opioids in chronic pain - semantic scholar...opioid drugs work as analgesics by binding at opioid...

Br. J. Anaesth. (1989), 63, 213-226

OPIOIDS IN CHRONIC PAIN

H. J. McQUAY

SITE AND MECHANISM OF ACTION

The aim in using opioid drugs in chronic pain isoptimal pain relief with a minimum of side effects.A rational approach requires understanding of theclinical pharmacology of opioids given by a varietyof routes, for the differences between routes maybe greater than the differences between drugsgiven by the same route. Those using opioids inchronic pain differentiate between their clinicaland laboratory pharmacology, a distinction whichis not so apparent in acute, operative andpostoperative care. The side effects which areperceived as limiting clinical use, such as res-piratory depression and dependence liability, areoften of minimal clinical importance in chronicuse, as long as appropriate doses are used to treatopioid-sensitive pain.

Opioid Receptors

Opioid drugs work as analgesics by binding atopioid receptors in brain and spinal cord. Aschematic view of the relationships between themu, delta and kappa receptor subgroups is shownin figure 1.

Exogenous opioids used in pain managementhave different binding selectivities on the differentreceptor subtypes. The functional role of thesedifferent endogenous systems is unclear. The musystem has an analgesic effect in both acute andchronic pain, although the endogenous ligand isunknown in certain areas. Enkephalins appear tobe the endogenous ligands at delta receptors andblocking the degradation of enkephalins producesanalgesia in animal pain models [15]. The kappasystem is more enigmatic. In animal models ofchronic pain increased quantities of dynorphin,the endogenous ligand, are found in the spinalcord. The relevance of this to analgesic activity isunclear because in behavioural studies direct cord

H. J. MCQUAY, D.M., F.F.A.R.C.S, Oxford Regional Pain ReliefUnit, Abingdon Hospital, Abingdon, Oxfordshire.

5-HT,

SomatostatinxA/Adenosine Ai-*j^~7

/50%\ T

GABAB

Acetycholine M2

\*-Dopamine D2

Higher centres

I

NMDA

\y

Nociceptiveinput

FIG. 1. Relationships between receptor subtypes. The majoropioid receptor subtypes are mu, delta and kappa. Sigma re-ceptors associated with the N-methyl-D-aspartate ion channeldo not meet all the criteria for true opioid receptors, but arecapable of providing analgesia. Delta and mu may coexist inthe same cell; kappa does not co-exist with mu or delta [47].The mechanisms by which they achieve their effect also ap-pear to be different, mu and delta operating through the potas-sium channel, kappa via the calcium. Kappa shifts the mudose response to the right, and this is shown by — in thefigure. The relative ability of ligands for the subtypes toachieve maximal analgesia on the dose-response measures isshown by the percentage figures in each section: mu 100%,

delta ?50% etc.

application of kappa ligands does not produceanalgesia in all test systems, although effects areseen with systemic administration [32]. Electro-physiological studies with intrathecal doses re-vealed two types of kappa effect, one decreasing Cfibre firing, the other increasing it; the net resultwas no analgesia [30]. The kappa system mayestablish the baseline activity on which mu anddelta operate. This may be important in chronicpain states.

Two strategies for future development ofanalgesics were proposed as a result of receptoridentification. The first was that analgesia without

214

side effects might be achieved by use of kappa- ordelta-selective drugs. This has yet to be provedclinically. The second was that blocking thedegradation of enkephalins might produce an-algesia, again without side effects, because anendogenous analgesic was being made to lastlonger. Blocking degradation is effective in animalmodels, although the maximum analgesic effectmay be considerably less than that achieved by muagonists [15].

Animal models of chronic pain suggest that theN-methyl-D-aspartate (NMDA) receptors mayalso be important. Specific NMDA antagonistsproduce analgesia, as do opioids with anti-convulsant actions [72]. Coherent strategies forfuture opioid analgesic development for chronicpain may need to focus on this site, because thosechronic pains which respond poorly to opioids(see below) are sometimes responsive to anti-convulsant and antidepressant drugs.

Conundrums in Opioid Clinical Pharmacology

The clinical pharmacology of the opioids hassome important differences from the effectsobserved in the laboratory. These differencesappear to depend on the presence or absence ofopioid sensitive pain when the drug is given. Inthe presence of such pain, appropriate doses donot lead to the problems of respiratory depressionand addiction. These are the two commonestreasons given for limiting prescription, so thatunderstanding of this "dual" pharmacology is ofmore than just theoretical interest, especially inregard to pain conditions which respond poorly toopioids.

Respiratory depression

It is easy to demonstrate the respiratory de-pressant effect of agonist drugs in volunteers. Inpatients with pain, however, clinically importantrespiratory depression is a rare problem, bothafter operation and in chronic pain states [69].The mechanism by which the presence of opioidsensitive pain protects against the respiratorydepressant effect is unknown, but is importantclinically. Taking a double dose of morphine atnight does not cause problems [56], but patientsadequately treated with opioids develop respir-atory depression if the pain is taken away by anerve block and the opioid dose is not decreased[22, 35]. The balance between nociceptive inputand opioid effect is necessary to avoid respiratory

BRITISH JOURNAL OF ANAESTHESIA

depression. After successful nerve blocks, opioiddosage should be decreased by 75%; furtherreduction may then be possible over the followingweeks.

