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Br. J. Anaesth. (1989), 63, 147-158

THE CONTROL OF ACUTE POSTOPERATIVE PAIN

R. W. D. MITCHELL AND G. SMITH

In recent years, the special knowledge and abilitiesof anaesthetists have extended into the fields ofchronic pain control and the control of pain inlabour. However, acute pain, and particularly thetreatment of postoperative pain, has received lessattention. Although there is now a surge of interestin acute pain [29], the majority of patientsundergoing major surgery still receive techniquesof pain relief that have changed little in the past 40years. This situation pertains despite manyadvances in the understanding of pain mech-anisms, the action of analgesic drugs and thedevelopment of sophisticated systems for drugdelivery. This review examines recent work onthe pharmacology of the analgesic drugs andsystems for their delivery, and considers theirsystemic use in the control of acute, especiallypostoperative, pain.

Definition of acute painThere is no clearly defined distinction between

acute and chronic pain. In general, acute pain isassociated with a distinct disease or injury and itis assumed that the time-course of the pain islimited to the period of repair of the injury.However, some acute pain states may progress tobecome chronic. This may result from progres-sion of the disease process or from a disturbancein neurophysiology following repair of the originalinjury.

Acute pain is an extremely complex sensationwhich extends beyond simple nociceptor input,the central processing of which is modulatedstrongly by emotive elements such as fear, anxietyor depression and by previous experience of pain.It is difficult to quantify the contribution of theseelements in the overall experience of acute painobserved in an individual patient. Although it iseasier to regard acute pain as a single sensation,some regard must be paid to the contribution of

R. W. D. MITCHELL, B.SC, F.F.A.R.C.S.; G. SMITH, M.D.,F.F.A.R.C.S.; University Department of Anaesthesia, LeicesterRoyal Infirmary, Leicester LEI 5WW.

each factor, despite the difficulty of assessment,because it may influence rational treatment. Thiscan be extremely difficult in practice and mayrequire complex multi-dimensional scoring tech-niques which are not often appropriate to acutepain and are frequently confined to the treatmentof chronic pain.

PSYCHOLOGICAL ASPECTS OF ACUTE PAIN

There are enormous individual variations inpatient response to acute pain and this variabilityis well recognized after surgery. Many clinicianshave encountered the occasional patient whorequires little or no analgesia even after majorsurgery, but they recognize that, at the otherextreme, there are those for whom it seemsimpossible to provide adequate analgesia, despitethe best efforts of the attendants. These extremespresumably lie at the opposite ends of a dis-tribution curve for susceptibility to pain and it iswidely held that psychological variables accountfor many of the observed differences. As notedabove, pain is a complex summation of nociceptiveinput, emotion, state of arousal, thought processesand social influences. Psychological approachesmay be utilized not only to assess the susceptibilityof an individual to acute pain, but also as part ofrational therapy [9].

Situational stressThe simple event of hospital admission pro-

duces a significant stress response. The indi-vidual's response to the strange environment hasbeen shown to correlate closely with subsequentpain perception. Four particular factors wereassociated: loss of independence, spouse sep-aration, isolation and lack of information.

Pre-existing psychological stressThree major variables influence the degree of

distress of patients undergoing surgery.

Anxiety-Tranquillity. The subjective state of

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148 BRITISH JOURNAL OF ANAESTHESIA

anxiety can be sub-divided in different ways."Anticipatory" anxiety is that evident before aforthcoming unpleasant event and "concomitant"anxiety is that associated with the event. Recentwork [36] suggests that the two are linearlyrelated, that is, patients who are anxious beforesurgery are more distressed afterwards. "State"anxiety is that associated with a certain set ofcircumstances and "trait" anxiety is applied tothose who tend to react with strong emotion toany stressful experience. Scott, Clum and Peoples[36] have shown that preoperative state anxietyhas a linear relationship with postoperative pain.

Some patients use the defence mechanism ofdenial as a means of removing the unpleasantfeeling of anticipatory anxiety. In doing so, theyrefuse to think of possible future events of whichthey are afraid. Thus, although they may havevery low anticipatory anxiety scores, they willvary greatly in their concomitant anxiety whenconfronted with pain. Some may be able tomaintain the process of denial throughout, whileothers may suffer great distress as the stimulusoverwhelms the denial mechanism. This obvi-ously depends on the severity of the stimulus andthe "coping" abilities of the patient.

Helplessness-active control. Helplessness is wellrecognized as a major cause of stress. Patients inacutely painful situations often feel powerless toexercise any control over their state. Thompson[42] has identified four components to this:(1) Behavioural control. This describes anymanoeuvre which the patient can use to decreasethe perception of pain; for example, relaxation orbreathing exercises or the provision of a patient-controlled analgesia device.(2) Cognitive control. This comprises the alter-ation of pain by thought processes. These can actboth to reinforce the pain (e.g. by concentrationon or re-interpretation of the pain) or decrease thepain (e.g. by denial, dissociation and distraction).(3) Information. Provision of adequate inform-ation reduces the uncertainty, and therefore thedistress, of a painful experience. Films or video-tapes may be useful, particularly in paediatricpractice, in familiarizing the patient with anunaccustomed experience.(4) Retrospection. The re-interpretation of a pastpainful event may alter the current implications ofthat event. This obviously has less bearing on themanagement of current acute pain.

Positive and negative feelings. When the patient

anticipates great benefit from the proposedoperation, he may be more willing to trade short-term discomfort for long-term gain. Where thesurgery involves mutilation, confirmation of apoor prognosis or no perceived gain in thepatient's mind, the additional anxiety may com-pound the difficulty of providing postoperativeanalgesia.

ASSESSMENT OF ACUTE PAIN

Therapeutic manoeuvres in medicine should bemonitored by assessment of effect. It is anindictment of the current practice of acute paincontrol that some measure of the adequacy of theanalgesia provided is not obtained routinely.Instead, reliance is placed on subjective assess-ment by nursing attendants, who have little powerto modify an inadequate prescription which isprovided by the physician on a " safe guess " basis.Research in pain control has yielded many, oftencomplex, assessment systems. While these arelikely to remain largely within the province of theresearch worker, there is a strong case to be madefor applying some of the simpler techniques ineveryday clinical practice.

