f and bypassing the bel lows, no other act ion is necessary. A handle is attached to the bel lows to faci l i ta te manual venti la tion when th is is required. Under normal c ircumstances, when e lectr ici ty is ava i lab le, i t is more convenient as wel l as more economical , to conserve cyl inders of oxygen and to use the concentrator to provide both the oxygen for the patient and, when I.P.P.V. is requi red, the compressed a ir to dr ive the venti la tor . In th is mode, a f low rate of oxygen of 2 L/Min del ivered in to the s ide arm of the reservoir tube ra ised the F iO2 to 50-55% in both spontaneously breath ing and vent i lated patients. This is satis factory in most cases and can be recommended for routine use. Higher F iO2 values, in the region of 75% can be obtained by increasing the oxygen flow to a maximum of 5L/Min. If s t i l l h igher oxygen concentrations are required, oxygen from the reserve cyl inders can be added. In the developing wor ld oxygen cyl inders are expensive to purchase and to transport and they should normal ly be kept in reserve, to be used only i f an e lectr ic i ty fa i lure renders the concentrator inoperable or to increase the F iO2 in an emergency. When I .P.P.V. is used, the dr iv ing gas for the ventila tor can e i ther be oxygen from the cyl inder (Group 3) , or compressed a ir from the concentrator (Group 4) . When the concentrator is in use, any in terruption in the supply of e lectr ic i ty t r iggers an audib le a larm. This a ler ts the anaesthetist that the concentrator has stopped. The reserve oxygen cyl inders are then turned on and the anaesthetic can cont inue wi thout inter ruption. When cyl inders are in use, conservation of suppl ies becomes extremely important. As has been clear ly shown in groups 1 & 3, satis factory F iO2's were achievable wi th min imal f lows of supplementary oxygen and indeed dur ing I.P.P.V. without the need fo r any addit ional oxygen whatsoever. Fur ther conservation is possib le because of the unique design of the Manley Multivent vent i la tor . With most other gas dr iven vent i la tors, the volume of dr iving gas required is equal to the pat ient's minute volume7 & 8. The Manley Mult ivent, however, was specif ical ly designed for economy and the requirement for dr iv ing gas reduced to 1/10 of the minute volume9. With the minute volume for example set at 4 l i tres per minute, the dr iv ing gas is uti l ised at a rate of 0.4 l i tres per minute and an E size oxygen cyl inder contain ing 680 li tres should not only be able to dr ive the vent i lator , but a lso supply the average oxygen requirement for a per iod of 28 hours. The Glostavent is therefore ideal for s i tuat ions where cyl inder supply is di ff i cu l t and conservation is important. Conclusion The Glostavent is much less expensive than the major i ty of cont inuous f low anaesthetic machines in current use and yet offers considerable advantages when used in di ff icu l t si tuations.These include, not only the low cost of the anaesthesia, but much more importantly , the abi l i ty to mainta in the del ivery of an anaesthet ic safe ly when cylinders of oxygen, n i trous oxide and compressed a ir and suppl ies of sodal ime may be scarce and the e lectr ici ty supply unrel iab le. Regardless of the condit ions in which they work, the aim of anaesthetis ts a l l over the wor ld is the same, that is to provide an anaesthetic service which is both ef fective and safe at a l l t imes. To achieve this, considerably greater demands are p laced on anaesthetis ts in the developing wor ld because of the lack of drugs, equipment and faci l i t ies than those in wealthy environments wi th greater resources. In the at tempt to make anaesthetic machines ever more foolproof for use when condi t ions are ideal, the basic problems that sti l l confront the major i ty of anaesthet is ts throughout the wor ld are easi ly forgotten. Modern sophisticated machines, however expensive, cannot be considered good enough for use in the developing wor ld i f they cannot be relied on

when condit ions become unfavorable. Only equipment which has been specif ica l ly designed to overcome their problems is adequate. The Glostavent can make a s igni f icant contr ibution towards meeting these requirements and is recommended for use in the developing wor ld. Summary The Glostavent is an anaesthet ic machine which has been designed to enable anaesthetis ts practicing in adverse condi t ions to overcome the d i ff icu l t ies they are l ike ly to encounter . These include inadequate or non-existent monitor ing and serv ic ing faci l i t ies and frequent d isrupt ion in the suppl ies of oxygen, n i trous oxide, soda l ime or e lectr ic i ty . An examination of the records of patients who were anaesthetised using the Glostavent wi th fu l l monitor ing, demonstrates i ts predictabi l i ty , re l iabi l i ty and economy over a wide range of c l in ica l si tuations. Suggestions are made for i ts cost ef fective operation. It is recommended as an anaesthetic machine capable of provid ing a safe and re l iab le anaesthetic in adverse condi t ions.

VAPORISERS Early vaporisers Vapor izer rather than the word inhaler is used when we are ta lk ing of inhalational anaesthesia by continuous f low anaesthetic machines. Component par ts of some ear ly vapor izers, which have not been complete ly deciphered, are a lso on exhibi t. They are Bernoys ether vapor izer (1) ,Ogestons ch loroform vapor izer (2) , Ohio no.8 ether vapor izer (3) .Victor Goldman ini t ia l ly designed th is in 1962 for administer ing halothane by in termittent f low machines (e.g. Wal ton V) for dental surgery. In Ind ia and the Armed Forcesi t found i ts maximum uti l i ty in cont inuous f low machines as a p lenum vapor iser and as a draw over vaporizer in por table anaesthetic apparatus. Its use in closed c ircuit anaesthesia (VIC) in a spontaneously breath ing patient has been descr ibed ,but we don t see i t be ing used in th is fashion. Its cal ibration at 30, 8 and 2 min-1 is therefore designed for i ts use in a part icu lar c ircui t. T i l l date four vers ions of the vapor izers have appeared. The Mk IV has four notches and lever for change in concentrat ion was made into a c l ick ing device. In India prototypes of the same were manufactured by Khushwaqt and anaesthetics because of the exorbi tant cost of there compensated vapor izers and in troduct ion of halothane in the Indian market. They are sti l l in use where sophist icated machines have not reached. Goldman type vaporizers The most common vapor izers incorporated in the anaesthetic machines avai lable in Ind ia were the Boyle s ether and tr i lene bott les. Many other vapor izers became popular before the tec ser ies of vapor izers became standard. Though popular dur ing the ear ly 1970s they are sti l l be ingused in many p laces. Goldman vaporiser 1 2 3 The one manufactured by Khushwaqt Industr ies. It is s imi lar to Mk III o f the or ig inal Goldman ser ies. And the one manufactured by Anesthetics, except for s ize the design is quite d i fferent in that i t has a screw on bott le, which tends to invar iably ch ip at the screws. Some of the next generation vapor izers were the OMV, AE Vapor izer, EMO inhaler , and the PDV. Al l of these had low internal resistance and could therefore function s draw over vapor izers. Apart from the pr imary agent these vapor izers incorporated scales for other agents. I t is a temperature compensated vapor izer . Chloroforms probably as good as an anesthetic as halothane but i t fe l l into d isrepute and lost popular i ty a l together s ince accurate vapor izers for i ts del ivery d id not exist when i t was in troduced. This vapor izer probably marked there in troduct ion of chloroform but never got a foothold. Penlon Draw over Vaporizer (PDV) Had been designed for methoxyflurane and has an addi t ional scale for t r i lene. It was at one time popular in the Armed Forces forward surg ical uni ts . I ts use decl ined with the wi thdrawal of methoxyf lurane due to i ts f lour ide toxic i ty .E ar l ier use of a s ingle vapor izer that could be used for mult ip le agents was a desi rable property of an idea lvapor izer . Manufactured by Cyprane th is was designed for halothane but has a d ial for chloroform and tr i lene. Oxford miniature vaporizer (OMV ) Was designed for halothane but has a scale for tr i lene. Two versions of OMV exist; OMV Fi f ty (Lt to Rt) for use in continuous flow machines and OMV Ten(Rt to Lt) for use in draw over anesthetic apparatus. Faci l i ty for temperature stabi l izat ion exist in this vapor izer .