The mechanism of this balance may be morespecific than arousal, which was the explanationgiven for the phenomenon of greater respiratoryeffects of opioids in anaesthetized volunteers [19].Medullary respiratory centre cells with nocicep-tive input have been demonstrated in the cat [1],and input here may act to balance the respiratorydepressant action.

Concern about respiratory depression shouldnot inhibit the appropriate use of opioids, which isto provide analgesia when the pain may reasonablybe thought to be sensitive. The corollary is that,when opioids are used for insensitive pain, or insensitive pain at doses greater than those requiredfor analgesia (as in the ITU to facilitate ventilationof the lungs), or for purposes other than analgesia,such as sedation, then the problem of respiratorydepression may be encountered.

Opioid-insensitive pain

In chronic pain it has long been realized thatnot all pain states are relieved by opioids [34]. Agood example is trigeminal neuralgia, in whichthey provide poor pain relief and the anti-convulsant, carbamazepine, works well. Opioidsensitive pain may be denned as pain whichresponds progressively to increasingly potentdrugs: the corollary is that opioid insensitive paindoes not. This distinction is shown by the failureof some patients with chronic pain to distinguishthe analgesic effect of i.v. drugs from placebo [3].

Arner and Meyerson [3] assessed the opioidsensitivity in three groups of chronic painpatients: those with "primary nociceptive pain",those with "neuropathic deafferentation" andthose with "idiopathic pain" (little or no de-monstrable pathology). Effective relief in noci-ceptive pain contrasted with lack of response inthe other two groups. The paper emphasized theclinical necessity of distinguishing between patho-logical pain conditions rather than consideringthem as homogeneous and assuming that theresponse to opioid treatment will be the same [8].

The commonest causes of opioid insensitivepain are nerve compression and nerve destruction(deafferentation) and the reason may be loss ofprimary afferent receptors with post-synapticpreservation. The deafferentation pain associatedwith nerve destruction in cancer patients usually

OPIOIDS IN CHRONIC PAIN 215

results from tumour infiltrating the nerve. Thepainful area may have decreased or alteredsensation. An analogous (and also opioid insen-sitive) pain is seen in post-herpetic neuralgia.Nerve compression may produce a neuralgic pain,often not controlled by opioids, in an area withnormal sensation. Other causes of opioid in-sensitive pain include gastric distension, rectaltenesmoid pain and central pain (thalamic pain;phantom limb pain).

The clinical difficulty lies in patients with painat more than one site (when that at one site issensitive and the other is not) or in distinguishinga dose response for mood elevation from onefor analgesia. Relative opioid insensitivity maybe predicted from history and examination.Management may be pharmacological, withunconventional analgesics (antidepressants, anti-con vulsants or steroids [34]), or with nerve blockor surgery.

AddictionThe fear of producing addiction is, together

with respiratory depression, one of the mainreasons for underuse of opioids in treating chronicpain. Addiction, the "...compulsion to take thedrug on a continuous or periodic basis in order toavoid the discomfort of its absence" [73], is, likerespiratory depression and tolerance, a facet ofopioid pharmacology which is rarely a clinicalproblem.

To determine the incidence of opioid addiction,the Boston Collaborative Drug Surveillance Pro-gramme examined the files of nearly 12000medical inpatients who had received therapeuticopioids. There were only four clear cases ofdependence in patients with no previous historyof addiction [54]. Such psychological dependenceshould be distinguished from physical depen-dence; in the context of successful nerve block theopioid dose may be decreased dramatically, andwithdrawal symptoms and signs may follow [29],as can happen in intensive care.

The other complicating factor is the politicalassumption that medical availability of opioidsnecessarily increases street addiction. While drugsupplies may go astray and be used by streetaddicts, patients who are prescribed opioids forthe management of sensitive pain do not becomeaddicts. To deprive them of this means of painrelief is unjust.

ToleranceTolerance may be denned as the need for a

larger dose (or greater plasma concentration) toachieve the same pharmacological effect. Theword is often misused in pain management tomean an increase in dose; this is only correct if thepain has not increased, and in chronic cancerpain the reason for increasing the dose is usuallyan increase in the pain [29]. Patients are oftenmaintained satisfactorily on the same oral dose ofmorphine for months, and this would not bepossible if tolerance always occurred.

Genuine tolerance does occur in other contexts.Addicts develop tolerance because they are usingopioids in the absence of pain. Acute tolerance hasbeen demonstrated in animal studies: controlgroups given a painful stimulus before theinjection of opioid did not develop acute tolerance[10]. The phenomenon of acute tolerance has alsobeen demonstrated in man [36]. Opioid injectionbefore surgery (before the patient is in pain) iscommon practice, both as premedication and inthe anaesthetic room. It does not create clinicalproblems because any increase in postoperativedrug requirement can be met.

Tolerance to spinal opioid has caused clinicalproblems in chronic pain management but manyof the reports are hard to interpret. In some casesspinal opioids were used for pain which had failedto respond to opioids given by conventionalroutes. On the basis of this and other clinicalcriteria, these were opioid insensitive conditions.The second problem with interpretation is inknowing whether the dose being given was theminimum necessary or was more than was needed.If the latter, tolerance would be expected.