Objective methods of scoring pain have reliedupon assessment of biochemical indices such aschanges in plasma concentrations of hormones,but these tend to be inaccurate, expensive and notapplicable in clinical practice. However, measure-ment of respiratory function, particularly FEV,and PEFR, is useful in patients who haveundergone thoracic or upper abdominal surgery[8]. Although an experienced observer may beable to make a coarse assessment of the degree ofpain suffered by a patient, it is accepted widelythat the amount of suffering may only truly beassessed by the individual concerned.

Unidimensional scales

With unidimensional scales, the patient is askedsimply to define the severity of the pain itself. Inits simplest form, the patient may be askedwhether or not he feels pain, without any measureof degree. The lack of sensitivity here is obvious.In many acutely painful situations, a total lack ofpain is not an obtainable endpoint. Some de-scription of intensity is therefore necessary. Asimple verbal rating scale (VRS), such as "none","mild", "moderate" and "severe" has beenshown to have the best correlation with visualanalogue scales (vide infra) and an acceptabledegree of variation between individuals. Numeri-cal rating scales allow a greater degree of sen-

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CONTROL OF ACUTE POSTOPERATIVE PAIN 149

sitivity. It is believed that they circumvent one ofthe problems of visual analogue scores, whichsome find confusing because of the wide freedomof choice presented.

Visual analogue scales (VAS) have now beenused widely as a sensitive and valid measure ofpain intensity. The common pattern is to use aline 10 cm long with extremes labelled "no pain"and "worst pain imaginable". However, somepatients find them confusing and they do requirea certain degree of wakefulness and co-ordinationto complete. These disadvantages can be circum-vented partly by the use of slide-rule devices,which may be processed electronically. VAS maybe more efficient for charting the progress of anindividual patient rather than for inter-individualassessment. Pain intensity difference (PID) is thedifference in pain score at a time after theadministration of a drug compared with the painscore at time 0—before any analgesic was given.Summed pain intensity difference (SPID), thesum of PID over a certain period, gives a usefulmeasure of relative efficacies of treatment over thestudy period, between different patients or groups.

Multi-dimensional scales

The Magill Pain Questionnaire is a well-established tool which assesses pain under threedimensions: sensory, affective and evaluative.While useful in research and in chronic painstates, it is too cumbersome for repeated evalu-ations of acute pain states in clinical practice. Asimpler method of introducing further dimensionsinto acute pain scoring is to use VAS ratings foranxiety-tranquillity in addition to no pain-severepain.

We suggest that, where possible, all patients inacute pain should have an assessment of theadequacy of analgesia. This should be as normalas recording of heart rate and arterial pressure. Asimple unidimensional scale (VRS or VAS) wouldbe better than no score at all and would provide

the degree of feedback that is lacking in present-day practice.

PHARMACOLOGICAL CONSIDERATIONS IN ACUTEPAIN

The burgeoning of knowledge in the neuro-physiology and pharmacology of pain in recentyears has been spectacular, although this knowl-edge has yet to have a major impact on thetreatment of acute pain for the majority ofsufferers.

Pharmacology of the Opioid DrugsThere have been great advances in two areas inrecent years: the understanding of opioid recep-tors and the development of new drugs acting onthese receptors.

Opioid receptor theory

For a fuller description of this topic the readeris referred to excellent reviews by Jordan [18] andYaksh [46].

In common with other neurotransmitter/hormone systems, it is now known that the opioidsystem comprises several distinct receptor sub-groups and a wide range of endogenous ligands.The physiological significance of the endogenousopioid peptides is not yet fully established, but itis possible that, in the future, synthetic analoguesof these substances may be produced and used inthe practical management of pain.

The original work of Martin [21] proposedthree receptor types: mu, kappa and sigma.Further work in animals has suggested theexistence of two other receptors, delta and epsilon,and possibly many others, the significance ofwhich is unclear at present. Table I describes thethree main receptor subtypes. Drugs may act asagonists, partial agonists or antagonists at any orall of these receptors. Thus the simplistic de-scription of some of the newer synthetic opioids as

TABLE I. Characteristics of the three main types of opioid receptor

Receptor

AnalgesiaRespirationBehaviourPupilMorphinewithdrawal

mu

YesDepressionEuphoriaMiosisSuppression

kappa

YesDepressionSedationMiosisNo suppression

sigma

NoStimulationDysphoriaMydriasisNo suppression

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TABLE II . Effects of seven agents on the three main types of opioidreceptor. NA = No activity; PA = partial agonist. (Adapted

from Rosow [31])

MorphineBuprenorphineMeptazinolNalorphinePentazocineNalbuphineNaloxone

mu

AgonistPAPAAntagonistAntagonistAntagonistAntagonist

Receptor

kappa

AgonistNANAPAPAPAAntagonist

sigma

NANANAAgonistAgonistAgonistAntagonist

"partial agonists" tends to obscure their trueaction. Table II illustrates a proposed receptorinteraction scheme for some currently availableagents.

Pure agonist drugs

Despite the current availability of several newagonist/antagonist or partial agonist drugs, thepure agonists remain the mainstay of the treat-ment of acute pain. Morphine is the "goldstandard" against which any new drug must becompared.

All opioid agonists produce analgesia, respir-atory depression, euphoria, decreased gut mo-tility, nausea and cough suppression, and have thepotential to cause urinary retention. In the dosesused in normal clinical practice, they produceanalgesia without marked depression of conscious-ness. Unlike most of the agonist/antagonist drugs,however, there is no "ceiling effect" to theiranalgesia and respiratory depression and verylarge doses have been used as a sole agent incardiac anaesthesia; even with these enormousdoses, loss of consciousness is not always assured.