POSITIONING ON THE OPERATING TABLE Posi t ion ing pat ients is an important dai ly routine for anaesthetis ts to faci l i tate surg ica l access or a number of procedures. Dif ferent posit ions produce a range of physio logica l stresses. Par ticu lar care is needed for posi t ion ing anaesthetised patients to avoid passive movements that would not normal ly be to lerated. Nerve damage and pressure necrosis commonly resul t from poor posi t ion ing, the incidence is increased by hypotension and hypothermia. Tourn iquets can cause nerve damage i f they are appl ied over a nerve trunk therefore the in fla t ion pressure and the t ime of appl icat ion should always be moni tored. Diabetics, pat ients with ar ter ia l disease, the e lder ly and those with neuro logical defici ts are also at par ticu lar r isk. Pat ients wi th rheumatoid ar thr i t is may suffer from cerv ica l sp ine instabi l i ty at the atlanto-occip i ta l level and i t is important that the i r range of neck movement be assessed preoperative ly. They should then be comfortably posi t ioned pr ior to induction and th is posi t ion mainta ined once anaesthet ised. Sandbags may be employed. Supine - On the back

The most common posi t ion. The arms should be carefu l ly secured e i ther next to the patients body, f lexed across the chest or out on armboards. Acute f lexion at the e lbow may cause u lnar nerve damage due to trapping where i t enters the cubi ta l tunnel. The brachia l p lexus is a re lat ive ly f ixed structure and therefore susceptib le to traction in jury. To avoid stretch on the p lexus, pronate the forearms when the arms are extended by the patient s s ides. When both arms are abducted on boards, prevent over- abduction and hyperextension and keep the head facing forward. When one arm is abducted, the head should be turned towards that s ide, again to prevent traction on the brachia l p lexus (F igure 1) . Legs should l ie f la t and uncrossed. A sof t pad ra is ing the heels f rom the table avoids pressure necrosis. Other s i tes susceptible to pressure damage are the sacrum and occiput and postoperative a lopecia (hair loss) has been reported after long operations where hypotensive techniques have been employed. The patients eyel ids should be carefu l ly closed and taped to avoid corneal abrasion and dehydration. Direct pressure on the eye should be avoided as centra l retina l ar tery occlusion may occur. Ensure that no part o f the breath ing c ircu i t, or other equipment, is pressing on the patients face. Trendelenberg - Head down Supine with head down ti l t . This posi t ion is used in laparoscopic and var icose vein surgery. Physio logical e ffects of this posit ion inc lude:

increased venous return Raised in tracrania l and intraocular pressure. Cerebra l oedema and retinal detachment may occur i f

Trendelenberg is pro longed and steep. I t is therefore impor tant to avoid th is posi t ion in a patient wi th potent ia l ly ra ised ICP.

lung compl iance and functional residual capacity (FRC) are decreased with increased V/Q mismatch, especia l ly in obese patients ( IPPV may be preferable to SV)

increased in tragastr ic pressure may result in ref lux of gastr ic contents venous stagnation with resul t ing cyanosis in the face and neck of p lethor ic patients

Reverse Trendelenberg - Head up Supine with head up t i l t . Reduced venous return in th is posi t ion may lead to a fa l l in card iac output and ar ter ial pressure. As baroreceptor act iv i ty is reduced under anaesthesia a vasopressor may be needed. Blood pressure readings should be in terpreted in the context of relative posi t ions of the b lood pressure cuff and the level o f the bra in above i t. Funct ional residual capacity (FRC) is improved.

Lawn chair posi t ion (F igure 2) Backache fol lowing anaesthesia is common and may occur from stresses on the in ter lumbar and lumbosacral l igaments, when the convexity of the lumbar sp ine is lost in the ly ing to attent ion posit ion. The lawn chair posi t ion was developed to reduce th is backstra in. The operating table is modif ied so that the patient l ies s l ight ly head up wi th hips and knees part ia l ly f lexed. It is par ticularly usefu l for patients undergoing awake local anaesthetic procedures.

Prone - Face down Used for sp inal surgery, l igation of the short saphenous vein and some ankle operat ions. In tubation is normal ly requi red (a l though for short procedures a Laryngeal mask a i rway is sometimes used). A wel l-secured, armoured endotracheal tube is most su i table. Adequate eye protection and padding is v i ta l because pressure on the eye can cause ret ina l ar tery occlusion and b l indness. A suff icient number of persons are required to turn the patient prone - the larger the patient the greater the number of assistants required. Usual ly 4 people wi l l suff ice: the anaesthetis t to control the head, and 2-3 assistants to support the torso and arms, buttocks and legs respective ly. The patient may be turned prone after t ransfer to the operat ing table or al ternat ive ly, turned in the process of the transfer . The head is posit ioned to one s ide or face down on a p iece of hol low foam or headrest. Pressure should be l im ited to the forehead. Avoid any pressure on the eyes and ensure the endotracheal tube is secure. The arms are posi t ioned fu l ly adducted so they l ie by the pat ients s ide or are abducted and flexed at the e lbow so they l ie a longside the head. Avoid undue pressure in the axi l lae as axi l lary nerve or brachia l p lexus neuropraxia may occur from overstretch ing (F igure 3) . Pressure points tend to be the head/face, anter ior super ior i l iac sp ines, knees and feet which should al l be wel l padded. Lung compliance is reduced due to decreased chest wal l and diaphragmatic excursion. To aid compliance, a Montreal mattress (a rectangular mattress with a hole in i ts centre) may be used to prevent the abdominal contents forc ing the diaphragm upwards. Alternat ive ly, p i l lows should be p laced under the i l iac crests and chest, leaving the abdomen unhindered. This a lso prevents undue movement of the back and a l lows for ef f ic ient drainage from the epidural ve ins by reducing in trathoracic and intra-abdominal pressure. When using frames that suppor t the anter ior super ior i l iac sp ines, the la tera l cutaneous nerve of the th igh may be compressed and stretched. The Tar lov knee-chest posit ion (prone seated posit ion) is a re l iable posi t ion for lumbar surgery. The buttocks are supported on a seat and the table t i l ted upwards. This posit ion rarely causes any damage other than an erythematous reaction on the skin of the knees. L i thotomy - Legs up Used for gynaecologica l and anal surgery. Both legs should be moved together to avoid strain on the pe lv ic l igaments and the knees should be posit ioned outs ide any meta l supports. Avoid p lacing arms at the s ide as meta l contact with the l i thotomy pole may occur and trapping of d ig i ts in the lower section of the table is possib le. Potent ia l problems include:

common peroneal nerve damage due to compression between the head of the f ibula and l i thotomy pole i f knee posit ioned inside the meta l support

saphenous nerve compression between l i thotomy pole and media l t ibia l condyle autotranfusion from the leg vessels wi l l increase preload. The effect on card iac output wi l l depend on the

pat ients volume status ? v i tal capaci ty is decreased

? r isk of aspiration is increased therefore anaesthesia should never be induced in th is posit ion. Further , i f re flux or vomit ing occurs dur ing induction, turn ing the pat ient wi l l be delayed.

Latera l - On the s ide Usual ly used for thoracotomies, renal, shoulder surgery and h ip operations. The la tera l posi t ion a l ters respiratory physiology: i f breathing spontaneously, the dependent ( lower) lung is eff iciently per fused and venti la ted. But with IPPV the dependent lung is better per fused and the non-dependent (upper) lung better vent i la ted, resul t ing in V:Q mismatch. Pressure points in this posi t ion are the dependent hip, shoulder and ankle and these should be padded where appropr iate. The pat ient may be stabi l ised wi th chest and h ip supports, or with a mattress which becomes r ig id when a ir is evacuated from i t . A p i l low is p laced between the legs, with the lower leg f lexed at the knee and the upper leg in a neutra l posit ion. The upper arm may be al lowed to hang freely above the head or placed in an arm support. Latera l decubi tus posit ion for nephrectomy The table is f lexed in the centre in addit ion to the la tera l posit ion. The latera l decubi tus posi t ion causes a V:Q mismatch as previously mentioned. This posi t ion can cause d irect caval compression resul t ing in decreased venous return and hypotension. It is important to moni tor b lood pressure c loselyan ar ter ia l l ine may be usefu l . Pressure points are the dependent h ip, shoulder and ankle. Once again, the patient is stabi l ised with chest and hip supports or with a mattress which becomes r igid when a ir is evacuated. Si tt ing Occasional ly for poster ior fossa neurosurg ica l procedures. It has a number of advantages over the prone posi t ion: better surg ica l access, more neck f lex ion, improved gravita tional dra inage of blood. Ser ious d isadvantages inc lude: postural hypotension, high r isk of venous a ir embol ism. This posi t ion has marked card iovascular ef fects: cardiac output and ar ter ia l pressure may decrease dramatica l ly due to pool ing of b lood in the lower extremi ties with result ing hypotension and reduced cerebra l b lood flow. Invasive moni tor ing (ar ter ial / central l ines) is required. In order to min imise the effects of changing from supine to a si tt ing posi t ion, a number of measures can be taken. These include flu id loading, compression stockings or G-suits and/or the use of vasopressors. The patient should be ra ised s lowly wi th e levation of the legs above the hor izontal once in the s i tt ing posi t ion to a id venous return. The head may be supported in a horseshoe headrest that al lows pressure to be appl ied to the head and neck wi thout movement. Alternat ive ly a skull c lamp may be used which min imizes pressure-re lated complications involv ing the face. Its inser tion is st imulating but may be attenuated by using local anaesthetic , a smal l bo lus of propofol or a shor t acting opio id. Flexion of the head on the neck a ids surg ica l access, but ra ises ICP and may cause swel l ing of the face and tongue because venous return is decreased. These patients are at marked r isk of a ir embol ism and should be moni tored using ETCO 2 , Doppler , t ransoesophageal ECHO or oesophageal stethoscope. The r isk is reduced by IPPV and by maintaining mean ar ter ia l pressure. Spontaneous venti la tion is permissible ( indicates that respiratory centre is in tact) , but is se ldom used now. Armchair posi t ion for shoulder surgery Occasional ly an armchair posit ion is adopted for surgical access. This posit ion has cardiovascular ef fects s imi lar to the s i t t ing posit ion namely, hypotension due to pool ing of b lood in the lower l imbs. These effects can be reduced by elevating the pat ient to a head up posi t ion s lowly, using vasopressors and flu ids as required, and e levation of the pat ients legs above the hor izontal . These pat ients are a lso at r isk of a ir embol ism. Nerve Si te of Po tentia l Damage Result o f Damage Supraorb ital Compression from a t ight facemask Photophobia, pain in the eye, numbness of