The enigma of opioid tolerance reinforces theconcept of a dual pharmacology. When the drugsare used in appropriate doses to treat pain whichis sensitive, tolerance (like respiratory depression)is not a clinical problem. When opioids are used inthe absence of sensitive pain, or in inappropriatelyhigh dose when the pain is sensitive, then (likerespiratory depression) tolerance can occur.

Indications for Treatment

Patients are often referred to a pain clinic becauseof failure of conventional analgesic regimens, orbecause the referring doctor is unwilling to usethe dose necessary to achieve analgesia. The use ofopioid drugs is only one of the possible approaches(fig. 2) and the first issue in deciding if they are

216 BRITISH JOURNAL OF ANAESTHESIA

Is the pain opioid-sensitive?

>f

Are other measures appropriate?

e.g. n e r v e b l o c k s ± minor analgesicsradiotherapy

Pain from malignancy

Yes

Opioid choice

No

? Choice of opioid may be limited tomixed agonist-antagonist

FIG. 2. Opioids as one possible approach in chronic pain.

appropriate is that of the sensitivity of the pain(see above). There is little logic in using opioids totreat a pain which does not show a cleardose-response relationship.

Opioids in non-malignant painThe second issue is that using opioids in non-

malignant pain is contentious. The argumentsagainst include the problems of addiction anddependence and the potential long term adverseeffects [61]. While there is little evidence to showthat these are major risks [18, 53, 64], there arefew advocates for the argument that long-term usein such conditions is ideal. The problem remainshowever, that it may be the only effective remedy.In the small number of patients for whom this isthe case, the prescriber should ask two questions:"Is the pain sensitive?", and "Is there no othereffective remedy?". If the answer to both ques-tions is yes, then the position must be explained tothe patient, the family practitioner and the othersinvolved in the patient's care. The use of drugssuch as the partial agonist buprenorphine may bemore socially acceptable for this patient groupbecause of the perceived lower dependence liab-ility.

CURRENT PROBLEMS

In addition to tolerance, some of the unresolvedclinical issues are the choice of opioid, the decision

to prescribe by the clock or as required, andchoice of route [18].

Choosing an Opioid

While morphine remains the standard againstwhich others are judged, other drugs may actfaster, last longer or have a better balance betweeneffect and side effect for a particular patient.Factors involved in choice of opioid thus include:

Efficacy and ceiling effectSpeed of onset and duration of actionSide effectsAgonist v. mixed agonist-antagonistPrescriber (or institution) preference

It is easy to forget that morphine is not availablein many countries of the world because of thepolitical decision that medical availability in-creases "street" availability. Knowledge of thealternatives is then a necessity. Mixed agonist-antagonists have particular importance in thiscontext because they have lower dependenceliability and may be the only permissible agents.For the same reason choice may be limited to thisgroup in non-malignant pain. Drug availabilityand prescriber or institution preference may thusbe the most important determinants of choice.

Efficacy and ceiling effect

When treating chronic pain it is always possiblethat the pain will increase as the disease pro-


gresses. This affects the choice of drug, because itcan be argued that there is no point in prescribinginitially an agent which will be incapable ofrelieving severe pain if the situation deteriorates.The argument is not wholly consistent, becauseprogressive prescribing from non-opioid to opioidis a legitimate strategy, but it highlights theproblem of the ceiling to analgesic effect. This isthe inability of a drug to relieve pain beyond acertain intensity, despite an increase in dose. Onereason that oral morphine has become the stan-dard strong oral analgesic for continuous treat-ment in cancer pain [66] is that it is effective (withno apparent ceiling) while being relatively safe.

Three types of analgesic ceiling may be dis-tinguished: that from toxicity at higher doses,ceiling as an intrinsic drug property and ceilingfrom a failure of compliance.

Toxicity. If increasing the dose increases theincidence of unwanted effects, this creates a limitto analgesic efficacy. Codeine and dihydrocodeineare usually classified as "weak" analgesics oc-cupying an intermediate rung on the analgesicladder. They are inadequate at the greater dosesrequired to control severe pain because of theunacceptable side effects produced with suchdoses. Similarly, pethidine in large doses (oraldoses of 200-300 mg 3 hourly, see below) pro-duces central nervous system toxicity.

Intrinsic drug property. Drugs acting as partialrather than pure agonists may be incapable ofrelieving severe pain. This may be more of atheoretical than a practical bar to use, because theceiling effect may occur only at high doses.However, this worry together with fear of negativeinteraction with pure agonists, has limited the use

of mixed agonist-antagonists (see below) in cancerpain.

Failure of compliance. If the dose of drug in eachtablet (or ml of solution) is small, and the doserequired is large, it may be physically difficult forthe patient to take the necessary dose.

Speed of onset and duration of action

Fast onset of effect is not a critical factor if thepatient is receiving regular medication, but maybe relevant for the patient taking a drug accordingto need. Several drugs have faster onset timesthan morphine (table I).

Alternative oral opioids might also be said tohave advantages over morphine if their analgesiceffect lasted longer, because fewer doses would beneeded each day. At least three alternatives do lastlonger than morphine. The long plasma half-lifeof methadone after a single dose (table I) is out ofstep with the duration of its analgesic effect, sothat it is more difficult than morphine to useeffectively and safely. There has been a great dealof confusion because of the disparity between theeffect half-life and the kinetic half-life, for metha-done and for other drugs. Patient self-titrationwith methadone is one method to achieve safe use[59]. Levorphanol also has a long plasma half-life(12—16 h), and an analgesic effect duration of 8 h.Buprenorphine has a duration of effect of 8 h, butis a partial agonist. However, the advent ofsustained release formulations of morphine meansthat there is now less reason for choosing anotheropioid on the grounds of longer duration of effect.

