Opioids are widely used in severe pain and should not be withheld in chronic noncancer pain. Our Drug review discusses the proper- ties of the available opioid analgesics and how and when to prescribe, followed by an analysis of the prescription data and sources of further information. T he management of pain remains a problem, partly due to poor medical education on the subject, at both undergraduate and postgraduate levels. On aver- age 1 per cent of the medical undergraduate curricu- lum is devoted to pain management, compared to three times this in veterinary medicine and physiother- apy. 1 It is estimated that 5–10 per cent of the British population suffers from persistent pain, which if inad- equately managed results in poor affect, sleep distur- bance and family unit dysfunction. It also interferes with the ability to carry out gainful employment. 2,3 Severe pain requires urgent attention – the diag- nosis usually being obvious in the acute situation. When pain persists beyond a few months, despite attempts at conventional management, it is deemed chronic. By its very nature and poor response to treat- ment, chronic pain is therefore difficult to manage. Pain due to tissue damage – the subject of this review – is referred to as nociceptive and usually responds to NSAIDs and opioids. If the pain is due to a disturbance www.prescriber.co.uk Prescriber 5 September 2012 25 Drug review Severe pain Guide to prescribing in today’s management of severe pain William Campbell PhD, MD, FRCA, FFARCSI, FFPMRCA, FFICM
Transcript
Opioids are widely used in severe pain and
should not be withheld in chronic noncancer
pain. Our Drug review discusses the proper-
ties of the available opioid analgesics and
how and when to prescribe, followed by an
analysis of the prescription data and sources
of further information.
The management of pain remains a problem, partlydue to poor medical education on the subject, at
both undergraduate and postgraduate levels. On aver-age 1 per cent of the medical undergraduate curricu-
lum is devoted to pain management, compared tothree times this in veterinary medicine and physiother-apy.1 It is estimated that 5–10 per cent of the Britishpopulation suffers from persistent pain, which if inad-equately managed results in poor affect, sleep distur-bance and family unit dysfunction. It also interfereswith the ability to carry out gainful employment.2,3
Severe pain requires urgent attention – the diag-nosis usually being obvious in the acute situation.When pain persists beyond a few months, despiteattempts at conventional management, it is deemedchronic. By its very nature and poor response to treat-ment, chronic pain is therefore difficult to manage.
Pain due to tissue damage – the subject of this review– is referred to as nociceptive and usually responds toNSAIDs and opioids. If the pain is due to a disturbance
www.prescriber.co.uk Prescriber 5 September 2012 25
Drug review Severe pain
Guide to prescribing in today’s
management of severe painWilliam Campbell PhD, MD, FRCA, FFARCSI, FFPMRCA, FFICM
of the nervous system, such as trigeminal or posther-petic neuralgia, it is considered neuropathic, and theresponse to NSAIDs and opioids is often poor.
Principles of prescribingWith the exception of certain clearly defined condi-tions, opioids are the most commonly used agents forsevere pain. In some conditions where prostaglandinsplay a significant role, such as renal colic, the NSAIDscan be as efficacious as opioids but with a lower inci-dence of side-effects.4
In the chronic pain situation, sustained-releasepreparations should be used on a regular basis tokeep pain under control; this results in more stableplasma concentrations of the drug, permitting thepatient to function in a more normal manner, ratherthan wondering when they should take their nextdose of medication. The steady plasma levels of opi-oids in particular help to reduce habit-formingbehaviour, since there is no ‘kick’ after each dose ora rapid withdrawal effect resulting in the suddenneed for another dose.
It may be necessary to use multiple therapies butwhen adequate relief is attained for a few weeks, onecan establish which drugs are making the largest con-
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• establish a treatment plan, with goals• regularly review patients for side-effects, sleep andmood changes, in addition to signs of abuse
• the primary outcome should be analgesia – not anxiolysis or sedation
• although psychological co-morbidity or alcohol prob-lems do not preclude opioid use, they do indicate theneed for specialist help, such as multidisciplinary painmanagement services or specialised addiction teams
• avoid injectable opioids• evidence of developing tolerance should prompt refer-ral to multidisciplinary pain management services orspecialised addiction teams
Table 1. British Pain Society recommendations for the use ofopioids in chronic noncancer pain7
tribution and rationalise therapy to the least required,in keeping with a realistic reduction in pain.