Differences between agents result largely fromdifferences in pharmacokinetic profiles or fromeffects on non-opioid systems, rather than distinctpharmacodynamic effects. For example, the onsettime for analgesia with morphine is slower thanthat with fentanyl because the former has a lowerlipid solubility, and the ability to cause histaminerelease possessed by morphine is absent withfentanyl.

It is well known that there are great variationsin plasma opioid concentration profiles after i.m.administration: for example, it has been demon-strated with pethidine that there is a 2-5 folddifference in peak plasma concentrations and a3-7 fold difference in the rate at which these

concentrations are achieved after a single i.m.injection [4]. Thus the pharmacokinetic proper-ties quoted usually for these drugs are thosecalculated after i.v. injection. Figures for theagents used commonly are shown in table III.These data do not have much bearing on thelatency or duration of action of an i.v. dose of thedrug—properties which are governed by the lipidsolubility and partition characteristics in blood.

All opioids are weak bases and at physiologicalpH they exist in both ionized and un-ionizedforms. Only the unbound and un-ionized form(which is relatively lipid soluble) is free topenetrate lipid membranes, gaining access to thesite of action or biophase. This proportion istermed the diffusible fraction and amounts to16% of plasma morphine, 2.5% of pethidine and1.4% of fentanyl. However, as stated, the actuallipid solubility of the drugs varies greatly. Theoctanol: water partition coefficient for morphine(free base) is 6, for pethidine it is 525 and forfentanyl 11220. The product of diffusible fractionand lipid solubility gives the " diffusing potential"into the CNS. Taking morphine to equal 1, therelative ratios for pethidine and fentanyl are 13.6and 162, respectively [17].

Variations in patient characteristics may lead towide variations in pharmacokinetic parameters.In hepatic disease, it has been shown that the betahalf-life of pethidine is approximately doubledbecause of decreased drug clearance. The oralbioavailability of pethidine is increased greatly inpatients with hepatic cirrhosis, although there islittle change with morphine or fentanyl [5].

The extremes of age have a marked effect. Inneonates, the terminal half-life of pethidine isseveral times longer than in an adult. In patientsolder than 80 yr, the clearance of pethidine isdecreased and the volume of distribution issmaller. The beta half-life of fentanyl is twice aslong in elderly patients and this has been attri-buted to decreased drug clearance [5]. Impairedhepatic metabolism or decreases in liver bloodflow may be factors in this observation.

Other drugs may affect the pharmacokinetics ofopioids. Enzyme inducing agents such as pheny-toin or phenobarbitone decrease the terminal half-life of pethidine. By inhibiting hepatic microsomalenzymes involved in oxidative processes, cimeti-dine impairs the metabolism of both pethidineand fentanyl. As morphine is metabolized pre-dominantly by glucuronidation, its clearance isnot affected.

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CONTROL OF ACUTE POSTOPERATIVE PAIN

TABLE III . Pharmacokinetic properties of some opioid drugs

151

Initial volume ofdistribution (litre)

Total volume ofdistribution (litre)

Initial half-life(min)

Terminal half-life(min)

Clearance(ml min"1)

Morphine

23

224

1.7

177

1050

Pethidine

88

305

7.1

222

1020

Fentanyl

60

335

4.1

185

1530

Alfentanil

11

27

8

98

238

Buprenorphine

14

188

2

184

1275

It is now well-recognized that the metabolitesof morphine, morphine-3-glucuronide (M3G)and morphine-6-glucuronide (M6G), are bio-logically active [13]. A recent study of patientsreceiving long-term oral morphine medicationshowed an analgesic ratio of morphine to M6G of1:10 [27], whereas an earlier study had shown aratio of 1:2.5 after a single dose [35]. This maypartly explain the higher analgesic efficacy ofrepeated doses compared with single doses, atleast in chronic pain. In end-stage renal failure itis known that the terminal half-life for morphineis the same as in normal subjects [1]. Recently, ithas been shown that the prolonged duration ofaction of morphine in these patients may be aresult of relative accumulation of M6G [37].

Opioid agonist/antagonistsWith pure agonist drugs, increasing the dose

generally causes an increase in analgesia and inrespiratory depression. Thus the maximumanalgesic effect obtainable is extremely high and isobtained with doses well outside those that can beused in clinical practice with spontaneouslybreathing patients.

Measurement of efficacy is extremely difficultwith regard to the agonist/antagonist opioids,largely because dose-response relationships forthese drugs are not linear. Indeed, depending onthe relative affinities of the drugs in their agonisticand antagonistic effects, the dose-response curvemay be U-shaped or bell-shaped. All the availableopioid drugs in this class demonstrate a bell-shaped curve in animal studies. This implies ahigh affinity for the agonistic effect and a lowaffinity for the antagonistic effect; thus in low drugconcentrations the agonistic effect predominates,but in higher concentrations antagonism pre-dominates. If the transition between agonism andantagonism occurs within the clinical dose range,

the drug has low efficacy at higher doses for severepain. This phenomenon has been demonstrated inpatients treated with nalbuphine after upperabdominal surgery [28].

The unusual dose-response relationships ofthese drugs also introduce difficulty in assessingequipotency. Given that the drug under study hasa sufficiently high "ceiling" (i.e. that the degreeof pain anticipated is not close to the plateau ofefficacy of that drug), the standard models ofpostoperative pain may be used to establishequipotency with a standard agent, for examplemorphine, in a certain dose. However, becausethere is no certainty that the log dose-responserelationship of the agent studied is linear, state-ments on equipotency with morphine can bemade only in relation to the dose used [19].

Pentazocine. This drug was the first agonist/antagonist to become established in clinical prac-tice. It is presumed to be an agonist at kappa andsigma receptors and an antagonist at mu receptors.Doses of 30-50 mg produce analgesia and res-piratory depression to an extent approximatelyequivalent to that obtained with morphine 10 mg;increasing the dose above this intensifies sideeffects, but does not increase analgesia. Penta-zocine causes an increase in heart rate, pulmonaryarterial pressure and cardiac work [2] and istherefore best avoided after myocardial infarction.