Sustained release formulations. Although thedrugs with longer kinetic half-life such as metha-done can be titrated safely by patients [59], the

TABLE I. Onset time, lime of peak effect, half-life and duration of relief with opioid drugs. (Adaptedfrom [65])

Onset(min)

Peak(min) (h)

Duration ofrelief (h)

DextromoramidePethidineMorphineNalbuphineLevorphanolPhenazocineDipipanoneBuprenorphineMethadoneMST

10-2040-606015-3020-602045-6060-12030-60

120

60-9060-12060-9045-6060-12045-6090-120

120-24030-120180 +

>2.53

?512-16

5

5

3.515/48

(3)

224466688

12


only real advantage appears to be fewer dailydoses than with morphine in solution, andeffectively a fixed dose schedule still operates.This advantage has been minimized with theadvent of sustained release formulations of mor-phine which also decrease the number of dosesrequired daily. These preparations are formulatedto release morphine over a prolonged period(12 h). Clinical experience and controlled studieshave both shown that twice daily dosage substi-tutes for the same total daily dose of morphinesulphate solution taken 4-hourly, and for manypatients twice daily doses are more convenient.One disadvantage is that the time to maximumplasma morphine concentration is longer than isfound with oral morphine sulphate solution(approximately 4 h compared with 1-2 h).

Specific side-effects and metabolismIf an opioid has no specific advantage over

morphine and has a specific disadvantage, such asa troublesome side-effect not found with mor-phine, then there is little logic in choosing thatdrug in preference to morphine. Given equivalentanalgesic potency, any drug which produced fewerside effects than oral morphine would be animprovement. For most clinically important sideeffects such as constipation or nausea, there is nocomparative evidence from chronic pain patientsto suggest that any of the alternatives producesfewer side effects while providing equivalentanalgesia. The evidence from single-dose post-operative studies shows a higher incidence ofuausea and vomiting with pethidine [45], anddysphoria (see below) with those mixed agonist-antagonists which have a relatively high affinityfor kappa and sigma receptors [68].

Dysphoria. This occurs with all opioids, but theincidence varies widely between drugs. There islittle sense in using one which produces a higherincidence of dysphoria than morphine withoutany compensating advantage. Pentazocine, butor-phanol and nalbuphine have this potential [24].The greater than 20% incidence seen withpentazocine and butorphanol contrasts sharplywith the 3% incidence seen with other opioids;drugs which produce this high incidence have noplace in the management of chronic pain.

Toxic metabolites. Pethidine is metabolized tonorpethidine, which is toxic [63]. It causesunwanted CNS changes, tremor, twitching, agi-

tation and convulsions, and the incidence of theseproblems increases considerably at doses above200-300 mg, and in the presence of impared renalfunction [7, 63]. Together with its short durationof action (2-3 h (table I)), this makes pethidine apoor choice for the management of chronic pain.

Active metabolites. Recent work on dia-morphine, on the metabolites of morphine and onthe method of excretion has some importantclinical implications. Of the drugs shown in figure3, diamorphine [28] and morphine-3-glucuronide(M3G) [9] do not bind to opioid receptors,whereas 6-monoacetylmorphine, morphine, mor-phine-6-glucuronide (M6G) and normorphinedo. Quantitatively, the most important activemetabolite is M6G, because M3G and M6G arethe major metabolites of morphine in man [6, 58]and because of the greater potency of M6Gcompared with morphine. In rats, M6G is 45times more potent than morphine intracerebrallyand nearly four times more potent subcutaneously[60]; intrathecal injection gave potency ratiosbetween 10 and 20 [62]. M6G may contributesubstantially to the analgesic effect of morphine,in both single and repeated doses [20, 39, 50].

Diamorphine is a classical "pro-drug". Devoidof analgesic activity itself, it initiates the "cas-cade" into the active 6-monoacetylmorphine,morphine and M6G (fig. 3). Because of the speedof these reactions, there is no clinical advantageover morphine by oral or i.m. routes, in termseither of greater analgesic efficacy or of improvedmood [28, 67]. This does not exclude advantagefrom i.v., spinal or other routes.

The major advantage of diamorphine overmorphine is solubility. This is relevant wheninjections of large doses are necessary, becausethey can be given in a small volume. This may alsomake diamorphine a logical choice when largedoses are necessary for subcutaneous infusion.

Renal functionUnexpected degree and duration of effect can

be obtained with morphine and its congenerswhen they are used in patients with severelyimpaired renal function [37]. Cumulation of M6Gis the probable explanation for this phenomenon.Prolonged respiratory depression has been re-ported in man in association with negligibleplasma concentrations of morphine, but with veryhigh concentrations of M3G and M6G [49]. Therelevance of this problem to chronic pain man-


Dlacetylmorphlne

6-Monoacetylmorphine

Morphlne-3-glucuronide

Morphine

Morphlne-6-glucuronlde

-CH

Normorphlne? Moiphine-6-sulphate

FIG. 3. Diamorphine, morphine and metabolites.

agement was shown by decreased oral morphinerequirement in patients with impaired renalfunction [57]. These patients (plasma creatinineconcentration > 180 umol litre"1) requiredsmaller doses (5 mg, 4 hourly) than the median(20 mg, 4 hourly).