the forehead

Facial L ies super fic ial ly and may be Para lysis of the face and orbicu lar ia occul i

damaged at the ramus of the mandib le (buccal branch

Axi l lary Prone to stretch ing when shoulders are Decreased abduction of arm, reduced skin la tera l aspect of upper extended and arms placed above the head (prone posit ion) sensat ion over arm.

Radia l At r isk of external pressure in axi l la i f Wrist drop arm hangs over the edge of tab le (poster ior cord)

Median Very uncommon in jury. At r isk of Inabi l i ty to oppose thumb and l i t t le f inger d irect needle trauma in ar tecubi ta l fossa Ulnar - May be compressed by edge of operating Hand weakness, t ing l ing and pain mat tress where i t l ies superf ic ia l ly in groove behind media l ep icondyle of humerous - In ternal compression between two heads of f lexor carp i ulnar is - Ful l f lex ion at e lbow causes compression where the nerve enters the cubital tunnel Sciatic Main source of damage d i rect trauma Para lysis of al l muscles and sensory loss

from misplaced i /m in jections below knee pneumatic tourniquet Femoral Susceptib le to damage where i t passes Loss of h ip and knee

extension, loss of sensation over anter ior th igh and anteromeaspect of cal f beneath inguinal l igament - excessive leg

f lex ion in l i thomy may cause entrapment Latera l cutaneous nerve of the thigh common peroneal

At r isk i f f rames are used to support anter ior super ior i l iac sp ines when the pat ient is prone may be compressed by l i thomy pole wherei t passes around the head of the f ibu la (superf ic ial ) Pudendal Compression against per ineal post used in h ip Loss of per ineal sensation, faecal

surgery incontinence Saphenous Compressed between medial t ib ia l condyle and l i thotomy pole ( leg la teral to pole)

NITRIC OXIDE AND PROPOFOL Abstract Propofo l , an intravenous anesthet ic , is s imi lar in chemical structure to the active nucleus of ant iox idant substances such as a lpha-tocopherol (v i tamin E), buty lhydroxyto luene and acety lsa l icy l ic acid (aspi r in) . Recent s tudies have demonstrated that some effects of propofo l may l ie in i ts ant iox idant properties and the l ike ly involvement of n i t r ic oxide. This review ar t ic le focuses on the relationship between n i tr ic oxide and propofo l . There is an implicat ion that n i tr ic oxide is responsible for the hemodynamic responses of propofo l . The antiox idant effect of propofol may a lso extend i ts anesthetic appl ication. In troduction Propofo l is a rapid ly acting in travenous anesthetic agent that has gained widespread acceptance for anesthesia and sedation. The rapid and complete recovery profi le associated with propofo l o ffers advantages over other in jectable anesthetic agents (1,2) . Administration of propofo l produces pronounced hemodynamic responses, par ticular ly the decrease in ar ter ia l b lood pressure (3-11). Publ ished reports have not agreed as to the mechanism of propofo l-mediated hypotension, but some investigators have attr ibuted s ignif icant decrease in systemic vascular resistance to the blood vessel-d i la tion property of propofol to (12,13) with the l ike ly involvement of endothel ium-der ived re laxing factor (n i t r ic oxide) (14). Most important ly , propofo l has been found to bear antiox idant capacity due to i ts structura l simi lar i ty to - tocopherol (15-43) , which is strongly re lated to f ree radica ls. At this point propofo l is not only an anesthet ic agent but also an ant iox idant drug. In th is review, we have focused on publ ished l i terature relating to free radica l ni tr ic oxide and i ts oxidative reaction wi th propofo l . Format ion, decomposit ion and reactivity of nitr ic oxide Nitr ic oxide (NO) is an inorganic gas synthesized by the enzyme ni tr ic oxide synthase (NOS) in which amino acid L-argin ine is oxid ized to NO and equal amount o f L-c i trul l ine(44-46). Three NOS isoforms have been identi f ied: neuronal NOS (nNOS), endothel ia l NOS (eNOS), and iNOS (47) . The former two isozymes are const i tu t ive ly expressed (consti tu tive NOS) and have physiologic ro les; the last is usual ly present only after the induction by in flammatory stimul i . The genes encoding eNOS, nNOS and iNOS have been cloned and sequenced (47-49) . These isoenzymes are d istinct and located on di fferent chromosomes (7, 12 and 17, respective ly) . They are structural ly re la ted to the cytochrome p-450 supergene family and consist o f a s ingle polypeptide chain conta in ing L-arg in ine, heme and calmodul in b inding s i tes as wel l as a complete NADPH diaphorase. Required co-factors inc lude oxygen, NADPH, calc ium (const i tu t ive NOS) and tetrahydrobiopter in (50, 51) . Neuronal NOS (nNOS) is main ly d istr ibuted in the nervous system. NO from nNOS functions as a neurotransmi tter (52-58) in long- term potentia tion (59), gonadotropin secretion (60-64) , sexual behavior (65-69), regulates emotional behaviors (70, 71) and autonomic outf low to the cardiovascular system (72,73). nNOS is a lso present in the kidney (74), skeletal muscle (75-77) and myocardium (78), as wel l as pancreatic is le ts (79, 80) . Endothel ial NOS is predominate ly present in the endothel ium of blood vessels. NO released from endothelium is found as endothel ium-der ived re laxing factor , or EDRF, which modulates vascular tone and accommodates change in b lood f low (81-84) . Endothel ia l NOS is a lso present in some immune cel ls (85, 86) . Accord ingly, eNOS 'knockout" mice are routine ly hypertensive (87-93). Inducib le NOS is expressed in t issues of the immune system (macrophages, leukocytes and other phagocytic ce l ls) on st imulat ion wi th cytokines and/or endotoxin (94-96) , vascular smooth muscle (94, 97) , endothel ium (97, 98) , k idney (mesangium, tubules) (99,100) and other s i tes (pancreas, l iver , enterocytes, a irway, pneumocytes) (101-113). NO from iNOS is present in a large amount. I t exerts antimicrobial , cytotoxic ef fects and immunoregulation (cytokine product ion, apoptosis and s ignal l ing) in the immune system. Therefore, inducib le NOS knockout mice exhib i t loss of immune function and minor hypotension (113-121). NO functions by d i f fus ion to k i l l bacter ia and other microbia l pathogens (122-124) or possib ly acts at the enzyme guanyly l cyclase levels and augmenting cycl ic guanosine monophosphate (cGMP) production (125-129) . Compared wi th neurotransmi tter receptors or re lated adenyly l and guanyly l cyclases (130,131), the NO receptor enzyme appears rather unremarkable. I t is composed of two d i f ferent subuni ts, but only two isoforms have been shown to exist a t the prote in level : the 11 isoform, which is expressed widely, and the 21 isoform present in human placenta (132-134). Severa l receptor systems, inc luding N-methyl-D-aspartate (NMDA) (135, 136) , muscarin ic (137, 138), and gamma-aminobutyr ic acid ( -GABA) receptors (139, 140) and A2-adrenoceptors (141) , have been shown to mediate thei r action v ia the NO-cGMP pathway.