A minority of patients have quite unrealistic expec-tations. It is therefore essential to discuss not only thediagnosis of their problem and the therapeutic optionsbut also realistic goals. Failing to do so can result inregular attendances at the surgery in an attempt togain a complete return of normality. In these situationsthe contribution of psychology is invaluable, since thepsychological component of pain can augment itsintensity many fold.
Opioids are agonists at mu, kappa and delta recep-tors, which are located at many sites within the CNS,in particular the substantia gelatinosa in the spinalcord and the periaqueductal grey matter of the brain.Opioids may be pure agonists like morphine, oxy-codone and fentanyl, or partial agonists such asbuprenorphine.
Tramadol is unusual in that most of its activity isthrough the modulation of noradrenaline and sero-tonin (descending nociceptive inhibitory pathways),with the remaining 20 per cent of its analgesia beingat opioid receptors.5,6
Tapentadol (Palexia) also has a dual mode ofaction – at the opioid receptor as well as noradrenergicreceptors – but without the disadvantage of serotoninactivity, like tramadol.7,8
Although strong opioids have been the primeagents used in severe acute and cancer pain, there isevidence that they should not be withheld in chronicnoncancer pain.9 The British Pain Society (BPS) haspublished recommendations for the appropriate useof opioids in chronic noncancer pain (see Table1).10,11 However, patients should have explored othertherapies before embarking on opioids beyond theequivalent of 30mg oral morphine per day, andadvised of the side-effects of long-term use – such aspossible immunosuppression, hormone dysfunctionand worsening of certain types of pain.
Patients often use less than the prescribed dose ofopioids due to side-effects such as sedation, nauseaand vomiting. The use of regular cyclizine or prochlor-perazine during the first week of treatment minimisesthis distressing symptom. Nausea and sedation gener-ally become much less problematic after one or twoweeks, but constipation usually continues.
When any opioid is prescribed it is important toensure that patients are aware of these potential prob-lems and that a gut stimulant is routinely prescribed.Although stool softeners work well with gut stimulants,they are usually ineffective by themselves.
A novel approach, which can be effectively used tomanage constipation when potent opioids are needed,
is to employ the combination medication Targinact(oxycodone 20mg with naloxone 10mg – and otherstrengths of tablet with this 2:1 ratio of opioid to nalox-one). This preparation provides a potent sustained-release opioid with naloxone, which has a direct opioidantagonist effect on the bowel (avoiding constipation),but the vast majority of the naloxone is metabolisedas it passes through the liver and thus does not have asystemic antagonistic effect on the CNS, where the opi-oid works.
A major concern with repeated dosing of any opi-oid is psychological dependence. It is important, ofcourse, to gain rapid control of severe pain whenacute. In the chronic situation, if this is not achievedwithin a few weeks one may consider the withdrawalof the opioid and the use of alternative therapy.Despite this, it is not unreasonable to use an escalatingopioid regimen with an agreed plan and goals overseveral weeks to establish efficacy. The continual needfor an escalating dosage after several weeks indicates
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Tolerance
A reduction in response intensity and duration followingthe repeated administration of a drug: this includes theside-effects as well as the beneficial effects. Analgesicresponse generally improves with an increase in dose.Although this is a normal pharmacological response, thedose should not have to be increased on multiple occa-sions.
Physical dependence
This is a normal physiological response. Receptorsbecome dependent on the presence of exogenous ago-nist. The sudden withdrawal of an agonist or the use of asubstance with antagonist properties will precipitate awithdrawal response.
Pseudoaddiction
If inadequate analgesia is provided the patient seeks fur-ther analgesia. In this situation, despite the patient ask-ing for increasing doses of analgesia (because ofinadequate pain relief), they tend to use their medicationas prescribed.
Addiction
True drug addiction is the overwhelming desire to con-tinue to use the same or greater doses of a substancewith psychomimetic properties. The desire is over andabove that for analgesia and involves both psychologicalas well as physical factors.
Table 2. Distinguishing between tolerance, dependence,pseudoaddiction and addiction
that tolerance may be occurring (see Table 2) and thatspecialist support should be sought. Although it isuncommon for patients in pain to become trulyaddicted to opioids when appropriately managed, it ispreferable that they attend the same healthcare pro-fessionals for follow-up and repeat prescriptions.5,12,13
A simple protocol such as that shown in Table 3can be valuable in providing good patient care whileminimising short- and long-term problems.