Problems should arise only if a fixed-doseschedule is used without taking account of renalfunction, or without adequate titration againstpain intensity. Drug doses should be decreasedmarkedly if creatinine clearance is less than 30 mlmin"1. With less severe renal dysfunction thepotential problem emphasizes the need for carefultitration, remembering that renal function deter-iorates with advancing age.

Hepatic function

Glucuronidation of morphine is altered little inhepatic failure [52]. Patients require the samemorphine dose as those with normal hepaticfunction [31, 57]; the mechanism of the problemsencountered in hepatic pre-coma is not known[31], but may be as much dynamic as kinetic.

Dose equivalence

When changing between the oral and theparenteral route, the dose of morphine must beadjusted, but the exact ratio for the change is notknown. In one study the effect of a single injecteddose was six times that of an oral dose [25]. In themultiple dosing context of chronic pain, ratios of2:1 or 3:1 are used successfully [66].

The discrepancy between a ratio of 1:6 withsingle doses for acute pain and 1:2 or 1:3 withrepeated doses for chronic pain has led to muchconfusion. Both are correct within their clinicalcontexts. The explanation for the discrepancymay be that active metabolites contribute more tothe analgesic effect with repeated doses than witha single dose [21, 39]. An important clinical pointis that patients differ, both in the bioavailability oforal morphine (15-64%, mean 38% [58]), and inthe effect of the drug, so that individual titrationis necessary.

Mixed Agonist-Antagonists

These drugs combine the ability to act likemorphine (agonist activity) with potential ant-agonist activity. Common to the group are lowerdependence liability than is found with agonistsand a ceiling to their efficacy.

These properties come from the presumedactivity of these drugs on more than one opioidreceptor type. The simplest (and clinically mostimportant) way of classifying these drugs is intothose which are morphine-like, because of partialagonist activity at the mu receptor (buprenor-phine), and those which are more similar tonalorphine (pentazocine, butorphanol, nalbu-phine), with agonist action on the kappa receptor.The classification is clinically important because,whereas morphine-type drugs predictably havesubjective and physiological effects like morphine,and do not cause a higher incidence of psychoto-mimetic reactions than morphine, the nalor-phine-type of mixed agonist-antagonists causeincreased incidence of psychotomimetic reactions(see above) and this limits their usefulness inchronic pain.

The ability of these drugs to antagonize otheropioids has led to the dictum that they should notbe prescribed together with agonists. This ant-agonist ability is, however, far from straight-forward, first because antagonism is more evidentwith chronic exposure [27], and second because


many patients who have been prescribed bothagonist and partial agonist drugs at doses withinthe "normal" therapeutic range, appear to haveadditive analgesia [33]. While co-prescriptionmakes little sense, because it invites problemsunnecessarily, the disparity between the clinicalobservations and the pharmacological predictionsremains to be explained satisfactorily.

The issue of ceiling to efficacy appears to berestrictive in chronic pain only for nalbuphine(ceiling equivalent to morphine 30 mg); for bu-prenorphine the ceiling has been estimated at 5 mgday"1 [77], at which point compliance is morelikely to be a limiting factor. Two benefits ofefficacy ceilings are that the ceiling for respiratorydepression appears to be equivalent to approxi-mately 20—30 mg of morphine, making the drugstheoretically safe in overdosage. Theoreticallythere should also be a ceiling to constipation.

Prescribe Regularly or as Required?

Should opioids be given on a fixed "by the clock"schedule or when the patient asks for them? Therationale for the safe and effective hospice teachingthat the fixed dose schedule for oral morphine isbest is that such schedules prevent the pain re-emerging. If this is allowed to occur, the relativelyslow onset of analgesic effect of oral morphinemeans that it takes time to re-establish control.Sustained release morphine formulations mayhave an even slower onset time, and hence be evenmore ineffective.

While there is no inherent merit in allowingthe pain to re-emerge in this way, some patientsfeel "drugged" when taking oral morphine on afixed dose schedule, and would prefer to take thedrugs when needed. Others require additionalrapid onset pain relief for pain which breaksthrough background analgesia. Unfortunately, thekinetic and dynamic profiles of the alternative oralopioids do not offer much advance over oralmorphine. Faster onset of analgesic effect isrequired for on-demand use, and this is claimedfor dextromoramide and levorphanol (table I),and for morphine hydrochloride compared withmorphine sulphate. A regimen may be tailoredwith background control with morphine and afaster onset oral opioid in addition, either toenable patients to titrate their pain relief againstany clouding of thought or to control unpre-dictable break-through pain.

Alternatively, judicious use of non-steroidal

anti-inflammatory drugs or paracetamol may beused to get round this problem, adhering thento the purist philosophy of only prescribing oneopioid at a time. Combining the effects of aspirinand opioid produces an additive increase inanalgesia [26], known as the opioid-sparing effectbecause greater analgesia is achieved withoutincreasing the opioid dose.

Route of Administration

Thirty years ago many doctors did not believethat oral opioids were effective analgesics, despitecenturies of use. Now that the oral route is theaccepted standard for chronic cancer pain, novelroutes are being explored to improve pain reliefand to minimize side effects.