NO is a lab i le species with a half- l i fe of only a few seconds in b io logical systems. It degrades rapidly to NO2- (n i t r i te) . Ni tr i te is unstable and i t is fur ther conver ted to the end product NO3- (n i tra te) . Putative in termediate metabol i tes inc lude an array of low and high molecular weight thiols--n i trosoglutath ione, n i trosoalbumin, S-n itrosohaemoglobin (142). This is not only a mechanism for scavenging NO but a lso serves to transpor t NO and is the molecular basis for bio logica l ef fects in i ts own r ight. In the presence of O2, NO reacts wi th O2- to form ONOO- (peroxyni tr i te) and other NO radica ls as wel l . Overproduction of NO can lead to cytotoxic i ty . NO rapid ly oxid izes sulfhydryl groups and th ioethers in peptide, prote ins and l ip ids (143). In addit ion, NO ni trates and hydroxylates aromatic compounds, including guanosine (DNA damage) (144), benzene (145, 146) ) , tyrosine (147), tryptophan (148) , 4-hydroxyphenylacet ic acid (149), and - tocopherol (150). These deleter ious ef fects of peroxynit r i te may d isturb cel l -s ignall ing processes (Fig. 1) . Structura l formulae of propofo l , a lpha tocopherol , buty lhydroxyto luene and acety lsal icy l ic acid. There is a hydroxyl subsi t i tuent and a benzene group in al l four compounds. Propofo l and i ts c l in ical re levance wi th NO Propofo l (2,6-d i isopropylphenol) is an intravenous anesthet ic that is widely used for both induction and maintenance of general anesthesia. The pharmacokinetics of propofo l is best descr ibed by a three-compar tment model: the central compartment, the shal low per iphera l compartment and the deep per iphera l compartment. Of the greatest importance is the rapid clearance of propofo l ( rapid and complete recovery) , which is approximate ly ten t imes faster than that of th iopenta l . This made propofo l the best control lab le in travenous hypnotic f rom a pharmacokinet ic point of view (1,2, 151) I ts c l inical uses inc lude ambulatory anesthesia, monitored anesthesia care, neuroanesthesia, cardiac anesthesia, pediatr ic anesthesia and sedation in the in tensive care uni t (2) . Use of propofo l for induction of anesthesia causes decrease in ar ter ial pressure and systemic vascular resistance. Systol ic ar ter ia l pressure (SAP) is decreased af ter the star t o f induction ; d iastol ic pressure (DAP) is decreased at 60 s af ter star t of induction and fur ther decreases are seen unt i l 210 s af ter induct ion (6) . The precise mechanism(s) of propofo l- induced hypotension is not known. Many studies have attr ibuted the hypotensive responses to decreases in peripheral resistance. Th is can be prevented by effective volume loading (152), but cannot be at tenuated by administration of a f luid pre load (10). Induct ion of anesthesia with an opio id-benzodiazepine combinat ion fo l lowed by a maintenance in fusion of propofo l , supplemented with an inhalational agent or opio id analgesic or both, appears to control b lood pressure as wel l (2) . Some studies suggested that propofol -mediated hypotension is due in par t to an inh ib i t ion of the sympathetic nervous system (153) and to an impairment of baroref lex mechanism (154). A reduction in p lasma norepinephr ine concentrat ions after propofo l has been demonstrated a lso (155). Recently , a possib le involvement of endothelium-der ived re laxing factor or n i t r ic oxide was proposed in the rapid onset of vasodi la tat ion produced by propofo l (14) . It was reported that propofo l s timulated ni tr ic oxide release from cul tured porcine aort ic endothel ia cel ls and an inh ib i tor of NO b locked the effects of propofo l (156). In a d i f ferent study, propofo l showed a contracti le effect in iso lated aortas from spontaneously hypertensive rats in the present of a n i tr ic oxide inh ib i tor (157). However , another study examined the effects of propofo l on rat aor tic and pulmonary ar tery r ings and demonstrated a marked relaxation, which was endothelium-independent (158). In addit ion, the same effect was observed in iso lated mesenter ic ar ter ies from humans . Further studies on the mechanism responsib le for the reduction in systemic vascular resistance and hypotension of propofol are needed. Ant ioxidant activ i ty of propofo l Free radicals are bel ieved to contr ibute the t issue injur ies associated wi th many pathological processes such as ischemia, t issue anoxia, inf lammatory process, in fection, carc inogenesis, neurodegenerative d isorder and diabetes (160-162). In such d iseases, antiox idants can protect t issues by inhib i t ing l ip id peroxide formation or increasing the activ i ty of the g lutath ione antiox idant system, among other mechanisms . Propofo l has a structure (2,6.d i isopropylphenol) s imi lar to that of known ant ioxidants (Fig. 2) , such as tocopherol (v i tamin E), acety lsa l icy l ic acid and buty lhydroxyto luene . The abi l i ty of propofo l to inh ib i t the formation of l ip id peroxides has been found in severa l media in which free radica ls are produced, e.g., l iver and bra in microsomes in the rat (16) , l iver mitochondria in the rat (18, 23) , and chemical media enr iched in arachidonic acid or l ino leic acid (Using normal rat t issues (36) and an in v i tro model of cerebral anoxia in the rat, i t was found that the ant iox idant effect of propofo l is mani fested not only as an inh ibi t ion of l ip id peroxidation, but a lso as a decrease in t issue consumption of glutath ione . Studies in animals show that propofo l , indeed, reduces the formation of l ip id peroxides) . In humans, there was no effect on p lasma l ip id peroxide levels in pat ients g iven propofol ) . However, others showed an increase in p lasma ant ioxidant capacity in patients anesthetized with propofol The h ighest levels of peroxides occur in ce ll membranes, rather than in p lasma, and the antioxidant g lutath ione pathway is an impor tant intracel lu lar ant iox idant system. In a group of surg ica l pat ients who were g iven propofo l anesthesia, propofo l showed ant ioxidant ef fects as evidenced by

the inh ib i t ion of l ip id peroxidase production in the p late let membrane and changes in the g lutath ione antiox idant system). In o ther exper iments, propofo l enhanced red blood cel l antiox idant capaci ty in swine and humans). Propofo l , l ike other phenol-based antioxidant compounds, a lso acts d irectly as a free radical scavenger. Studies on the amel iorating effect of propofo l in inh ib i t ing radical production revealed that i t preferentia l ly scavenges organoradical species. In aqueous suspension i t is more eff ic ient than buty lated hydroxy- to luene (BHT) as a free radica l scavenger of r ibof lav in radicals and in b locking formation of malondia ldehyde degradation products generated from l ip id hydroperoxides of arachidonic acid (20) . In addit ional exper iments i t was found, using electron spin resonance (ESR), that propofo l reacted wi th oxygen free radica ls or peroxyni tr i te to form phenoxyl radica l) . Moreover, i t was demonstrated employing mass spectrometry, that propofo l could react with NO to generate ni tro-propofo l in v i tro ( forming phenoxyl radical )) . Thus, propofol is a peroxynitr i te scavenger. Because of these reactions, propofo l has neuroprotect ive proper ties against in jur ies caused by ischemia/reoxygenat ion Also, propofo l prevents and reverses the inh ibi t ion of exci ta tory amino acid uptake in astrocytes exposed to ter t-buty l hydroperoxide. The abil i ty of propofo l to defend against peroxide-induced inhib i t ion of g lutamate c learance may prevent the pathologic increase in extracel lu lar g lutamate at synapses, and thus delay or prevent the onset o f exci totoxic neuronal death) . Fur thermore, propofo l had a protect ive effect in neurons against acute mechanical in jury A water-solub le prodrug of propofol protects from neuronal cel l death from oxidat ive in jury caused by glutamate (43). This is consistent with the c l in ica l observation that use of propofo l is associated with s igni f icant cerebral protection. The same protection was obta ined in heart reperfusion in jury. Iso lated perfused Wistar rat hear ts were subjected to ei ther warm global ischaemia (Langendorff) or co ld St. Thomas' cardiop legia (working heart mode) in the presence or absence of propofol . I t was found that with the presence of propofol the heart in jur ies were signi f icantly less, probably as a result o f d imin ished oxidative stress (172). In iso lated, working rat hear ts subjected to ischemia, fol lowed by reperfusion, i t was observed that propofo l a ttenuated mechanical dysfunction, metabol ic derangement, and l ipid peroxidat ion dur ing reperfusion (24, 173). Addit ional exper iments demonstrated that in v ivo, propofo l amel iorated dysfunct ion of the myocardium but not of the coronary endothel ium result ing from br ie f ischaemia and reper fusion. The protection may be related, at least in par t, to i ts abi l i ty to reduce l ip id peroxidat ion (174). However, the ant iox idant propert ies of propofo l are di fferent depending on the formulation of propofo l . Propofo l inh ib i ted the chemi luminescence (CL, a measure of oxidat ive stress) produced by stimulated polymorphonuclear (PMN) leukocytes in a dose dependent manner (unt i l 5 x 10 -5 M, a c l in ica l ly relevant concentration) , whi le Dipr ivan ( the commercial form of propofo l ) and intra l ipid ( IL , vehic le so lut ion of PPF in Dipr ivan, composit ion: 1.2% egg phosphatide, 2.25% glycerol ) were not dose-dependent inh ib i tors. The CL produced by endothel ial ce l ls was dose-dependent ly inhib i ted by Dipr ivan and PPF, and weakly by IL (not dose-dependent) . In ce l l free systems, dose-dependent inhib i t ions were obta ined for the three products wi th a lower ef fect for IL . Dipr ivan ef f icaciously protected endothel ial ce l ls submitted to an oxidant stress, whi le IL was ineffec tive. By HPLC, i t was demonstrated that PPF was not incorporated in to the cel ls . The drug thus acted by scavenging the active oxygen species re leased in to the ex tracel lular medium. IL acted in the same manner, but was a less powerfu l antiox idant (38) . In conclusion, there is an impl ication that propofo l enhances NO production in vascular system and that NO is probably responsible for the hypertension. The unique ant iox idant abi l i ty and free radica l scavenger o f propofo l may lead to fur ther broaden i ts current c l in ica l appl ication in the future.