Opioids in common useMorphineThe drug most often associated with potent analgesiawithin the general population is morphine and it tendsto be the standard against which other analgesics arecompared. A naturally occurring substance, it has beenavailable for many centuries as a constituent of opium.Although associated with side-effects, it remains a rel-atively popular analgesic in the management of severepain. It can be administered by the oral (conventionalor modified-release preparations are available), rectal,parenteral (sc, im and iv), spinal and epidural routes.Due to its low lipid solubility it cannot be administeredby the transdermal route.
When taken orally or rectally 70 per cent of thedose undergoes conjugation in the liver to form mor-phine-3-glucuronide (M3G) and 5–10 per cent mor-phine-6-glucuronide (M6G). The M6G has beenshown to be considerably more potent than the parentcompound. These metabolites depend on renal excre-tion, with important implications for those with renalimpairment.14
Dosage and response can vary widely, regardless ofweight, in the adult population. Older people mayrequire smaller doses due to receptor sensitivity andimpaired renal function, whereas the very anxious indi-vidual in pain may require a larger-than-expected dose.
Sedation, dizziness and nausea can be problematicas well as constipation. This is especially common inthe frail or elderly, and when using large doses.Euphoria, dysphoria and itching (see Table 4) may alsooccur with morphine, and important drug interactionsare shown in Table 5. Despite these adverse effects mor-phine is a remarkably safe and effective analgesic.
DiamorphineDiamorphine is available as a white powder for recon-stitution. It is approximately twice as potent as mor-phine. Essentially a prodrug, it is activated bydeacetylation in the plasma to monoacetylmorphineand hence to morphine. It is very lipid soluble andrapidly crosses tissue membranes, with a much morerapid onset than morphine. However the duration ofaction is also shorter, in the region of two hours. Thisrapid onset and offset, especially when administeredby the iv route, greatly increases its addiction potential.
It is possible to achieve extremely high concentra-tions of diamorphine in solution for sc administration,and hence its value in palliative care of the terminallyill, where high doses may be required.
PethidinePethidine was the first totally synthetic opioid. It hasapproximately one-tenth of the potency of morphine,and like other opioids undergoes extensive first-passmetabolism (47–73 per cent). Convulsions may occurwith repeated dosing due to one of the metabolites,norpethidine, which is a proconvulsant. In addition itshould not be administered to patients taking MAOIsas the combination can cause hypertension, hyper-pyrexia, convulsions and coma.
It was favoured in the past as a drug that avoidedsmooth muscle spasm in conditions such as renal colic.It is not as popular now and is no longer considered afirst-line analgesic due to concerns over adverse reac-tions, drug interactions (see Table 5) and norpethi-dine neurotoxicity.15
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Table 3. Considerations for prescribing strong opioids insevere, chronic pain
• an initial assessment, including function and activitylevels, should be performed
• the reasons for using strong opioids should beexplained
• it should be made clear that pain will be modified butrarely completely controlled
• side-effects and interactions should be discussed• when prescribing, an informal ‘contract’ or opioid trialcan be useful
• the oral route of administration should be used, if pos-sible
• only one opioid should be used at a time• agents with toxic metabolites, eg pethidine, should beavoided
• compound analgesics, eg those containing anti -emetics, should be avoided
• regular dosing as opposed to ‘as-required’ prescribingshould be used
• long-acting opioids or sustained-release preparationsare preferred
• changes in dosage should be made quickly to gainrapid control of pain
• regular follow-ups should be arranged
• it should be ensured that documentation is clear andcomplete
OxycodoneThis drug is licensed for severe pain and has twice thepotency of morphine. It undergoes first-pass metabo-lism (50 per cent) when taken orally, initially 5mg fourhourly. It has similar side-effects to morphine but pos-sibly less sedation. Like morphine, it is available as asustained-release preparation (OxyContin), deliveringanalgesia for about 12 hours. Also see Targinact, men-tioned earlier.
Other opioidsCodeine, dihydrocodeine and methadoneDue to its metabolism to morphine varying consider-ably between individuals, codeine is not particularlyreliable in treating severe pain. Dihydrocodeine has a
similar potency to codeine but is available as oral andparenteral formulations. The typical oral dose is 30–60mg every four hours, but the sustained-releasepreparation (DHC Continus) can be used at 120mgevery 12 hours. When used by the sc or im route thedose is up to 50mg every four hours. These drugs havea dose/response ceiling and are of limited value in themanagement of severe pain.