Two clinical issues have become confused indiscussion of alternative routes. The first is clinicalnecessity; some patients may have to be managedby a "non-standard" route of administration,such as those cancer pain patients who cannot takeoral medication. The overall proportion ofpatients in this category is not known, but is likelyto be greater in a pain clinic or hospice becausereferral will follow failed oral treatment. Thesecond is the potential of novel routes to providebetter analgesia or fewer side effects than standardroutes, so that the novel route supplants thestandard. The current problem is providingcogent clinical evidence to confirm these potentialbenefits [16].

The sublingual and spinal routes are discussedin some detail because they are current clinicalalternatives to conventional routes of adminis-tration. Other proposed routes (nasal, trans-dermal, inhalation, etc.) should be subject to thesame questions: what is the kinetic logic of theroute, and what is the clinical logic?

Sublingual and buccal opioids

Kinetic logic. The kinetic logic behind using thesublingual and buccal routes is that the drug isgiven without injection, but is absorbed system-ically (analogous to an i.m. dose), avoiding anyfirst-pass effect. Circumventing this increasesrelative systemic bioavailability, but the realclinical gain is that it should make the effect of agiven dose more predictable both within andbetween patients than an equivalent oral dose. Itis the variability of the first-pass effect whichmakes short-term use of oral opioids difficult. Anadditional gain of faster onset of analgesic effect


was anticipated by analogy with other drug classesused sublingually (15 min for anti-angina drugs).

Sublingual buprenorphine provides the bestexample of the kinetic gain in availability. Afteroperation, 0.4 mg sublingually produced analgesiaequivalent to that obtained with 0.3 mg i.m.Relative systemic availability was 55 % (range16-94%). The relative systemic availability oforal buprenorphine, in contrast, was about 15%[38, 71]. Substantial gains in onset time foranalgesic effect have not been found; 30 min is theaccepted time in chronic use.

The kinetic advantage of sublingual use wouldbe predicted for high clearance drugs with asubstantial first pass effect when taken orally, butnot for low clearance drugs. No advantage forsublingual use of methadone, which has a lowclearance and high oral availability, would beexpected and none was found [38]. Similarly littlekinetic advantage was found with sublingualmorphine [38, 51, 71], and recent work withbuccal morphine [4] had no oral controls, so thatno advantage over oral relative systemic avail-ability could be shown.

Little is known about the influence of for-mulation and physico-chemical properties ofdrugs, such as lipophilicity, on sublingual andbuccal availability. Manipulating the drug for-mulation may maximize the availability andminimize problems of taste and local irritation; itwill not change the logic that avoiding the first-pass effect is an advantage only for high clearancedrugs which are subject to a substantial first-passeffect. Such manipulation might also result in afaster increase in plasma concentrations and henceproduce faster onset of analgesic effect; thisadvantage would apply to both high and lowclearance drugs.

Clinical logic. Sublingual use is an alternativefor patients in whom swallowing is difficult, andwhen a drug can produce analgesia as goodas could be achieved by injection. Sublingualbuprenorphine produces analgesia equivalent toparenteral doses. This advantage should beconsidered particularly when potent opioids areneeded in contexts where injection is mostproblematic: in children, in subjects with hae-mophilia or in patients who cannot swallow. Theagonist drug phenazocine has also been usedsublingually [5], but there are no comparisonswith the use of oral morphine.

Subcutaneous injectionInjection of opioids is necessary when a patient

cannot swallow medication, cannot absorb it orhas persistent vomiting. The choice of drug forparenteral use may be dictated by consideration ofthe volume to be injected, particularly if repeatedinjections have to be given in cachectic patients.Diamorphine is much more soluble than mor-phine (100 mg will dissolve in 0.2 ml) and is usedwidely in Britain for this purpose. The dose givenfor injection is half the orally effective dose ofdiamorphine (30 % of the orally effective dose ofmorphine). Morphine acetate and hydro-morphone hydrochloride are alternatives.

Subcutaneous infusions using a battery-drivenportable syringe driver [48] may be useful for thepatients (e.g. those with inoperable bowel ob-struction) who need longer term parenteral medi-cation.

Intravenous useHospitalized patients and those with long-term

central venous cannulae may be managed with i.v.bolus or infusion, and the route has been usedsuccessfully in the young [42, 43].

Spinal OpioidsGiving opioids by spinal (a generic term forintrathecal and extradural) routes in chronic painmanagement is contentious, for it has potentiallygreater morbidity than conventional routes. Theimportance of spinal opioids is the potential for aquality and duration of pain relief greater thanthat achieved with conventional routes. Thispotential puts spinal opioid use in the category ofnovel routes for which the risk:benefit ratiocompared with conventional routes must bedefined [16]. The belief that applying opioiddirectly into central nervous system (CNS) pro-duces an absolute difference in incidence ofanalgesia and side effects compared with con-ventional routes has little logic behind it; thedrugs act on the same receptors however they aregiven, so that the difference can be only relative.Spinal opioid use in chronic pain has had a strongphenomenological flavour. The appropriate clini-cal role is not resolved.

