20 <strong>Australasian</strong> <strong>Anaesthesia</strong> <strong>2011</strong>Pethidine: the case for its withdrawal 21Epidural Pethidine for Post Caesarean AnalgesiaAnother area in which pethidine use is commonly encountered in <strong>Australian</strong> practice is via the epidural route topatients recovering from caesarean section. There have been a small number of papers published on this topic. 32Paech et al demonstrated an advantage of the epidural administration of pethidine over the intravenous route byimproving analgesia, <strong>and</strong> at the same time reducing both side effects <strong>and</strong> total dose requirements. 33A valid alternative to the use of pethidine in this scenario is morphine. Of the comparative studies between thesetwo agents, Roseag <strong>and</strong> Lindsay’s 1994 publication reporting a favourable side effect profile with pethidine is oftencited by clinicians as providing justification for pethidine’s preferential use. 34,35 Patients administered a dose of3 mg epidural morphine had the symptoms of pruritus <strong>and</strong> nausea recorded at a rate 3 times that for those providedwith pethidine via patient controlled epidural analgesia. The high recorded incidences for nausea of up to 56% <strong>and</strong>pruritus up to 84% are seemingly disconcordant with the lower rates observed by experienced obstetric anaesthetistswho regularly administer epidural morphine. Contemporaneous studies of epidural morphine in the obstetric patient(post vaginal delivery, morphine 2.5 mg epidural) report rates for nausea <strong>and</strong> pruritus of only 9% <strong>and</strong> 12% respectively– a clinically tolerable rate which is only modestly increased compared to placebo (5% <strong>and</strong> 6%, respectively). 36Therapeutic advantage from neuraxial opioids can be optimised by paying heed to the highly suggestive natureof itch as a symptom <strong>and</strong> its powerful nocebo (I shall harm) properties. 37 The so called ‘sabotaging’ of care, throughuse of poorly chosen or negative wording, can therefore be prevented when anaesthetists avoid drawing undueattention of patients to the itch induced by neuraxial opioid administration.A number of benefits arise from the use of epidural morphine over pethidine post caesarean section. Morphinenot only provides superior analgesia at rest but importantly also improves dynamic pain relief. 35 This reduction inpain with activity is of high value to mums <strong>and</strong> their wish to participate in the care of their newborn without beinglimited by pain. Epidural morphine allows earlier de-medicalisation of patients encouraging earlier mobilisation <strong>and</strong>so most closely emulates the concepts of modern enhanced recovery after surgery programs. These factors likelycontribute to the higher satisfaction rates reported by mothers receiving morphine compared with those givenpethidine. 35 Finally, in contrast to pethidine, epidural morphine allows immediate decatheterisation of the epiduralspace. This allays the concern held by many obstetric anaesthetists for development of frank bacterial infectionposed by the additive effect of duration of catheterisation upon the frequent presence of bacterial colonisation oflabour epidural catheters. 38Postoperative ShiveringThe incidence of postoperative shivering has declined in recent years. Traditionally, this condition has been treatedby the administration of low dose (25 mg) pethidine, <strong>and</strong> there is no doubt that this is effective. 39However, this effect is not unique to pethidine, <strong>and</strong> in fact any opioid will provide similar relief. Alternatives topethidine that have been studied include clonidine, alfentanil <strong>and</strong> tramadol. Tramadol is often preferred as thefirst-line alternative to pethidine, owing to the lessened risk of hypotension, sedation or respiratory depression thatcan bedevil clonidine or alfentanil use. Tramadol dosed at 1 mg/kg IV is equally effective as pethidine once shiveringis established 40,41 or when administered intraoperatively to hypothermic patients to prevent shivering during recoveryfrom general anaesthesia. 