The usefulness of pentazocine is limited by thehigh incidence of dysphoria, hallucinations andbad dreams associated with its administration.The technique of "sequential analgesia" [30], inwhich pentazocine was used at the end of surgeryto antagonize large doses of fentanyl given duringoperation has not found widespread acceptance.

Nalbuphine. This agent was introduced to theU.K. relatively recently, but has been available in

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the U.S.A. for many years. It appears to act as akappa and sigma agonist and has quite potent muantagonist properties. Although it is thought to beapproximately equipotent with morphine, severalstudies have shown that it has a low ceiling effect.If adequate analgesia is not obtained with a lowdose, waning of analgesia occurs with increasingdosage, although it then causes marked depressionof conscious level [28]. Therefore the agent is notrecommended for the treatment of severe painsuch as follows upper abdominal surgery [12]. Itdoes not possess the deleterious haemodynamiceffects of pentazocine when used for the pain ofmyocardial infarction.

Buprenorphine. This agent is thought to act as apartial mu agonist. It appears to have limitedefficacy, but an extremely high affinity for thereceptor. It has a very high lipid solubility, but itsspeed of onset is limited by a low diffusiblefraction and a rapid decrease in plasma con-centration (because of a large total volume ofdistribution) after a single i.v. dose. Its durationof action is prolonged (5-6 h after i.m. injection).Its potency is approximately 25-50 times that ofmorphine. High lipid solubility lends this agent auseful property: that of excellent absorption bythe sublingual route. If buprenorphine isswallowed, extensive first-pass hepatic metab-olism results in a low bioavailability and thereforelittle danger of overdosage if a patient accidentallyswallows the tablet(s). A ceiling effect for res-piratory depression has been demonstrated withthis agent in animals, but significant respiratorydepression may occur with the doses used clini-cally. The effects of buprenorphine are notantagonized readily by naloxone. Doxapram, arespiratory stimulant, is recommended if signifi-cant depression of respiration occurs.

Buprenorphine is relatively devoid of sideeffects such as dysphoria and hallucinations andcauses subjective effects similar to those ofmorphine. In controlled trials in acute severepain, the incidence of nausea and vomiting wasnot significantly greater than that observed withmorphine. The often-reported clinical observa-tion that nausea and vomiting are major problemswith this agent may simply be a reflection of itswidespread use in less severe pain. Because of itsextremely high affinity for the mu receptor, thereis a theoretical possibility that the effects of pureagonist drugs given during anaesthesia may beattenuated in a patient receiving this drug before

operation. Indeed, buprenorphine has been sug-gested for use in a modern resurrection of thetechnique of "sequential analgesia" {vide supra).

Buprenorphine is probably the most usefulagent among the recently-introduced agonist/antagonists. It is the only one currently availablewhich has been found consistently of value inacute, severe pain.

Meptazinol. This agent is unusual in that, inaddition to partial agonistic effects at the mureceptor, it appears to act by other mechanisms.The role of these other mechanisms, which arethought to be mediated through cholinergicsystems, is not clear in man. It has been shown tobe effective in postoperative pain [38] by par-enteral administration and has a potency approxi-mately similar to that of pethidine. It is wellabsorbed rectally, but it has been shown that adose of 150 mg by this route is not adequate fortreatment of pain on the first day followinghysterectomy [23]. It is said to have a low potentialfor respiratory depression and its effects can bereversed with naloxone. However, recent work(Hanning and colleagues, in preparation) hasshown that the frequency of episodes of arterialdesaturation in elderly patients after hip replace-ment was similar in patients receiving eithermeptazinol or morphine by patient-controlledanalgesia. Side effects (nausea and vomiting) havebeen reported to be troublesome in obstetricanalgesia and it does cause sedation. However, itcauses a low incidence of dysphoria and halluci-nations, presumably because of lack of action at thesigma receptor.

Non-Steroidal Anti-Inflammatory Drugs inAcute Pain

There is a bewildering number of non-steroidalanti-inflammatory drugs (NSAID) currentlyavailable. Although their major use is in chronicpain, there is an increasing interest in their use asadjunctive therapy for acute pain states. Therationale for this is that soft-tissue inflammationmay be a potent factor in postoperative pain.However, most of these agents require oraladministration and are not usually appropriate forsevere acute pain, although some are available assuppositories. While Martens [20] showed thatrectal naproxen greatly decreased the requirementfor opioids after orthopaedic surgery, work in ourdepartment (in preparation) has shown that

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suppositories containing diclofenac 150 mg hadno morphine-sparing effect after cholecystectomy.However, this agent has been found effective forpost-tonsillectomy pain in children [44]. Ibu-profen by suppository has been found to producea 20% decrease in morphine requirements afterlower abdominal surgery [24].

Diclofenac is noteworthy in this group forbeing currently available in an injectable form (fori.m. use only). This has been shown to be of valuein acute renal colic, and has been found to be aseffective as i.m. papaveretum after hip surgery [7].A study in patients after abdominal surgery [15]showed a significant morphine-sparing effect,although the study may be criticized for failing tostandardize between upper and lower abdominalsurgery.

It seems likely that NSAID will prove moreeffective for analgesia after orthopaedic surgerythan after abdominal surgery. The question ofwhether or not the well recognized side effects ofthese drugs (inhibition of platelet function andgastrointestinal irritation) represent significantproblems in the management of acute pain canonly be answered by large scale studies.

POSTOPERATIVE PAIN

This is obviously the area of acute pain control ofmost interest to anaesthetists. It comprises thelargest group of patients suffering acute pain andmanagement has long been recognized as sub-optimal. Its transitory nature, however, shouldrender it more amenable to treatment than chronicpain [39].