LEVOBUPIVACAINE A long acting local anaesthet ic, with less cardiac and neurotoxicity

In troduction The proper ty of isomer ism occurs when two or more compounds have the same molecular composit ion, but a d i fferent structure which often resul ts in d i f ferent propert ies. There are two types of isomer ism - structural and stereoisomersim. Structura l isomer ism means that the compounds have the same molecular formula, but a d i fferent chemica l structure. This may resul t in the compounds having s imi lar actions l ike the anaesthetic vo lat i le agents isoflurane and enflurane or di fferent act ions l ike promazine and promethazine. Stereoisomer ism descr ibes those compounds which have the same molecular formula and chemical structure, but the atoms are or ientated in a d i fferent d irection. There are two isomers, each a mirror image of the other, ca l led enantiomers. They are a lso called opt ica l isomers because they rotate the p lane of polar ised l ight e i ther to the r ight refer red to as +, dextro, d or D isomer, or to the le ft re ferred to as - , laevo ( levo), l or L isomer. More recent ly th is c lassif ication has been replaced by the R- /S- notation, which describes the arrangement of the molecules around the chira l centre (R is for rectus the Latin for r ight , and S for s in ister , le f t) . The R enantiomer rotates l ight to the r ight and the S enantiomer to the le ft . As wi th other isomers, they can have d i f ferent propert ies. The molecule of bupivacaine, a long act ing local anaesthetic , has an asymmetr ic carbon atom. For th is reason, wi th th is asymmetr ic carbon as a chiral centre, bupivacaine exhib i ts this phenomenon. In the commercial presentat ion of th is local anaesthet ic there is a 50:50 propor tion: levobupivacaine, L ( - ) isomer, and dextrobupivacaine D (+) isomer. This preparation which conta ins both enantiomers is ca lled a racemic mixture. The preparat ion of levobupivacaine conta ins only the levorotatory isomer present in the commercia l preparations of bupivacaine. In terest in levobupivacaine arose af ter severa l cases of severe card iotoxic i ty ( inc luding death) were reported where i t was shown that the D isomer of bupivacaine had a higher potential for tox ic i ty . Consequent ly , i t was thought that i f i t was possib le to use only the levorotatory isomer , levobupivacaine, the r isk for card iac and neurotoxici ty could be less than with the racemic bupivacaine but with s imi lar cl in ica l e ffects. Chemistry Here we wi l l expose some general concepts about a l l local anaesthet ics, with a special re ference to levobupivacaine. Local anaesthetic molecules a l l have three character is t ic por tions : A benzene r ing - aromatic head An in termediate chain An amino group The benzene r ing is very so luble in l ipids. The in termediate port ion, a br idge between the other two, can have one of two types of chemical structures: Ester (COO-), or Amide (CONH-) ( f igure 2) . Therefore, chemical ly, there are two large groups of local anaesthet ics, depending on th is intermediate portion of the molecule: Ester type and Amide type local anesthet ics. Procaine is the prototype of the f i rs t group ( f igure 3) , and l ignocaine is the prototype of the second one ( f igure 4) . The fi rs t group more commonly cause a l lergic reactions and have a shor t length of act ion as they are rapidly metabolized by chol inesterase. In contrast the second group, amides, rarely case a l lerg ic react ions but are more l ikely to cause toxic react ions i f the dose is exceeded. Levobupivacaine is an amide, which l ike the other amides, is a weak base. Depending on the pH, the amino group can adopt the ter t iary or the quaternary form. The drug is in dynamic balance between the ter t iary form, a free base, and the quaternary form, which has a posit ive charge, making i t very water-so luble. The pKa of levobupivacaine is 8.1, simi lar to the pKa of the racemic bupivacaine. (pKa is the pH at which 50 % of the molecules are free base and 50 % of the molecules have a posi t ive charge - ion ised). I f b icarbonate is added to levobupivacaine, the pH is increased leading to a r ise in the percentage of f ree base molecules. Those molecules cross more easi ly through the axon membrane and the pharmacologica l action begins more quickly. In contrast, i f the pH is low (acid) , as happens when there is a local in fection, there wi l l be less free base molecules to cross the axon membrane result ing in smal ler act ion over the axon. Prote in b inding of levobupivacaine is more than 97%, mainly to acid a lpha1-glycoprote in, rather than to albumin. This union to proteins is somewhat h igher than the union of racemic bupivacaine to prote ins (95%). This means that less than 3% is f ree in plasma. It is the free levobupivacaine, a small fraction of the to ta l concentration that can have an act ion on other t issues, causing the unwanted s ide-ef fects, and producing the toxic manifestations. In hypo-proteinaemic, undernour ished patients, patients wi th the nephrot ic syndrome and in the newborn there is less prote in for b inding, causing h igher levels of free drug, result ing in toxic ef fects being seen at lower doses