Kinetic logicSpinal administration uses injection of exogen-

ous neurotransmitters close to the CNS to workdirectly on the receptors. The kinetic problems of


conventional routes, such as uncertain absorptioninto, and delivery by the circulation to, CNS sites,are hence circumvented. The process, however,substitutes a different set of problems. Theprinciples which underlie the systemic kineticdifferences between drugs, such as the influenceof lipophilicity on the ability to cross the blood-brain barrier [23], are circumvented by directspinal application [40]. This is evident in thepotency of different mu agonists given i.v. orintrathecally. Methadone 10 mg given systemic-ally produces analgesia equivalent to that fromsystemic morphine 10 mg. Intrathecally, however,the ED50 for methadone is 18 times that ofmorphine [40]. These differences between sys-temic and spinal dose requirements have not beenapplied as they should have been in determiningequianalgesic doses.

The benefit of giving opioid extradurally asopposed to using conventional parenteral routescomes from the fraction of the extradural dosewhich crosses the dura directly. While the kineticsof this fraction will be predictable from intrathecalkinetics, the proportion of drug absorbed systemic-ally will follow the kinetic principles for systemicabsorption. Taking the example of methadone,the "systemic" fraction is equipotent with mor-phine, but the " spinal" fraction is not, because oflipophilicity. This additional complexity has notbeen addressed adequately.

The high drug concentrations achieved afterlumbar intrathecal injection [44] spread rostrally[46], and make a combination of spinal andsupraspinal effect possible. This may be a necess-ary combination for adequate analgesia. Systemicabsorption from the extradural space would alsotake drug to supraspinal receptors. The high CSFconcentrations, however, also raise the spectre oftoxicity, which may be of particular importance ifspinal opioids are to be used in non-malignantpain. None has been found, either in prolongedstudies in monkeys (4-16 months extraduralmorphine [75]), or in man after 6 monthsextradural morphine [41]. Both dural thickeningafter chronic intrathecal administration [12] andpain on extradural injection [76] are attributableto disease rather than to the spinal opioids. Theuse of the more potent agents should perhaps berecommended, on the basis of fewer non-specificactions, until more is known.

Clinical logic

Analgesia. For chronic pain there is evidence

that a small dose of drug given spinally canprovide analgesia equivalent to that from largerdoses given orally or by conventional injectionroutes. The duration of effect of these smallerdoses may also be greater. There is little com-parative evidence for a lower incidence of sideeffects.

Opioids are often administered spinally inchronic pain when they have failed by con-ventional routes. This presumes that the failure isbased on the drug not reaching the receptors inthe CNS so that, if it is given directly, analgesiawill ensue. Unfortunately, it is difficult to be surefrom the literature that reports of success or offailure are reports of patients who fulfil thiscriterion. Overall, the proportion of patients forwhom conventional routes fail is low (? 15 %), andthe majority of these have pain at one or morerelatively opioid-insensitive sites.

The crucial issue is whether or not the pain issensitive, because there is no point in usingopioids if it is not [2], and even less point indelivering them by a route which has a highmorbidity. Sensitivity may be determined usingthe i.v. route [3], or by double-blind comparisonbetween intrathecal opioid and saline [17]. Mostsensitive pain can be managed successfully withoral administration, so the high morbidity spinalroute is appropriate only if the pain is sensitiveand conventional routes are contraindicated. Thesuspicion remains that spinal opioids can producea better quality of analgesia with fewer side effectsthan conventional routes, but this is not proven. Ifthis suspicion were to be confirmed, then thebalance of the equation would be tipped in favourof more widespread use of the spinal route inpatients managed currently with opioids given byconventional means.

A simple method of converting from theconventional route is to try 1 % of the total dailydose as the daily intrathecal dose, and 10 % as theextradural dose [11]. Initially, the intrathecal dosemay be given once daily and the extradural dosetwice. The doses used in chronic pain (0.05-1 mg[70]) may be increased as disease or tachyphylaxisdevelop [2]. There is no comparative evidence torecommend infusion rather than bolus adminis-tration, or to prefer constant infusion to systemswith which additional demands can be met as inpatient-controlled analgesia. Efficacy of low doseextradural infusions [14] suggests that the doseresponse for infusions may be different (responseat lower doses) from that for bolus injection. If, at


these low doses, the same quality of analgesia isprovided with fewer side effects, infusion may bepreferable. It is unclear whether or not the same istrue for intrathecal administration. The over-riding principle is to balance the dose and thepain. If infusions contravene this rule, the in-cidence of side effects is increased and tolerancewill develop if a dose greater than that requiredfor pain relief is given. If low dose infusion ispreferable, the infusion must be "tailored" to thepain.

Intrathecal or extradural} The intrathecal routeoffers certain availability of the drug in CSF whencompared with the extradural route. Spinal avail-ability is a function of drug lipophilicity and thereis variability between drugs. Technical difficultieswith extradural injections and catheters causevariability between and within patients. There isan analogy to the certain availability of the i.v.route when compared with the i.m.

Intrathecal administration requires dural punc-ture, and the relative merits of repeated punctureagainst an intrathecal catheter [70] must be con-sidered. The advantage of implantable intrathecalcatheter systems is claimed to be a lower infectionrate. The disadvantages are the extra logisticdifficulty and the cost. Again, not all chronic painis relieved by spinal opioids [2], and caution mustbe exercised before "leaping in" with an im-planted system. Intraventricular catheters wereused effectively for tuberculosis treatment andmay have considerable advantage over long-termlumbar catheters, the usefulness of which maybe limited by problems with CSF leakage andcatheter maintenance [70].