Methadone has similar potency to morphine but isassociated with less sedation and euphoria. It has ahigh oral bioavailability (80 per cent). Due to its longhalf-life (about 24 hours) it should not be adminis-tered more frequently than 12 hourly, yet analgesiamay not exceed five to six hours.
An unusual property of methadone is its ability toinhibit N-methyl-D-aspartate (NMDA), which is asso-ciated with central excitation in some persistent painstates.16 Clinical studies in patients with cancer do not,however, support the potential benefits seen frombasic science work.17
FentanylFentanyl is 100 times more potent than morphine andthe parenteral preparations are generally only used inareas of close continual monitoring. As fentanyl is 500times more lipophilic than morphine, it can be admin-istered by the sublingual (Abstral), buccal (Actiq,Effentora), nasal (Instanyl and PecFent) and transder-mal (Durogesic, Fentalis, Matrifen, Mezolar, Osmanil,Victanyl) routes. These latter routes are valuable inthat the transdermal preparation gives up to three daysof potent analgesia, while the buccal preparationworks very rapidly to control the onset of severe break-through pain.
Since the transdermal preparation is available in areservoir or matrix formulation, it is best to continuewith the type initially used as bioavailability may varybetween products.
Transdermal fentanyl is now available as a 12µgpreparation, allowing for greater ease of titration,especially in the patient where side-effects may beproblematic.
Instanyl is an intranasal spray of fentanyl availablein 50–200µg dosage. Since it works like buccal fen-tanyl (through mucous membranes) its onset timeis fast and the same precautions apply. As there isvariable bioavailability, dosage must be titrated toeffect.
PecFent is a gel-based nasal fentanyl spray forbreakthrough cancer pain. It is available as 100 or400µg dosage per spray, in a pectin-based gel. Thisavoids a high peak plasma level of fentanyl but releasesthe fentanyl over an hour.18
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Table 4. Side-effects that may occur when treating severe pain with opioids
Side-effects are most common when an opiate dose is being increased rapidly – they should be anticipated, analysed and treated promptly
Respiratory depression
• opioids reduce the sensitivity of the central chemoreceptors to CO2• pain is a natural antagonist to this effect• if patients are tachypnoeic, opiates reduce the rate but increase the depthof respiration
• if rate is less than 10 breaths per minute, discontinue administration; nalox-one if cyanosed, unrousable or rate less than 6 breaths per minute
Sedation and euphoria
• usually beneficial in the acute situation• if excessive, respiratory obstruction may occur, particularly if the patient islying supine and/or snoring
• dysphoria can occur as well as euphoria
Constipation
Nausea and vomiting
• opioids stimulate the chemoreceptor trigger zone
Smooth muscle effect
• increase in circular smooth muscle tone in bile ducts and ureters
Cardiovascular effects
• peripheral vasodilatation and postural hypotension
Histamine release
• common with morphine, includes occasional urticaria, vasodilatation andbronchoconstriction
If the patient is very ill they are likely to be sensitive to small changes in opioid dose, especially if opioid naive. Are the signs and symptoms secondary to the opiate or the disease?
Like the buccal route, the nasal route of fentanyladministration is not recommended by the author forchronic noncancer pain.
Table 6 gives approximate equivalent doses of thevarious opioids available.
Opioids with partial mu receptor activityBuprenorphineThis partial agonist has 30 times the potency of mor-phine. Buprenorphine binds intensely to the mu recep-tor, although its intrinsic activity is low.6 It undergoeshigh first-pass liver metabolism if swallowed, but dueto its high lipid solubility (200 times that of morphine)it is readily absorbed from the oral mucosa. Due to thisfeature it is very effective when administered sublin-gually (Temgesic) or as a transdermal preparation.
Unlike the stronger buprenorphine transdermalpreparations (Transtec 35, 52.5 or 70µg per hour deliv-ery over three days), the lower-dose preparations havea seven-day duration of action and can be introducedat an earlier stage in pain management (BuTrans 5,10 or 20µg per hour delivery).
Although buprenorphine can also be adminis-tered parenterally, the rapid rise in drug plasma levelstends to be associated with more side-effects, includ-ing respiratory depression that is not reversible by theadministration of naloxone, so that other respiratorysupport measures may be necessary. Sedation andnausea tend to be worse than that seen with morphinebut euphoria is less common.