Conventional Therapy

Treatment has traditionally failed to recognize thecomplex problems involved. Standard practice isto prescribe i.m. administration of a fixed dose ofan opioid on a "PRN" (as required) basis. Thusa dose of analgesic is given, at the discretion of anurse, on demand by a patient in whom the painthreshold has been exceeded. This type of regimengives poor results for the following reasons:(1) Responsibility for management of the patientis delegated from the anaesthetist to juniormedical staff who, in turn, delegate responsibilityto the nursing staff.(2) Nursing staff vary widely in their degree ofrapport with the patient and they may be too busyto deal immediately with a request for analgesia.Administration of opioids takes time because of

the necessity for checking the drugs according toControlled Drugs Act regulations. Nurses maywithhold opioids because of fear of side effects,particularly respiratory depression, and the per-ceived potential for producing physical depen-dence. While there is little evidence to suggestthat the treatment of acute pain with opioids for2-3 days after operation is likely to cause ad-diction, respiratory depression remains a validconcern.(3) In the absence of personal experience of theseverity of postoperative pain, it is difficult fornursing staff to acknowledge the extent of apatient's suffering in the postoperative period.

Other major difficulties in the treatment ofpostoperative pain include:(1) Difficulties in quantifying pain (see above).(2) Difficulty in titrating doses of drug to ameasured effect—there is no easily defined"endpoint".(3) Analgesic requirements vary widely accordingto the type and severity of surgery.(4) Analgesic requirements vary widely as a resultof pharmacokinetic and pharmacodynamic vari-ations between individuals.(5) Administration of adequate doses of anal-gesics may be inhibited because of induction ofside effects such as nausea and vomiting orrespiratory depression.

Thus the list of disadvantages of the con-ventional method of administering i.m. opioids isdaunting: the dose prescribed may be too small(inadequate analgesia) or too large (side effects);the technique results in widely fluctuating plasmaconcentrations of the drug; i.m. injections arepainful; and the technique induces a feeling ofdependency on the nursing staff. There are,however, some advantages of this conventionalmethod. It represents familiar practice and thusmay be inherently safe because of accumulatedexperience. It requires no special equipment andis therefore inexpensive, and the gradual onset ofanalgesia permits observation of the gradual onsetof possible overdose.

Newer Approaches to Treatment

New drugsAs discussed above, it is unlikely that any of the

current agonist/antagonist drugs represents amajor advance on pure agonist drugs in mostsituations. Those with a low propensity for

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respiratory depression also have a low "ceiling"for analgesia.

New methods for old drugsThese techniques embody the philosophy that

established agents are more effective if given in amanner which optimizes their action. To obtaineffective analgesia, the aim is to maintain a steady-state plasma concentration of opioid in the regionof the "minimum effective analgesic concen-tration" (MEAC (table IV)). As this varies widelybetween individuals, it is not possible to predict adose regimen for a particular patient in advance ofsome assessment of that patient's susceptibility toopioids. With bolus i.v. and continuous i.v.techniques, the assessment of the patient's re-quirements is in the hands of the observer. Withpatient-controlled analgesia (PCA), a feedbackloop is established whereby the patient controlshis own plasma opioid concentration according toneed.

Bolus i.v. administration. It is common practiceto administer small i.v. boluses of opioid in therecovery room to produce analgesia in the periodimmediately after surgery. In the setting of thehigh-dependency area, this technique may becontinued in the later postoperative period, andmay be acceptable, providing there is a 1:1nurse: patient ratio, to permit detection of res-piratory depression. This technique produceswide fluctuations of plasma opioid concentrationwhich may be lessened by continuous infusion orPCA methods.

If titrating an i.v. opioid against pain in theshort term, it is inadvisable to use an agent with aslow onset, such as morphine or buprenorphine,unless the time to maximal effect of each in-crement (approximately lOmin) is observed be-fore administering a further increment. In situa-tions where rapid control of pain is desired, it ispreferable to use an agent with a faster onset timesuch as fentanyl, diamorphine or pethidine.

TABLE IV. Minimum effective analgesic concentration (MEAC)for some opioid drugs in plasma

AgentMEAC plasma concn

(ng ml"1)

MorphinePethidineFentanylAlfentanil

16455

110

Continuous i.v. infusions. Various authors haveattempted to assess the patient's opioid require-ments by means of small i.v. boluses untiladequate analgesia is achieved. They then pre-scribed a fixed continuous i.v. infusion based onthe initial quantity of opioid administered [10, 33,34]. There are several problems associated withthis technique, the most important being thepotential for overdosage and respiratory depres-sion, particularly if the initial assessment of opioidrequirement did not take into account the slowonset of some drugs. More complex regimenshave been developed which take into account thecomplex pharmacokinetics of opioids [3, 17, 40].In the view of the authors, continuous infusiontechniques based on observer control should beused only in high-dependency nursing areaswhere the inherent problems of respiratory de-pression can be rapidly diagnosed and treated. Itis worth noting that hypovolaemia may cause arelative overdose of opioid if the initial assessmentwas made when the circulating volume wasnormal.

Patient-controlled analgesia (PCA)The concept of PCA may be regarded as a

simple closed-loop system. Unlike simple in-fusions, for which the observer determines theplasma concentration of drug, the patient deter-mines the dose required to maintain adequateanalgesia. The optimum plasma concentration, asdetermined by the patient, is that which satisfieshis subjective requirement for analgesia whileavoiding excessive dosage which would produceunacceptable side effects such as nausea andvomiting or such a degree of CNS depressionwhich would by itself inhibit further activation ofthe apparatus.

The most basic form of PCA apparatus, such asthe original Cardiff Palliator, administers a bolusdose of drug on receipt of a correctly delivereddemand. The size of the bolus dose and the "lock-out time" (the minimum time interval betweendoses) is set by the operator. The rate of infusionof each bolus can also be set. A problem with thisform of apparatus is that, if the patient falls asleepand thus makes no demand for some time, theplasma concentration of analgesic decreases belowthe MEAC for that patient and the patient maywaken in pain. It may then take several demandsto restore adequate analgesia. Even so, it has beensuggested that there is less disturbance of noc-turnal sleep during PCA compared with con-ventional therapy [25].