An extradural catheter might be thought tohave considerable logistic advantage and produceless morbidity than an intrathecal one, but there isno comparative evidence. The long-term (morethan 1 year) use of extradural catheters in thiscontext has been shown to be effective [13, 78],but with problems of obstruction, kinking, re-moval and infection. Tunnelling the catheter mayreduce infection, but does not appear to reducethe incidence of the other complications [11]. Theadvantages of implanting injection reservoirs orsystems remains to be seen. These "high-tech"approaches have often been used in patients withinsensitive pain, making the.results (other thanlogistic success) uninterpretable.

Side effects. The major problems encounteredin acute pain are itch, urinary retention and

respiratory depression. In chronic pain these havenot been problematical [11]. The reason is notthat chronic pain per se protects against thesephenomena, but rather that previous opioidexposure seems to minimize the incidence. Com-parisons of the incidence of side effects of chronicoral and chronic spinal administration are lacking.Anecdotally, patients whose use of oral morphinewas restricted by side effects have had analgesiawithout side effects when spinal opioids wereused. Comparisons of the incidence of side effectswith different opioids given chronically by spinalroutes are also lacking. Both types of comparisonwill require equianalgesic doses to be established.

The development of tolerance to spinal opioids(that is the need for larger doses to obtain thesame effect), has been seen often in the treatmentof chronic pain. Tolerance developed faster whenopioid was infused spinally than when bolusinjections were made on demand [17], but theproblem is not insuperable, because increasingthe dose defeats the tolerance. Temporary ab-stention has the same effect, presumably relatedto the advent of new (previously unexposed) re-ceptors. The reason that tolerance develops fasterwith infusion than does demand may be thatinfusion at higher than necessary dose predisposesto development of tolerance (see above).

PRACTICAL PRESCRIPTION OF ORAL ANALGESICS

Two concepts underlie the sequential use ofanalgesics, "by the ladder" and "by the clock"[74]. In chronic pain of increasing severity,analgesics of increasing strength are used sequen-tially—ascending the ladder. In acute pain weakeranalgesics are used as the pain intensity de-creases—descending the ladder.

The standard non-opioid analgesic is aspirin.Paracetamol may cause fewer side effects andprove equally effective, despite a lack of anti-inflammatory activity. Non-steroidal anti-inflam-matory drugs are more powerful analgesics thaneither aspirin or paracetamol, and may becomethe first line treatment. The archetypal weakopioid is codeine, but the combination of dextro-propoxyphene with paracetamol is preferred .bymany patients because of lower incidence of sideeffects, particularly constipation. The standardstrong opioid is morphine.

The concept of regular "by the clock" adminis-tration was discussed above. For codeine andmorphine ("normal" formulations) a 4 hourly


regimen is optimal. A 6 hourly prescription maybe satisfactory for levorphanol, phenazocine ormethadone (table I).

The following guidelines are suggested:

Non-opioid and weak opioid. With mild ormoderate pain, use a non-opioid initially. If reliefis inadequate, add a weak opioid, and titrate thedose against effect. Simultaneous prescription oftwo weak opioids makes no sense. If increasingthe dose of the chosen drug does not relieve thepain, a strong opioid should be prescribed, ratherthan waste time by prescribing an alternativeweak drug.

Strong opioid. Oral morphine should be usedwhen the less potent drugs fail to control the paindespite regular use at an appropriate dose. Theaim with opioid responsive pain is to titrate thedose of analgesic against the pain, increasing thedose appropriately until the patient is pain-free.The effective dose varies from patient to patientand from time to time; the correct dose for thepatient is that which gives good pain relief for atleast 4 h without unacceptable side effects. Therange of morphine doses used is between 5 mg and1000 mg 4 hourly, emphasizing the differencebetween patients; most never need more than100 mg, and many need considerably less, themedian 4 hourly dose of oral morphine sulphatesolution being 10 mg [66].

The starting total daily dose of oral morphinefor most patients whose medication is beingchanged from a weak opioid is 60 mg/24 h (10 mgaqueous formulation 4 hourly or 30 mg twicedaily sustained release). The patient should betold from the start to take an extra dose (" escape "analgesic) if relief is inadequate. At the nextassessment, these escape doses are added in to thecalculation of total daily dose requirement, andthe by the clock prescription is increased ac-cordingly. If twice daily administration is pref-erable to 4 hourly, a sustained release formulationshould be used. To convert the dose, the totaldaily oral dose (mg) is calculated and divided bytwo to give the sustained release dose in mg.However, adjusting the morphine dose can bedifficult. It takes time (3 days) to judge whetherthe increase in dose has been effective, and smalland ineffectual changes lose both time and thepatient's confidence. The general rule is that thetotal oral daily dose is increased by 50%, from

60 mg/24 h to 90 mg, to 120 mg, to 180 mg, to240 mg and to 360 mg.

Opioids should not be used without thought forconstipation [55]. The use of anti-emetics as aroutine is contentious. Initial nausea and drowsi-ness after commencing therapy with a strongopioid often decrease after about 3 days, andmany patients never need an anti-emetic.

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opioids in chronic pain - semantic scholar...opioid drugs work as analgesics by binding at opioid...

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