Pentazocine and meptazinolThese partial agonists are not widely used. Pentazocineis available for oral administration (50mg every threeto four hours), or parenterally 30–60mg every threeto four hours. It is associated with particularly unpleas-ant side-effects such as hallucinations and deperson-alisation (6–10 per cent).6
Meptazinol (Meptid) can be administered par-enterally or orally, the oral dose being 200mg three tosix hourly, the iv dose 50–100mg two to four hourly.
These drugs have partial mu and kappa receptoractivity, and when given to patients on established muagonists may induce withdrawal symptoms.
TramadolTramadol is considerably less potent than morphineand, although it has some opioid activity, the majorityof its efficacy is through noradrenaline and serotoninreuptake inhibition. Parenteral and oral preparationsare available, the latter as an immediate- or sustained-release product. Typical adult dosing is up to 400mgper day. If side-effects such as sedation or nausea are
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problematic, the compound preparation of paraceta-mol with tramadol (Tramacet) may be better tolerated.
Tramadol has considerably less potential for abusethan most of the other potent analgesics, such as puremu agonists. Since it lowers seizure threshold it is bestavoided if there is a history of epilepsy.
Tramadol should be used with caution in patientswho concurrently take tricyclic antidepressants, asthey have a similar mechanism of action. For the samereason, their concurrent use with MAOIs should beavoided.
TapentadolTapentadol is a potent opioid but with actions at bothmu and noradrenergic sites.7,8 It does not have anyaction at the serotonin receptor and so is devoid ofseveral of the side-effects seen with tramadol use. Theoral analgesic equivalent dose of morphine 20mg oroxycodone 10mg is tapentadol 50mg. The dual actionof tapentadol may be valuable in the management ofneuropathic pain, but if being used in chronic painstates slow-release tapentadol is the preferred product.
It should be noted that the action of tapentadol isindependent of liver activation, unlike tramadol andcodeine, and to date no active metabolites have beenidentified.
Routes of administrationWhen pain is acute and severe, the iv administrationof analgesia is preferable since there is a rapid onsetand the ability to quickly titrate the dose to thepatient’s needs. This should not be a problem in a hos-pital or hospice situation. Acute severe pain in thecommunity is problematic in that a clinician is gener-ally not immediately available to administer iv analge-sia. However, the iv route is still preferable for acutepain, such as that due to MI.
An alternative for those who suffer from acute exac-erbations of chronic pain, such as chronic pancreatitis,is buccal fentanyl, which has a rapid analgesiconset.19,20 A 400µg lozenge has similar potency to 4mgiv morphine or 12mg oral morphine. However, it isessential that careful selection criteria, goals and lim-itations in the availability for individuals are madebefore prescribing rapidly acting opioids to minimisetolerance. Buccal fentanyl has been shown to reducethe number of calls for primary-care physicians, as wellas calls to accident and emergency departments,because of pain.21
If pain is chronic the oral route is often preferred,but to prevent plasma levels rising and falling rapidlythroughout the day, 12- to 24-hourly preparations arepreferred. An alternative is to consider fentanyl or
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Table 5. Common drug interactions with opioids
All domperidone, metoclopramide antagonism of GI effect CNS depressants enhanced depressant effect anticonvulsants increased opioid metabolism cimetidine reduced opioid metabolism
Dextropropoxyphene warfarin, carbamazepine enhanced effect of interacting drug
Methadone phenytoin faster elimination of opioid rifampicin faster elimination of opioid
Morphine older than 50 years reduced clearance of opioid clomipramine, amitriptyline increased bioavailability of opioid
Pethidine phenobarbital accumulation of norpethidine phenytoin faster elimination of opioid MAOIs CNS excitation, hyperpyrexia and convulsions
Tramadol cardiac glycosides increased risk of digoxin toxicity SSRIs increased CNS toxicity MAOIs sympathomimetic pressor response – this can occur up to 2 weeks after discontinuing the MAOI
Opioid Interaction Effect
buprenorphine patches. These release a lipid-solubleopioid through the skin into the subcutaneous fatfrom where it is absorbed into the systemic circula-tion.22 These preparations are very potent but plasmalevels take 6–12 hours to become therapeutic.Likewise, when the patch is removed a depot of thedrug remains in subcutaneous fat continuing to havean effect for a further 12–24 hours. When a new patchis applied it should be at a different site to the previ-ous one.