42Allergy to MorphineTrue immune mediated allergy to morphine is rare. Most commonly when morphine appears in the allergy box ofa patient’s chart it represents a simple adverse effect of the drug. Simple urticaria <strong>and</strong> erythema in the skin overlyingthe injected vein is a demonstration of the pharmacodynamic action of morphine <strong>and</strong> is not believed to representan allergy as such. This can be bothersome but is generally harmless.If for whatever reason, morphine is to be avoided then it is worth noting the days of the simple dichotomy ofchoice between morphine <strong>and</strong> pethidine are long past. There are a number of alternative opioids available for usein Australia. For the purposes of this paper’s message, a brief discussion on each is provided:1. FentanylMany clinicians are able to provide effective pain relief with fentanyl. In order to achieve this, it is necessary tobe familiar with the pharmacological challenges of fentanyl. To maintain an effect site concentration of fentanylin the therapeutic range it is necessary to push the pharmacokinetics beyond one determined by the very shortdistribution half-life (t1/2 alpha) to one determined by the much longer elimination half-life (t1/2 beta). This isaccomplished by a generous intraoperative loading dose (+/- 100 – 300 mcg per hour) <strong>and</strong>/or by the provisionof an appropriately sized PCA bolus dose of for example, 20 – 30 mcg five minutely for an average adult. Thepharmacodynamic challenges arise because although fentanyl has profound antinociceptive properties; it canbe a poor analgesic, in the broader sense, for some patients. This is likely due to the weak anxiolytic propertiesof fentanyl (particularly when compared with morphine) <strong>and</strong> so patients do not experience a relief from theirsuffering to such a great extent with the use of fentanyl. Clinicians may have encountered this in their ownpatients who report an ineffectiveness <strong>and</strong> poor satisfaction with fentanyl. A dramatic <strong>and</strong> rapid improvementis often witnessed when such patients are switched to an alternative opioid, like morphine, possessing greateranxiolytic properties.2. Oxycodone.Injectable oxycodone has been available in Australia since 2007. It is simple to administer (having similar numericaldosages to morphine), is as effective as morphine, <strong>and</strong> has a tolerable side effect profile. Clinician preferencefor the use of injectable oxycodone for their patients is increasingly encountered. Use carries the advantage ofsimplicity of dose conversion since oral oxycodone, in immediate release or extended release forms, is a favouredagent for step-down analgesia.3. Hydromorphone.Use in Australia of injectable hydromorphone tends to be limited to chronic <strong>and</strong> cancer pain <strong>and</strong> is infrequentlyadministered in the acute setting. The latter is for no particular reason, other than perhaps simply a lack offamiliarity or perceived need. Hydromorphone use in the perioperative period is commonly encountered in NorthAmerican hospitals. The main downside to hydromorphone is unfamiliarity <strong>and</strong> so potential for confusion withmorphine, leading to drug administration errors. This was the topic of a recent NSW Department of Health SafetyAlert. Orders for hydromorphone are recommended to include use of TALLman lettering (i.e. HYDROmorphone)as well as addition of the commercial name Dilaudid, placed in brackets immediately next to the order.DISADVANTAGES OF PETHIDINE USEMuch has already been published on the complications from pethidine use. The following discussion will aimto summarise that which is already well known <strong>and</strong> provide an extended discussion on issues of current interestto anaesthetists.Pethidine SeizuresThe seizure provoking activity of pethidine is unique as it is the only opioid for which this side effect is encounteredat the doses prescribed for acute pain. Pethidine’s predominate metabolite nor-pethidine is a neuroexcitant, loweringthe seizure threshold. At low blood levels nor-pethidine leads to nervousness, tremor <strong>and</strong> twitching. As nor-pethidineaccumulates <strong>and</strong> blood levels rise the seizure threshold is eventually reached. It is critical to appreciate that evenfollowing the recommended dosage guidelines (upper limit 600 – 1200 mg per day) does not provide surety ofavoiding nor-pethidine toxicity. Seizures have been reported with doses as low as 540 mg/d. 43 In order to preventseizures from nor-pethidine accumulation, pethidine should be avoided in: repeated doses, PCA delivery or in renalimpairment. 44Drug IncompatibilitiesConcomitant use of pethidine with tricyclic anti-depressants, monoamine oxidase inhibitors <strong>and</strong> tramadol hasresulted in serotonin syndrome, a condition capable of causing seizures <strong>and</strong> rarely, death, due to the additive effectof pethidine’s uptake inhibition of a number of neurotransmitters, predominantly serotonin. Patients medicated withthese agents often have an unfavourable co-existence of the psychological conditions that would also make themattracted to pethidine use, making for a dangerous mix.AddictionIt is in the area of addictive potential that pethidine so strikingly st<strong>and</strong>s apart from the alternative opioids. This isparticularly noticeable when compared to the phenanthrene family of opioids of oxycodone, hydromorphone <strong>and</strong>morphine, which all have a similar mid-range addiction potential. 