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To obviate this theoretical problem, otherworkers have developed machines which deliver acontinuous low-dose background infusion onwhich the patient may superimpose additionaldemands for bolus doses. This philosophy wasextended even further [17] by Hull in hisdevelopment of the on-demand analgesia com-puter (ODAC) apparatus which will give 50 % ofthe demand doses of the previous 1 h as acontinuous infusion over the succeeding 1 h,thereby gradually decreasing the rate of con-tinuous mandatory infusion as the patient's painstate gradually improves.

The problem with all continuous infusionstrategies is the possibility of respiratory de-pression. In the original, experimental ODACdevice, a pneumograph monitor was incorporatedwhich inhibited the infusion if there was a 15-speriod without respiratory movement. It has notbeen possible to incorporate this feature in thecommercial version of the device. For safety,therefore, it may be best to accept a mandatoryinfusion rate which falls some way short ofmaintaining a steady-state plasma concentrationclose to the MEAC value, and allow supplemen-tation by bolus demand.

The Cardiff Palliator is no longer available andhas been replaced in the U.K. by the moresophisticated Graseby patient-controlled anal-gesia system which, like the on-demand analgesiacomputer, is a microprocessor-controlled pumpwhich permits a background infusion in additionto patient-demanded boluses; however, the rate ofthe background infusion is operator-controlled.The philosophy of patient-controlled analgesiaand development of apparatus has been reviewed[22, 25].

Efficacy of PC A. Although experience withPCA is expanding rapidly, especially in theU.S.A., its use has not become widespread inroutine clinical practice in the U.K. Nevertheless,there are sufficient data to suggest that it repre-sents a major advance in analgesic therapy inpostoperative pain. Obviously, not all patientswill be suitable for the technique: the very youngand those who cannot comprehend what isrequired need an observer-based technique.

Most workers have reported consistent resultswith PCA: it has a high degree of patientacceptability and subjects tend to maintain arelatively constant plasma concentration of opioid(although there may be a 4-5 fold difference inconcentrations between individuals). Dose re-

quirements are generally smaller than the maxi-mum which would be available if the same drugwas given on a PRN basis. There is no suggestionthat PCA leads to more side effects such assedation, nausea or respiratory depression thanconventional i.m. analgesia. However, cases ofsevere respiratory depression as a result ofoperator or machine error have been reported,and this emphasizes the need for full training inthe technique for all staff concerned [35, 39, 41,45]. Work from our department [43] suggests thatthe "low dose infusion + bolus" technique withmorphine yields marginally better results thanbolus alone.

Routes of administration. Most work with PCAhas used the i.v. route. It is important that eithera dedicated i.v. cannula or a one-way valve is usedto ensure that each dose reaches the patient anddoes not accumulate by retrograde flow into ani.v. infusion. The i.m. and s.c. routes have alsobeen used satisfactorily. Extradural administra-tion of opioids has also been reported on a PCAbasis, but this technique should be confined tohigh-dependency areas.

Other routes of administration of opioids

Oral. The use of sublingual buprenorphine hasbeen considered above. The oral route of admin-istration of drugs is the most widely used for alltypes of medication and is often the mostacceptable to the patient. However, apart fromminor ambulatory surgery and in the late post-operative period after more major surgery, theoral route of administration of opioid analgesicshas several major disadvantages:(1) Delay in gastric emptying is common aftersurgery. Because absorption of these drugs occursfrom the small intestine, analgesia may failbecause of lack of absorption. More seriously, thedumping of a large volume of drug into the smallbowel when gastric motility resumes may result inoverdose at a time when the patient may be underless close surveillance. Work with the slow-releasetablet formulation of morphine (MST Continus,Napp Laboratories) after abdominal surgery con-firms that absorption is delayed within the first24 h of surgery [26]. Thus the use of this formul-ation is not recommended within 24 h of surgery.(2) Nausea and vomiting in the postoperativeperiod may preclude the use of oral medication.(3) Because of considerable first-pass metabolismin the liver, the bioavailability of oral opioids isgreatly reduced. Prediction of adequate dosage is

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thus even more difficult than with parenteraladministration.

Although some reports have stated that ade-quate analgesia may be achieved using this route,the oral route is generally regarded as unsuitablefor the administration of strong opioids in theearly postoperative period.

Rectal. The use of rectal diclofenac and mepta-zinol has been noted above. Rectal administrationof drugs is relatively unpopular in the U.K., butthis route does possess some advantages:(1) Absorption of drugs from the lower part of therectum bypasses the portal venous system. Drugsabsorbed in the upper rectum pass into thesuperior rectal vein and are, therefore, subject tofirst-pass metabolism. The overall bioavailabilitymay thus depend on the siting of the preparationin the rectum.(2) Absorption of drugs is unaffected by delay ingastric emptying, or by nausea and vomiting.(3) Administration of the drug may be discon-tinued simply by removal of the suppository.

The rectal route has been used with sustained-release preparations of morphine (the morphinehydrogel suppository) and this technique may beuseful in producing a low sustained plasmaconcentration of the drug which can be augmentedby further systemic doses [14].

Transdermal. Transdermal administration ofdrugs is now well established in therapeutics, andsuitable delivery systems for glyceryl trinitratehave been available for several years. Recently, atransdermal delivery has been developed forfentanyl, and encouraging results have beenobtained in the treatment of postoperative pain[32]. Holley and Van Steennis [16] and Duthieand colleagues [11] reported that the TTS-fentanyl patch (TTS = transdermal therapeuticsystem) was capable of providing an analgesicplasma concentration of fentanyl. The product isdesigned to provide a sustained release of 100 ugh"1. However, it should be applied 2 h before theexpected painful stimulus and a bolus of i.v.fentanyl is necessary as a loading dose.

SAFETY CONSIDERATIONS

Although traditional PRN methods of administer-ing postoperative analgesia may be inadequate,they do have the merit of simplicity and familiarityin use which provide a degree of inherent safety.New techniques and drugs must be shown not to

entail any unjustifiable hazard to the patient.When dealing with opioid drugs, the overridingconcern of the prescriber is the avoidance ofdangerous respiratory depression.