Skin temperature affects peripheral blood flow soit is important to be aware that a sustained rise in ambi-ent or body temperature can increase drug uptake sub-stantially – a rise in body temperature of 3°C will resultin an increased absorption rate of 30 per cent.
Practical aspectsRespiratory and cardiovascular depressionDepression of the CNS due to excessive opioid dosingcan be readily reversed by the iv administration of theopioid antagonist naloxone. This agent has a durationof action in the region of 20 minutes so that repeateddosing may well be required, since most opioids havea considerably longer action. Dosage is in the rangeof 0.1–0.4mg, and if given in increments may not nec-essarily reverse all of the analgesia from the opioid. Itis not a particularly effective antagonist for partial-ago-nist analgesics, such as buprenorphine, where othersupportive measures may be necessary.
Naloxone will reverse all side-effects seen with mor-phine, including CNS depression, nausea and itch. Ifgiven to habitual opioid users it will produce markedwithdrawal symptoms, such as abdominal cramps,sweating and agitation.
AddictionExpert opinion leans towards the view that opioidtreatment does not carry a high risk of iatrogenicaddiction in patients suffering chronic pain, publi-cations on co-morbid chronic pain and addictionbeing dominated more by opinion than by evi-dence.23
DrivingLike all sedative medication, opioids are thought toworsen the performance of psychomotor tasks such asdriving. This may well be the case on starting opioids,but when patients in chronic pain use opioid medica-tion for many weeks, this impression has not been con-firmed. In a structured evidence-based review, therewas no evidence of impairment of psychomotor abili-ties immediately after being given doses of opioids, orany consistent evidence for a greater incidence inmotor vehicle violations or accidents in opioid-depen-dent or -tolerant individuals.24
Rather than impairing psychomotor tasks, it hasbeen illustrated that test scores significantlyimproved in patients with chronic back pain duringthe long-term use of oxycodone or transdermal fen-tanyl.25 Long-term therapy with opioids does notinevitably impair complex skills such as driving, butthe decision to permit driving must be made in indi-vidual cases.26
PregnancyThe prescription of any medication during conceptionor pregnancy is best avoided where possible.Manufacturers of NSAIDs recommend avoiding theiruse during pregnancy, especially towards term, sincethey can interfere with closure of the fetal ductus arte-riosus in utero, resulting in persistent fetal pulmonaryhypertension. Babies born to women taking opioidshave about a 50 per cent chance of showing symptomsof drug withdrawal,9 but methadone, buprenorphineand morphine have all been used to treat women seek-ing recovery from opioids without any evidence ofharm to the newborn.27
Opioids appear to be a safe pharmacologicaloption for the treatment of pain during pregnancy,and should be considered if analgesia is needed forsevere pain as they are amongst the least organ-toxicagents.
Renal dysfunctionAlthough the majority of medications used in paincontrol are excreted by the kidney, the initial dose ofmost medications does not need to be reduced inrenal failure: it is the subsequent doses that need to
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Table 6. The approximate potency of various opioids – oral (po) and transdermal(td). This is only a guide – since there is considerable interpatient variation in theresponse to these drugs it is essential to titrate the dose.31,32 atransdermal med-ications are continuously released, so equivalent doses are given as µg per hourbsince tramadol and tapentadol have more than one mode of action, the above 24-hour equivalence dose is not totally related to their opioid activity.
morphine po 30mgcodeine po 240mghydromorphone po 6mgoxycodone po 10–15mgmethadone po 30mgfentanyl td 12µg/hra
buprenorphine td 20–35µg/hra
tramadol po 120mgb
tapentadol po 50–75mgb
Opioid Route Equivalent 24hr dose
be reduced or the time interval between dosesincreased. Opioids such as codeine and morphine areconjugated to glucuronides and these are excreted bythe kidney. If the active metabolites cannot be excreteddue to renal dysfunction, side-effects such as sedation,or worse still respiratory depression, can ensue.