Bupivacaine has stereoisometr ic proper ties as explained earl ier . Commercia l production of levobupivacaine for c l inical use was star ted because i t was observed experimenta l ly that the D i somer had a lower threshold for causing tachycard ia and dysrhythmias, which inc lude, AV b lock, QRS widening and ventr icu lar tachycard ia and fibr i l la tion than e i ther the L isomer or the racemic preparation. The levo isomer was used in rats and i ts effect was compared with the dextro isomer . It was found that wi th doses of 2mg/kg, a l l the animals of the dextro group developed apnoea, bradycard ia, hypotension and fina l ly d ied. In contrast, no animal in the levobupivacaine group had apnoea and only 30% had a sl ight bradycardia. In sheep exper iments in which racemic bupivacaine was administered in toxic quanti t ies, i t was found that the concentration of the dextro isomer was h igher in the myocardium and bra in than the concentration of the levo isomer. This work together wi th other s imilar studies, led the invest igators to conclude that levobupivacaine was less toxic than the racemic bupivacaine, but wi th s imi lar c l in ica l activ i ty . Addit ional ly , e lectrophysiologica l s tudies have been made which demonstrate that b lockade of the inactive sodium channels is stereoselective, with the D isomer being more potent and faster than the L isomer. As th is inc ludes the card iac f ibres, i t expla ins the higher card iotoxic i ty associated wi th the D isomer .[1] Some of the f i rs t cl in ica l s tudies in humans in Brazi l , compared the ef fects of the racemic preparation and the levo isomer of bupivacaine when g iven per idura l ly . No s igni f icant d i f ference in onset t ime, qual i ty of anaesthesia and level of b lockade has been found. Pharmacokinetics There are di ff icu l t ies in carry ing out pharmacokinet ic studies with bupivacaine. Classic pharmacokinet ic studies are usual ly per formed using an in travenous appl icat ion of the drug. These studies are more accurate because there are fewer possib le causes of error , than when other access routes are used, such as in tramuscular or subcutaneous in fi l t ra tion. Wi th both these routes of administration, the rate of absorption is an important but unknown factor affecting the rate of absorpt ion between patients with di fferent pathologies. In addi t ion intravenous administration of bupivacaine or levobupivacaine, for pharmacokinetic studies has l imitat ions, because of the r isk of fa ta l tox ic i ty . Addit ional ly , in cl in ical practice th is drug is not used in travenously. Pract ica l c l in ica l s tudies have been carried out g iv ing the drug for epidural and regional b locks. Placenta l transfer of levobupivacaine is s imi lar to that of bupivacaine resul t ing in lower r isk to the fetus. L ike racemic bupivacaine, levobupivacaine is metabolised in the l iver , pr imar i ly by the cytochrome P450, specia lly the CYP1A2 and CYP3A4 isoforms. Clearance is reduced when the hepat ic funct ion is damaged. Pharmacodynamics The mechanism of action of levobupivacaine is exactly the same as that of racemic bupivacaine and that o f a l l the local anesthetic drugs in cl in ica l use today. When the min imum local analgesic concentration (MLAC) close to the membranes of the axons is reached, the molecules block the sodium channels, in the rest ing posi t ion. In th is way, the transmission of the nerve impulses stops. This act ion is produced with an onset very simi lar to that of racemic bupivacaine. The duration of act ion is a lso s imi lar to that of the racemic substance. Recent research work has been directed at the toxic i ty associated with the levo isomer, and how i t compares with the racemic preparation. Differences were found between the two isomers. The concentration necessary to produce cardiac and neurotoxic i ty is h igher for levobupivacaine than for racemic bupivacaine. The safety margin is estimated at 1.3 which means that tox ic ef fects are not seen unti l the concentration r ises by 30%. Toxici ty Volunteers have been given bupivacaine or levobupivacaine in travenously at a rate of 10mg/min, unti l the appearance of ear ly symptoms of centra l nervous system toxic i ty. These appeared at a lower dose (Mean 47.1mg) wi th bupivacaine than wi th levobupivacaine (56.1mg). Simi larly there was a greater reduct ion in the myocardia l e jection fraction and systo l ic and accelerat ion index with racemic bupivacaine when compared to levobupivacaine. When 40mg of ei ther levobupivacaine or racemic bupivacaine were administered over a 10min per iod, the EEG was s ignif icant ly slower after racemic bupivacaine. Thus at s imi lar doses, e lectr ica l activ i ty is more af fected by racemic bupivacaine.[2] Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in h igher concentrat ions. Clinical Applicat ions Levobupivacaine has been in troduced in to c l in ica l pract ice wi th in the last few years. It has been used at al l si tes: epidural , subarachnoid, di f ferent levels of brachial p lexus block - interscalene, supra and in fraclavicular , in tercosta ls and per ipheral nerve blockade, per ibulbar and retrobulbar b lockade, local in fi l t ra tion, obstetr ic analgesia, postoperat ive pain management, acute and chronic pain management. The doses used are very s imi lar to those of bupivacaine. As a resul t o f i ts lower card iac and neurotoxic i ty compared to racemic bupivacaine, anaesthetis ts fee l safer working wi th levobupivacaine, than with bupivacaine.

Nevertheless, we must a lways remember that i t is s t i l l a potential ly tox ic local anaesthetic . The in i t ial l icensing author i ty recommended a maximum single dose of 2mg/kg, and 400mg (5.7mg/kg) in 24h. Since then, some studies have shown that h igher doses are safe, but fur ther work is required. Special caution is recommended for hypoprote inemic patients, inc luding adults wi th nephrot ic syndrome, severe hepatic disease and the newborn. In Colombia, we have been using th is new local anaesthetic for a year, with excel lent results. [3 ] We only have the 0.75% formulat ion and use a lmost the same dose as when using bupivacaine. We have had no repor ts of tox ic reactions. Dur ing the Colombian Congress of Anesthesiology (2001), a paper was presented, compar ing levo-bupivacaine with ropivacaine in epidura l anaesthesia. The two drugs were comparable, wi th a very good qual i ty of epidural anaesthesia. However there were three cases of bradycardia in the levobupivacaine group which were treated successfu l ly with atropine. The duration of the motor blockade in the postoperative per iod was less than after racemic bupivacaine. Adverse Effects These are the same as caused by racemic bupivacaine and any other local anaesthetic . They inc lude hypotension, bradycard ia, nausea, vomiting, prur i tus, headache, t inn i tus, d izziness, constipation, vomiting and convuls ions. There have been reports of cases where the drug has been g iven in higher doses than that recommended, with no apparent tox ic i ty . In one case, a s ingle dose of levobupivacaine of 250mg for a brachia l p lexus b lock, far exceeding the maximum recommended dose (150mg), without tox ic i ty symptoms, a l though fur ther data wi l l be needed before the safety of th is level o f dosage is conf irmed. There is a repor t where approximate ly 1.7mg/kg racemic bupivacaine was injected probably by an accidenta l in travenous in jection dur ing an at tempted supraclav icu lar brachia l p lexus b lock. The patient lost consciousness, developed a tachycardia, hypertension and general ized twitch ing, was managed with oxygen and propofol , with a successfu l recovery af ter a few minutes with no sequelae.[4] The authors stressed the r isks associated with administration of h igh doses of bupivacaine, even in experienced hands and under l ine the need for possib ly safer agents such as levobupivacaine. Conclusion Levobupivacaine is a re latively new long acting local anaesthetic , with a pharmacologica l act iv i ty very simi lar to that of racemic bupivacaine. The fi rs t s tudies in humans confirm the animal studies and the in vi tro s tudies, which showed that th is new molecule is less cardiotoxic and less neurotoxic than the racemic bupivacaine. Levobupivacaine can be used for al l indicat ions in which the anaesthetis t needs a long act ing local anaesthet ic . The reduced toxic i ty of th is new local anaesthetic is an advantage for the pat ient. The cost in Colombia is 40% higher , than racemic bupivacaine.

A NEW MANDATE FOR THE ANESTHESIOLOGIST-CANCER PAIN SPECIALIST: EXPERTISE IN PRESCRIBING ANALGESICS

Introduction The anesthesio logist with an interest in the management of cancer pain may make important contr ibutions to the wel l being of the cancer pat ient with pain, as wel l as to the effectiveness of teams organized to del iver pain and symptom control . Tradit ional ly , the ro le of the anesthesio logist has been somewhat narrowly conceived of as that o f a sk i l led technician provid ing invasive procedures when warranted, a " job descr ip t ion" re lated in large par t to the ski l l fu l adaption of regional anesthetic techniques to the management of chronic symptoms., The practice of cancer pain management has evolved considerably over the last decade, mandating careful scrutiny of the anesthesio logist 's role in contemporary cancer pain management. This ar t ic le outl ines a rationale for an expanded ro le for the anesthesio logist-pain specia l is t and reviews the basic aspects of the pharmacologic contro l o f cancer pain. Basis for Expanded Role of the Anesthesiologist The rationale for adopting a broader v iew of the anesthesio logist 's contr ibution to cancer pain control re late to severa l fundamenta l concepts that have come to serve as foundations for the contemporary practice of cancer pain medicine, hospice care and pal l ia t ive care. These factors can be conceived of as including: (1) the acquis i t ion of new pharmacologic knowledge and consequent ly , a greater emphasis on pharmacotherapy, (2) a reappraisal o f the ro les of invasive versus noninvasive in terventions that views them as complementary rather than mutual ly exclusive; (3) an emphasis on quali ty of l i fe as the end point of a broad based therapeut ic armamentar ium, the goals of which inc lude the management not just of pain, but a lso of o ther symptoms. A New View of Opioid Pharmacotherapy Foremost among these factors is a reappraisal o f the pharmacology of chronica l ly administered opio ids, and a growing understanding of the s ignif icant d i fferences in pharmacology that exist wi th chronic as opposed to acute administration. Most of the knowledge g leaned about opio id pharmacology, unti l recently, was der ived f rom single or l imited dose studies conducted in the presence of ei ther exper imenta l ly induced or acute pain. In a construct that recognizes chronic and acute pain as d ist inct d isorders, there is l imi ted justi f ication for applying knowledge gained from one sett ing to the other uncr i t ica l ly . The inadequate scienti f ic basis for prescr ibing practices is l inked to and compounded by f i rmly held bel ie fs regarding the dangers of opioid therapy. Such bel iefs are now widely understood to be based more on cu l tura l b iased than medical considerations.,, Recognit ion that the uncr i t ica l acceptance of these b iases has h istor ica l ly impeded legit imate scient i f i c inquiry and the d issemination and implementation of knowledge al ready on hand has engendered an a lmost unparal le led scienti f ic activ ism to d ispel these myths. Guidelines re leased by the World Health Organization,, Amer ican Pain Society, Amer ican Society of Cl in ical Oncology, Oncology Nursing Society the Amer ican Society of Anesthesio logists and U.S. government Agency for Health Care Pol icy Research, stress the importance of opio id therapy and ar ticulate the need to overcome exaggerated concerns about i ts r isks. Through the Lookinglass: "Oral Opioids Are Ineffect ive" In pr ior eras ora l morphine was deemed ineffect ive, with the f i rs t ed it ion of the A.M.A. Drug Evaluation Manual (1971) referr ing to ora l ly administered morphine simply as "not recommended." Biases against the use of oral opio ids can be traced to an incomplete understanding of the ir c l in ica l properties, especia lly the concepts of parenteral :ora l bioavai lab i l ity , lack of ce i l ing doses and a propensity for the rapid development of tolerance to most adverse ef fects. An i l lustrat ive study was conducted by Beecher and col leagues.16 They compared the effectiveness of 10 mg oral morphine, aspir in and p lacebo in postoperative patients, and demonstrated that morphine was no more effective than placebo and was less ef fective than aspir in . Having administered oral morphine in doses expected to be therapeutic , they concluded that ora l morphine was ineffective as an analgesic. Only in l ight of la ter studies demonstrating the l im its of oral morphine 's b ioavailab i l i ty , does i t become apparent that Beecher 's study uti l ized sub-therapeutic doses of ora l morphine, and as such s imply provided prel iminary ind irect evidence of a parentera l :ora l analgesic equivalency of greater than 1:1. Other contemporary research has demonstrated a lack of cei l ing ef fect to opio id-mediated analgesia and a h igh incidence of the rapid development of to lerance to adverse effects such as nausea and sedation. The Contemporary View: Oral Opioids as Treatment of First Choice Oral morphine and i ts congeners were not widely used unti l the exper ience g leaned from the Br i t ish hospice movement in the 1960's exerted i ts in fluence dur ing the 1970's and 1980's. In large par t as a result of the World Health Organization 's identi f icat ion of cancer pain as a major g lobal heal th problem,9,10 wel l contro l led, cross cultura l ly va l idated tr ia ls of ora l pharmacotherapy have s ince been performed that demonstrate eff icacy in 70% or more of pat ients wi th cancer pain.,, , Such eff icacy combined with the favorable safety prof i le of ora l op io ids