Monitoring of respiration

The maintenance of adequate pulmonary gasexchanges is obviously essential to life. Unfortu-nately, it is difficult to make a simple bedsidejudgement of the adequacy of ventilation, es-pecially in the sleeping subject.

The work of Holley and Van Steennis [16]confirmed previous observations that randomcounting of ventilatory rate does not correlatewith the presence of hypercapnia. In a study withi.v. and transcutaneous fentanyl, subjects withPaCO2 > 6.7 kPa had ventilatory rates varying from7 to 22 b.p.m.; conversely, in subjects withventilatory rates of 10 b.p.m. or less, PaCo2 valuesranged from 3.3 to 7.1 kPa. Catling and colleagues[10] observed a high incidence of episodes ofarterial oxygen desaturation during continuousopioid infusions in postoperative patients andemphasized the need for continuous oxygenadministration in these patients: this was foundlargely to obviate decreases in saturation.

If simple observations do not suffice, what maybe utilized ? Pulse oximetry detects arterial oxygendesaturation but, in the presence of supplemen-tary oxygen, may not detect mild respiratorydepression. Electromechanical strain-gauge de-vices may be used for continuous monitoring ofchest-wall movement, but may not detect thepresence of an obstructed upper airway. Inpractice, however, continuous monitoring withthe pulse oximeter is probably the safest methodof assessment.

It should be noted that there is some debate onthe incidence of significant sleep apnoea in thenormal population [6], although there is generalagreement that the condition is commoner inmales, in heavier subjects and with increasing age.

THE ACUTE PAIN SERVICE

The deployment of more sophisticated forms ofacute pain relief (local anaesthetic techniques,extradural opioids, PCA) has been constrained bythe facts that these techniques may be time-consuming and that correct application requiresspecialist skills and knowledge. Ready and col-leagues [29] have described their experience withan Acute Pain Team to supervise patient-con-

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trolled analgesia and extradural opioid analgesia.It may be difficult to provide a similar serviceelsewhere because of manpower constraints, butmany of the advantages of this type of servicecould be obtained by greater stratification ofpatient care in hospital. The provision of high-dependency units, which would concentrate onthe provision of care for patients in the immediatepostoperative period, would greatly facilitate theuse of effective analgesic techniques and mayallow the more efficient deployment of nursingand medical staff.

In conclusion, we have attempted to examinesome of the recent advances in postoperativeanalgesia using systemic drugs. Perhaps the mostimportant task we have is to heighten awareness ofthe size of this problem and to ensure that all staffare aware of the variables involved. Most patientsin hospital will continue to receive i.m. opioidsbecause of the simplicity of, and familiarity with,this technique. However, the introduction ofsimple methods of pain scoring and a greaterdegree of flexibility in the administration ofopioids would lead to considerable improvementin acute pain therapy.

REFERENCES1. Aitkenhead AR, Vater M, Cooper CMS, Smith G.

Pharmacokinetics of single-dose i.v. morphine in normalvolunteers and patients with end-stage renal failure.British Journal of Anaesthesia 1983; 55: 905P.

2. Alderman EL, Barry WH, Graham AF, Harrison DC.Hemodynamic effects of morphine and pentazocine differin cardiac patients. New England Journal of Medicine1972; 287: 623-627.

3. Austin KL, Stapleton JV, Mather LE. Pethidine clearanceduring continuous intravenous infusions in postoperativepatients. British Journal of Clinical Pharmacology 1981; 1:25-30.

4. Austin KL, Stapleton JV, Mather LE. Multiple intra-muscular injections: a major source of variability inanalgesic response to meperidine. Pain 1980; 8: 47-62.

5. Bentley JB, Borel JD, Nenad RE, Gillespie TJ. Age andfentanyl pharmacokinetics. Anesthesia and Analgesia 1982;61: 968-971.

6. Bixler EO, Soldatos CR, Scarone S, Russek E, Kales A,Thomson KC. Sleep apneic syndromes in insomniacpatients and normal subjects. Sleep Research 1978; 7:214.

7. Buchanan JM, Halshaw J, Baldasera J, Dallard JK, PoolePH. Postoperative pain relief; a new approach: narcoticscompared with non-steroidal anti-inflammatory drugs.Annals of the Royal College of Surgeons of England 1988;70: 332-335.

8. Chapman CR. Assessment of pain. In: Nimmo WS,Smith G, eds. Anaesthesia. London: Blackwells, 1989;1149-1165.

9. Chapman CR. Psychological factors in acute and chronicpain. In: Nimmo WS, Smith G, eds. Anaesthesia.London: Blackwells, 1989; 1166-1174.

10. Catling JA, Pinto DM, Jordan C, Jones JF. Respiratoryeffects of analgesia after cholecystectomy: comparison ofcontinuous and intermittent papaveretum. British MedicalJournal 1980; 2: 478-480.

11. Duthie DJR, Rowbotham DJ, Wyld R, Henderson PD,Nimmo WS. Plasma fentanyl concentrations duringtransdermal delivery of fentanyl to surgical patients.British Journal of Anaesthesia 1988; 60: 614-618.

12. Fee JPH, Brady MM, Furness G, Moore J, Dundee JW.Has nalbuphine a place in severe pain? Anesthesia andAnalgesia 1987; 66: S54.

13. Hanks GW, Hoskin PJ, Aherne GW, Turner P, Poulaw P.Explanation for potency of repeated oral doses of mor-phine. Lancet 1987; 2: 723-725.

14. Hanning CD, Vickers AP, Smith G, Graham NB, McNeilME. The morphine hydrogel suppository. British Journalof Anaesthesia 1988; 61: 221-227.

15. Hodsman NBA, Burns J, Blyth A, Kenny GNC, McArdleCS, Rotman H. The morphine sparing effects of diclo-fenac sodium following abdominal surgery. Anaesthesia1987; 42: 1005-1008.