A 25 per cent reduction in morphine dosage is rec-ommended if creatinine levels are 150–300mmol perlitre. At levels above 300mmol per litre it is recom-mended that 25 per cent of the normal dose is usedand at less frequent intervals, but titrated to an appro-priate response.14
Pethidine is normally demethylated to the activemetabolite norpethidine which, although a CNSdepressant, is proconvulsant and tends to accumulatein renal failure. One of the main metabolites of tra-madol, together with the parent drug, accumulatesin renal failure, and methadone and hydromorphone(Palladone) also depend heavily on renal excretion.Although the manufacturers of oxycodone adviseagainst its use in severe renal failure, its half-life isonly increased by one hour in partial renal impair-ment.28
Generic prescribingThere is a general consensus that it is best not toswitch between differing preparations of potent opi-oids, especially transdermal and sustained prepara-tions, as bioavailability may differ to a clinical extent.Some trusts now have specifically listed medications,including opioids, that are unsuitable for generic pre-scribing.29
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Figure 1. Recently introduced tapentadol is active at mu and
noradrenergic sites but not at the serotonin receptor, so is
devoid of some of the side-effects seen with tramadol
Pain Management ProgrammesOver the past few decades the multidisciplinaryapproach to managing difficult, and in particularchronic, pain has led to the establishment of PainManagement Programmes. The aim is to use cognitivebehavioural principles to improve the quality of lifeby educating patients about the physiological and psy-chological aspects of pain, and how self-managementcan help.
This multidisciplinary approach tends to be run ina nonhospital setting with groups of patients workingtogether led by physiotherapists, psychologists andother appropriate healthcare professionals. This canlead to changes in pain beliefs and habits that con-tribute to pain disability.
Further details can be found in the BPS documentRecommended Guidelines for Pain Management Programmesfor Adults.30
ConclusionSevere pain requires swift control. Nociceptive pain,especially that of visceral origin, responds best to opi-oids, preferably by the iv route. Renal colic and jointand bone pain respond better to opioid medication ifused in conjunction with an NSAID due to the highlevels of prostaglandin involved in the initial genera-tion of the nociceptive signal.
Potent opioids should not be withheld in cases ofsevere chronic pain but should be used in accordancewith specialist guidelines mentioned earlier.10
Updated guidelines were published by the BPS in2010;11 in addition to replacing the previous docu-ment, this highlights the limits and hazards in the long-term use of potent opioids. These include theendocrine effect of opioids and their immunosuppres-sion and hyperalgesic effects.
References1. Briggs EV, et al. European Journal of Pain 2011;15:789–95.2. Newton J, et al. Clinical Standards Advisory Group.Services for patients with pain. London: The Stationery Office,1999. 3. Worz R. International Association for the Study of Pain2003;11:1–4.4. Holdgate A, et al. Cochrane Database Syst Rev 2004;1:CD004137.5. Rang HP, et al, eds. Analgesic drugs. In: Pharmacology.Edinburgh: Churchill Livingstone, 1995:609–33.6. Bovill JG. Opioid drugs. In: McCaughey W, et al, eds.Anaesthetic physiology and pharmacology. New York: ChurchillLivingstone, 1997:227–51.7. Schroder W, et al. European Journal of Pain 2010;14:814–21.8. Tzschenke TM, et al. The Journal of Pharmacology and
Experimental Therapeutics 2007;323:265–76.9. Simpson KH. Br J Anaesth 2004;92:326–8.10. Recommendations for the appropriate use of opioids for persistentnon-cancer pain. A consensus document prepared on behalfof The Pain Society, the Royal College of Anaesthetists, theRoyal College of General Practitioners and the Royal Collegeof Psychiatrists. 2004.11. British Pain Society. Opioids for persistent pain: good practice.January 2010. http://bit.ly/NlFLFo.12. Rowbotham MC. The debate over opioids and neuro-pathic pain. In: Kalso E, et al, eds. Opioid sensitivity of chronicnoncancer pain. Progress in pain research and management.Seattle: IASP Press, 1999;14:307–17.13. Dertwinkel R, et al. Clinical status of opioid tolerance inlong-term therapy of chronic noncancer pain. In: Kalso E,et al, eds. Opioid sensitivity of chronic noncancer pain. Progress inpain research and management. Seattle: IASP Press,1999;14:129–41.14. Farrell A, et al. European Journal of Palliative Care 2000;7:201–5.15. Beckwith MC, et al. J Pain Palliat Care Pharmacother2002;16:45-59.16. Callahan RJ, et al. Anesth Analg 2004;98:653–9.17. Bruera E, et al. J Clin Oncol 2004;22:185–92.18. Chaplin S, et al. Prescriber 2011;22(6):20–22.19. Lichtor JL, et al. Anesth Analg 1999;89:732–8.20. Payne R, et al. J Pain Symptom Manage 2001;22:575–83.21. Tennant F, et al. J Pain Palliat Care Pharmacother 2002;16:37–44.22. Kornick CA, et al. Drug Saf 2003;26:951–73.23. Littlejohn C, et al. J R Soc Med 2004;97:62–5.24. Fishbain DA, et al. J Pain Symptom Manage 2003;25:559–77.25. Jamison RN, et al. J Pain Symptom Manage 2003;26:913–21.26. Strumpf M, et al. Schmerz 1997;11:233–40.27. Wunsch MJ, et al. Clin J Pain 2003;19:148–55.28. Kaiko D, et al. Clin Pharmacol Ther 1996;59:130–7.29. Health and Social Care Board. Items unsuitable for genericprescribing. January 2010. 30. British Pain Society. Recommended guidelines for pain man-agement programmes for adults. April 2007. http://bit.ly/QB6kWx.31. Olarte JMN. Clinical pharmacology of opioids: adverseeffects of opioids. In: Sykes N, et al, eds. Clinical pain manage-ment. Cancer pain. 2nd ed. London: Hodder Arnold, 2008:179–99.32. Shaheen PE, et al. J Pain Symptom Manage 2009;38:409–17.