( revers ib i l i ty , t i t ra tabi l i ty , absence of long term organ toxic i ty) has caused cancer pain exper ts from mult ip le d isc ip l ines to advocate the use of ora l op ioids as the treatment of f i r st choice for cancer pain that has not responded to anti tumor therapy.10,11,, This t rend establ ishes an imperative that the anesthesiologist develop and mainta in expert ise in pharmacotherapy, even i f the i r pr imary focus remains neura l b lockade. Changing Views on the Role of Nerve Blocks and Other Procedures Far f rom el iminating the need for invasive procedures, new evidence supporting the use of ora l op io ids as the mainstay of therapy for pat ients with cancer pain has refined the ro le of such procedures. Although th is construct d ictates that invasive procedures should be confined to those 30% of cases or so where pain or s ide effects persist despi te the judic ious use of opio ids, th is represents a substantia l population in need of invasive treatments. Even wi th in the realm of invasive therapies, new developments have fur ther c ircumscr ibed thei r ind ications. Advances in microprocessor technology and the maturation of organized home care, together wi th the more faci le use of parenteral op io ids have resul ted in an in termediate role for subcutaneous and in travenous opio id infusions (with or wi thout pat ient contro l led analgesia) , especia l ly for patients with a l imentary dysfunction. These same trends, together wi th the in troduct ion of in traspinal opio id therapy have made an entire set of new modal i t ies avai lab le for both ambulatory and bedbound pat ients. Whi le neura l b lockade remains an important option for se lected pat ients, parentera l and in traspinal opio id therapy have the advantages of t i tratabi l i ty , revers ibi l i ty and eff icacy for general ized and multi focal pain. The la tter feature is par ticu lar ly impor tant in v ir tue of the fact that most cancer patients exper ience more than one distinct pain problem. Enhanced in terest and knowledge about cancer pain and the more l ibera l use of opio ids has had another important effect on the ind ications for neura l b lockade. In the context of an h istor ical v iew that considered the use of opio ids as being pr ima facie undesirable, there was a tendency to corre late the outcome of nerve b locks wi th whether opio id use could subsequently be d iscontinued or dramatica l ly reduced. With the current emphasis on qual i ty of l i fe , independent of opio id doses per se,18,28 nerve blocks are more readi ly v iewed as occupying a role that complements rather than replaces that of opio ids. Reduct ions in opio id use are of ten sti l l sought as a means to reduce drug side effects and as indirect evidence that the correct procedure has been selected and proper ly executed. Nevertheless, eff icacy is not general ly judged d irect ly in l ight of changes in dose requirements, but instead on c l inica l reports of pain and toxici ty . Juxtaposing opio id therapy and neural blockade as complementary rather than mutual ly exclusive modal i t ies demands profic iency in pharmacologic management. With in such a construct, the l ikel ihood increases that patients wi l l cont inue to uti l ize opioid analgesics even af ter an invasive procedure, albei t with dose ti tra tion. Careful dose adjustments are perhaps most essentia l in the event of a h ighly successfu l procedure: reduct ion in the dose of systemic opio ids is often necessary to c i rcumvent toxic i ty when abrupt reduct ions in pain resul t in unopposed opio id effects , whi le downward t i tra t ion must be tempered to avoid symptoms of physica l withdrawal (abstinence). Symptom Control and Quality of Life Another lesson from the hospice movement re lates to the identi f icat ion of qual i ty of l i fe as an end po int of treatment. A focus on quali ty of l i fe is a lso a hal lmark of pal l iat ive care,, a d iscipl ine that grew out of hospice and which has achieved the status of a d ist inct medical subspecia li ty in some countr ies. Qual i ty of l i fe refers to the pat ient's overal l funct ional status and sense of wel l being, and includes a focus on physica l, but a lso psychological and spir i tual aspects of the person.30 More than an abstract concept, qual i ty of l i fe has been the subject of considerable research that has inc luded the development of val id measurement tools. Studies documenting the frequency of symptoms in patients wi th cancer have demonstrated that pain is one of the most common problems, present in about 2/3 of patients overa l l (up to 25% of those with ear ly d isease and up to 90% in the sett ing of advanced d isease). Other symptoms are, however, h ighly prevalent (see Table 1) and i f unrel ieved result in h igh levels of distress among pat ients and fami ly members. If o ther symptoms are not addressed, even successful pa in management wi l l fa i l to impact on qual i ty of l i fe in a meaningfu l way. Pall ia tive care experts recommend br inging the same intensity of e f for t to bear on treating other symptoms as is appl ied to the management of pain.21, Management of o ther symptoms is predominant ly pharmacologic, and pr incip les govern ing such management have been advanced in the same way as have guidel ines for pain management.21,38 Treatment is of ten relative ly stra ightforward. I t is notewor thy, however that recent developments have suggested therapeut ic a l ternat ives for symptoms resistant to standard approaches as wel l as to symptoms previously v iewed as ir remediable l ike cogni t ive fa i lure, dyspnea, anorexia and weight loss. Expertise in the management of re lated symptoms and toxic i t ies is essent ia l for the anesthesio logist-subspecia l is t, and is fac i l i ta ted by their expertise in c l in ica l pharmacology. The dictum that treatment wi th opio ids should proceed unt i l pain is control led or unpleasant s ide effects supervene implies that s ignif icant s ide ef fects wi l l be present in a h igh proport ion of patients referred for consultation. Treatment modali t ies insti tu ted by the anesthesio logist to contro l pa in may produce new symptoms or exacerbate preexisting symptoms. The anesthesio logist 's involvement