16. Holley FO, Van Steennis C. Postoperative analgesia withfentanyl: pharmacokinetics and pharmacodynamics ofconstant-rate i.v. and transdermal delivery. British Journalof Anaesthesia 1988; 60: 608-613.

17. Hull CJ. The pharmacokinetics of opioid analgesics withspecial reference to patient controlled administration. In:Harmer M, Rosen M, Vickers MD, eds. Patient ControlledAnalgesia. London: Blackwell Scientific Publications,1985; 7-17.

18. Jordan CC. Opioid receptors. In: Kaufman L, ed.Anaesthesia Review 3. Edinburgh: Churchill Livingstone,1985.

19. Kay B. Relative potency of agonist and partial agonistopioids. British Journal of Anaesthesia 1985; 57: 719-720.

20. Martens M. A significant decrease in narcotic drug dosageafter orthopaedic surgery. A double-blind study withnaproxen. Acta Orthopaedica Belgica 1982; 48: 900-906.

21. Martin WR, Eades CC, Thompson JA, Huppler RE,Gilbert PE. The effects of morphine and nalorphine-likedrugs in the non-dependent and morphine-dependentchronic spinal dog. Journal of Pharmacology and Ex-perimental Therapeutics 1976; 197: 517-532.

22. Mather LE, Owen H. The scientific basis of patient-controlled analgesia. Anaesthesia and Intensive Care 1988;16: 427^47.

23. Moores MA, Frater R, Parry P, Hanning CD. Double-blind comparison of the efficacy and safety of single dosesof meptazinol as a suppository and morphine by i.m.injection. British Journal of Anaesthesia 1988; 60: 542-546.

24. Owen H, Glavin RJ, Shaw NA. Ibuprofen in themanagement of postoperative pain. British Journal ofAnaesthesia 1986; 58: 1371-1375.

25. Owen H, Mather LE, Rowley K. The development andclinical use of patient-controlled analgesia. Anaesthesiaand Intensive Care 1988; 16: 443-447.

26. Pinnock CA, Derbyshire DR, Achola KJ, Smith G.Absorption of controlled release morphine sulphate in theimmediate postoperative period. British Journal ofAn-aesthesia 1986; 56: 868-871.

27. Poulain P, Hoskin PJ, Hanks GW, A-Omar O, Walker VA,

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Johnston A, Turner P, Aherne GW. Relative bioavail-ability of controlled release morphine tablets in cancerpatients. British Journal of Anaesthesia 1988; 61: 569-574.

28. Pugh GC, Drummond GB. A dose-response study withnalbuphine hydrochlorine for pain in patients after upperabdominal surgery. British Journal of Anaesthesia 1987;59: 1356-1363.

29. Ready LB, Oden R, Chadwick HS, Benedetti C, RookeGA, Caplan R, Wild LM. Development of an anesthesi-ology-based postoperative pain management service.Anesthesiology 1988; 68: 100-106.

30. Rifat K. Sequential anaesthesia. British Journal ofAnaesthesia 1972; 44: 175.

31. Rosow CE. Newer synthetic opioid analgesics. In: SmithG, Covino B, eds. Acute Pain. London: Butterworths,1985.

32. Rowbotham DJ, Wyld R, Peacock JE, Duthie DJR,Nimmo WS. Transdermal fentanyl for the relief of painafter upper abdominal surgery. British Journal ofAnaesthesia 1989; 63: 56-59.

33. Rutter PC, Murphy F, Dudley HAF. Morphine con-trolled trial of different methods of administration forpostoperative pain relief. British Medical Journal 1980; 1:12-13.

34. Saha SK. Continuous infusion of papaveretum for reliefof postoperative pain. Postgraduate Medical Journal 1987;57: 686-689.

35. Sawe J, Kager L, Svensson J-O, Rane A. Oral morphinein cancer patients; in vivo kinetics and in vitro hepaticglucuronidation. British Journal of Clinical Pharmacology1985; 19: 495-501.

36. Scott LE, Clum GA, Peoples JB. Preoperative predictorsof postoperative pain. Pain 1983; 15: 283-293.

37. Sear JW, Hand CW, Moore RA, McQuay HJ. Studies onmorphine disposition: influence of renal failure on thekinetics of morphine and its metabolites. British Journal ofAnaesthesia 1989; 62: 28-32.

38. Slattery PJ, Harmer M, Rosen M, Bickers MD. Com-parison of meptazinol and pethidine given i.v. on demandin the management of postoperative pain. British Journalof Anaesthesia 1981; 53: 927-931.

39. Smith G. Postoperative pain. In: Nimmo WS, Smith G,eds. Anaesthesia. London: Blackwell, 1989; 1175-1197.

40. Stapleton JV, Austin KL, Mather LE. A pharmacokineticapproach to postoperative pain: continuous infusion ofpethidine. Anaesthesia and Intensive Care 1979; 7: 25—32.

41. Thomas DW, Owen H. Patient-controlled analgesia—theneed for caution. Anaesthesia 1988; 43: 770-772.

42. Thompson SC. Will it hurt less if I can control it? Acomplex answer to a simple question. PsychologicalBulletin 1981; 90: 89-101.

43. Vickers AP, Derbyshire DR, Burt DR, Bagshaw PF,Pederson H, Smith G. Comparison of the LeicesterMicropalliator and the Cardiff Palliator in the relief ofpostoperative pain. British Journal of Anaesthesia 1987;59: 503-509.

44. Watters CH, Patterson CC, Mathews HML, CampbellW. Diclofenac sodium for post-tonsillectomy pain inchildren. Anaesthesia 1988; 43: 641-643.

45. White PF. Mishaps with patient-controlled analgesia.Anesthesiology 1987; 66: 81-83.

46. Yaksh TL, Al-Rodhan NRF, Mjanger E. Sites of action ofopiates in production of analgesia. In: Kaufman L, ed.Anaesthesia Review 5. Edinburgh: Churchill Livingstone,1988; 254-268.

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