Declaration of interestsDr Campbell has received honoraria from Grünenthalassociated with chairing and presenting data on tapen-tadol, as well as support for attending educationalmeetings from several pharmaceutical companies.
Dr Campbell is consultant in anaesthesia and pain medicine at Ulster Hospital, Belfast
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ResourcesGuidelinesBritish Pain Society. The assessment of pain in older people. National guidelines. October 2007. http://bit.ly/Pxbqb9.
British Pain Society. Opioids for persistent pain: good prac-tice. January 2010. http://bit.ly/NlFLFo.
British Pain Society. Recommended guidelines for painmanagement programmes for adults. April 2007. http://bit.ly/QB6kWx.
Groups and organisationsAction on Pain. National charity providing supportfor patients and carers. Tel: 01362 820750; PainLine:0845 6031593 (Mon–Fri 10am–4pm); e-mail:[email protected]; website: www.action-on-pain.co.uk.
Chronic Pain Policy Coalition. A forum to unitepatients, professionals and parliamentarians in a mis-sion to develop an improved strategy for the prevention,treatment and management of chronic pain. Tel: 0207202 8580; e-mail: [email protected]; website: www.policyconnect.org.uk/cppc.
Pain Concern. Information and support for pain suffer-ers and their carers. Tel: 0131 6695951; helpline: 03001230789 (Mon–Fri 10am–4pm); e-mail: [email protected]; website: www.painconcern.org.uk.
The Pain Relief Foundation. UK charity that fundsresearch into the causes and treatment of chronic painand is concerned with education of health profession-als about pain management. Tel: 0151 5295820; e-mail:[email protected]; website:www.painrelieffoundation.org.uk.
Pain Support. Friendly and informative nonprofitorganisation for those with chronic pain. An inter -active site with a confidential contact club and livelydiscussion page. Website: www.painsupport.co.uk.
Prescription reviewIn 2011, GPs in England wrote approximately 19million prescriptions for analgesics for moderate tosevere pain at a total cost of £268 million. This is an8 per cent increase in volume over 2010 but lessthan 1 per cent in cost. Tramadol remains the most frequently pre-scribed opioid (37 per cent of volume, 18 per centof spending). Its use has increased by 7.5 per centsince 2001. Codeine and dihydrocodeine accountfor 17 and 19 per cent of scrips respectively, withmorphine, buprenorphine, fentanyl and oxycodonetogether making up almost a third of total volume.Use of morphine and buprenorphine has increasedby 15 per cent since 2001 whereas oxycodone pre-scribing has increased by 12 per cent. Tramadol, codeine, dihydrocodeine and mor-phine are the least expensive opioids, with costs perscrip less than £10. Buprenorphine, meptazinol,methadone, pethidine and tapentadol form a sec-ond group ranging in cost per scrip from >£10 to<£40. The most expensive opioids, at £40–£60 perscrip, are diamorphine, fentanyl, hydromorphoneand oxycodone +/- naloxone.
The most expensive formulations of fentanyl arethe buccal tablets and the lozenge (£20–£60 perscrip), with most brands of the spray and patch cost-ing less than £13 per scrip.
Table 7. Number, total cost and average cost per scrip of pre-scriptions for strong opioids, England, 2011