in overa ll symptom management is fundamental to the conceptual ization of the ir ro le as a consul tant ra ther than a technic ian, or the "doctor at the o ther end of the needle." Trends in Pharmacologic Management Pharmacologic management is considered the f i rs t l ine of therapy for patients with cancer pain and when proper ly appl ied resul ts in adequate analgesia in the major i ty of cases. Treatment is effect ive in adul ts and chi ldren and across di fferent cu l tures. The analgesia that is associated with systemical ly administered medications is t i tra table and sui table for pain that is mult i focal and/or progressive. Effects and s ide effects are revers ib le, and widespread implementation does not depend on sophisticated technology or scarce resources.27 Inter individual Var iabil ity Cancer pain, and indeed pain in general, is characterized by in ter ind iv idual var iabi l i ty that is manifest in mult ip le ways., For example, not a l l bone metastases result in pain. Even when pain is present, sel f-report var ies dramatica l ly as do responses to therapy. The regular administration of an aspir in- l ike drug may suff ice for some pat ients, whi le others wi l l require t reatment wi th morphine or another potent opioid. In the la tter group, even pat ients wi th s imi lar d isease character is tics vary dramatica l ly in the ir analgesic requirements to the extent that dai ly doses of morphine may need to be dispensed in mi l l igrams for some pat ients and grams for others.6 Even in the same patient, one standard opio id analgesic may produce dose- l im it ing s ide effects , whi le a pharmacological ly s imi lar drug may be to lerated wi thout d i f f icu l ty due to incomplete cross to lerance. This high degree of in ter indiv idual var iabi l i ty mandates carefu l assessment, , and even wi th the l ike l ihood of favorable treatment outcomes, makes cancer pain management a demanding and time- intensive endeavor. Nonopioid Analgesics A deta i led descr ipt ion of pharmacologic propert ies and c l inica l use of these agents is beyond the scope of th is paper, but is avai lab le e lsewhere.11,28,43. Nonsteroidal Anti- inf lammatory Drugs The nonstero idal anti - in flammatory drugs (NSAIDs) are ind icated for mi ld pain, and combined wi th stronger analgesics, for moderate to severe pain.11, The NSAIDs are particular ly ef fective for pain of bony metastat ic or igin, as wel l as for pain associated with in flammation, due to their inh ib i tory effects on prostaglandin synthetase (cyclo-oxygenase) ,46 an enzyme involved in prostaglandin synthesis. Regular (around-the-c lock or a- t-c) admin istrat ion is most ef fective. Gastro intest ina l, hematologic and renal tox ici ty may occur, as wel l as masking of fever, a part icu lar concern in patients with reduced marrow funct ion. In contrast to opioids, the use of the NSAIDs is associated with a ce i l ing effect , above which dose escalat ions do not result in enhanced analgesia. The cei l ing dose in a g iven ind iv idual may d i f fer f rom the recommended dose by up to two-fo ld though, and as a result some dose-t i t ra tion may sti l l be ind icated. Selection is based on the patient 's pr ior exper ience, minor d i f ferences in toxic i ty , physic ian exper ience, schedule and expense.43,50 Coanalgesics/Analgesic Adjuvants The so-cal led "adjuvant analgesics or coanalgesics" enhance opioid-mediated analgesia, reduce opio id-mediated toxic i ty or help contro l o ther symptoms of cancer. They are a heterogeneous group of medicat ions developed for purposes other than rel ie f o f pain, but subsequent ly determined to have a complementary ro le in pain management. Of drugs wi th purported coanalgesic proper ties, evidence most strongly suppor ts the c l in ica l use of se lected ant idepressants, anticonvulsants, ora l local anesthetics and cor t icostero ids (see references for deta i ls) . Coanalgesics versus Opioids In contrast to the opioids, which are relative ly usefu l for a l l types of pain, the coanalgesics are ind icated only in speci f ic sett ings, eg: antidepressants,52,, , ,, , ant iconvulsants52,, , and ora l local anesthetics43,, for neuropath ic pain and cor ticostero ids,,, , ,66 for pain associated with in flammation and per i tumoral edema. The dose-response re lationship for these drugs and the opioids d i ffers in important ways. The administrat ion of a suff ic ient dose of an opio id invar iably resul ts in some degree of analgesia, which increases l inear ly with the dose in a c lose temporal re lationship to each administrat ion. Depending on the under lying pain mechanism and other more obscure factors, administration of the coanalgesics may or may not resul t in analgesia. The onset of analgesia may be delayed by days or even weeks after ini t ia ting therapy, and the qual i ty of analgesia is less closely l inked to dose increases. As a resul t, ser ia l t r ia ls of each c lass of coanalgesics, and even of d i fferent agents within the same class are ind icated. Opioid Analgesics Oral analgesics are the mainstay of therapy for patients wi th cancer pain, and are reported to control pa in in 70-90% of patients when they are prescr ibed in accordance with contemporary guidel ines.11,23,27,28 The recent in troduction of transdermal and ora l transmucosal fentanyl provides a l ternat ive means to contro l pa in noninvasive ly.,, Pain contro l can be achieved in a h igh proportion of remain ing patients when opio ids are administered parentera l ly (subcutaneously or in travenously) regional ly ( in traspinal ly or in traventr icular ly) and when

these techniques are combined with other more invasive approaches. The Wor ld Heal th Organizat ion (see Figure 1) has adopted a " ladder" approach to cancer pain management that re lies on the administration of oral agents.10 Simi lar guidelines have been promulgated by the Amer ican Pain Society11 and other authori t ies.27,28 Addiction Redefined Despite widespread use, the opioids are among the most st igmatized c lasses of medical ly avai lable drugs. Misconcept ions and other nonmedical factors that detract from opt imal use have been descr ibed (Table 2) , and of these, issues re lated to the potential for habi tuation predominate. Tolerance, physical dependence and psychologica l dependence (addiction) , once considered together as par t o f a s ingle syndrome are increasingly recognized as dist inct phenomena (see Table 3) . Physica l dependence and to lerance are physio logic effects that are almost invar iably associated wi th chronic opio id use, and as such can be conceived of as independent and d istinct f rom addiction. Addiction (psychologica l dependence) is regarded as a psychologica l ly-mediated disorder with possib le genetic in fluences that occurs only rare ly as a consequence of medical use, and then id iosyncratica l ly . Given acceptance of the val id i ty of th is construct, physica l dependence, to lerance need not be regarded as impor tant impediments to the successfu l management of cancer pain wi th opio id analgesics (see d iscussion below). Addict ion exerts only an indi rect negative effect, that corre lates with the degree to which c l in ic ians overestimate i ts r isk. Physica l dependence, which a lso occurs wi th drugs other than the opio ids (eg, benzodiazepines) , re fers to the probabi l i ty that a sta te of withdrawal (abstinence syndrome) wi l l occur i f drug administration is abruptly d iscont inued or a suff ic ient dose of a speci f ic antagonist is administered. I f t reatment with the opio ids should become unnecessary, physica l dependence can be readi ly managed (avoided) by gradual ly taper ing opio id doses (10-25%/day) and avoid ing the use of antagonists. Tolerance exists when, over t ime, an increased dose of a drug is requi red to achieve a given ef fect. I t is usual ly f i rst manifest by a decrease in the observed duration of ef fec t of each administered dose. When to lerance is suspected to be responsib le for increased reports of pain, i t can usual ly be countered safe ly and ef fective ly by s imply increasing the dose, especia l ly s ince to lerance a lso develops to many of the adverse effects of the opioids, notably nausea and sedation. Addict ion is a complex psychobehaviora l syndrome character ized by overwhelming involvement in the acquisi t ion and nonmedical use of a substance despi te the threat of physio logic and/or psychological harm.77 Although i t is a rare sequelae of medical exposure and therefore should not markedly in fluence prescr ib ing habi ts, the r isk of ia trogenic addict ion remains a ser ious concern among practi t ioners.6 Selecting an Opioid The mainstay of treatment for cancer pain of moderate to severe in tensity is with potent opioid analgesics, which occupy the h ighest t ier of the three step ladder schema (see Figure 1) recommended by the Wor ld Health Organization.9 Patients may access this ladder at any level and may be star ted on potent opio ids in i t ia l ly for severe pain. Also of note is that when pat ients ascend the ladder ser ial ly , less potent analgesics should not be automatica l ly e liminated s ince the NSAIDs may provide addi t ive analgesia and the mild opioids may be useful for breakthrough or incident pain. The var ious opioids produce analgesia by simi lar mechanisms and when administered in comparable doses, the qual i ty of analgesia and spectrum of s ide effects are s imi lar .? Nevertheless, indiv iduals vary id iosyncratica l ly in the ir sensit iv i ty to the analgesic effects and toxic i ty of the var ious drugs ( incomplete cross to lerance), forming the basis for the c l in ica l use of morphine a l ternat ives. Other reasons for se lecting al ternate opio id preparat ions and routes inc lude convenience of dosing and patient satis faction, var iable patterns of pain, gastro intest ina l dysfunct ion, the need for concentrated formulations, and pr ior favorable c l in ic ian and pat ient experience. Mild Opioids Tradi t ional ly when treatment with the NSAIDs is associated wi th insuff ic ient re lie f o f pain or is poor ly to lerated, the addi t ion of a member of the c lass of drugs referred to as the "weak opioids" is recommended as an analgesic of in termediate potency.11 Most mi ld opio ids are avai lab le only as combination analgesics (wi th acetaminophen or aspir in) , and whi le there is probably no cei l ing dose for the opio id component of these formulations, the number of tab lets that can be taken safe ly is l im ited by the amount of s imple analgesic (aspir in