45,46 There is increasing awareness <strong>and</strong> much mediapublicity of oxycodone misuse. The rapid rise in rates of oxycodone misuse is not thought to result from any greateraddictiveness possessed by oxycodone, but rather from the marked increase in prescribing of oxycodone fornon-cancer pain, combined with the large milligram content (e.g. 80 mg) of pharmaceutical-grade purity found inthe extended release formulation often prescribed. OxyContin subsequently has become an ideal agent for diversion<strong>and</strong> supply to the recreational drug market.Pethidine’s two structurally related synthetic phenylpiperidine opioids of fentanyl <strong>and</strong> alfentanil have beenpurported to also possess high addictive potentials, based largely on their pharmacokinetic properties allowingrapid entry into the CNS. Where these two agents diverge from pethidine, <strong>and</strong> hence why there have not been callsfor the removal of these agents, is in the lack of translation of this potential into a high number of reported addictioncases in the general community. This may be due to availability issues, for example: fentanyl <strong>and</strong> alfentanil are notprescribed by general practitioners, whereas pethidine often is, making for a more readily accessible supply source.The exception to this is fentanyl misuse by operating theatre personnel, who, largely on account of their access toa reliable supply source, demonstrate a preference for fentanyl (see below for further discussion).Our knowledge of the powerful addictive qualities of pethidine stems from a multitude of sources. On an individualbasis each piece of information may be argued away, but when drawn together they build a consistent <strong>and</strong> concerningargument.
22 <strong>Australasian</strong> <strong>Anaesthesia</strong> <strong>2011</strong>Pethidine: the case for its withdrawal 23Pethidine HighFor many patients, administration of pethidine produces a profound <strong>and</strong> complex “high” <strong>and</strong> far more so than isexperienced with the alternative opioids. 47 This euphoric high is in addition intensely reinforcing with a greaterpotential to develop an uncontrollable urge to recreate the experience, leading to addiction. Generally, addictionrisk increases with repeated dosing. Pethidine however is so intensely reinforcing that concern is held by addictionmedicine specialists for even a brief exposure to pethidine (as brief as a single dose) because it will conceivably,in individuals with an addictive personality, lead to a highly vulnerable state for opioid addiction (S. Jurd, personalcommunication, 25 August <strong>2011</strong>).Similarities between cocaine <strong>and</strong> pethidineThe stimulant effects of pethidine observed in humans have long been compared to those seen with cocaine. 48This led to the proposal for a non-opioid receptor mediated mechanism to explain at least some of pethidine’sactions. This is supported firstly by experimental research demonstrating incomplete reversal of pethidine actions,including nociception, following administration of opioid antagonists. Further support for a non-opioid receptorinvolvement lies in research with trained monkeys capable of discriminating cocaine from saline, whereby thesimultaneous administration of pethidine <strong>and</strong> the mu-antagonist naltrexone led to a response in the monkeysidentical to that seen with cocaine. 49The cocaine <strong>and</strong> pethidine molecules share a number of structural features, including a piperidine ring, whichare thought responsible for their similar actions. Notably, pethidine <strong>and</strong> cocaine have comparably high potenciesfor dopamine uptake inhibition in rat brains. Morphine was found to be devoid of such actions. Dopamine is heavilyimplicated in the neurobiology of addiction <strong>and</strong> so pethidine’s actions to inhibit dopamine uptake to a similar degreeas cocaine may explain its strong addictive potential. 50Lessons learnt from use in chronic painPethidine is not recommended for use in chronic pain states owing to the high likelihood of developing addiction. 51Of all the patients who present to pain clinics, it is those who have been maintained on pethidine that are notoriouslymore difficult to manage. Weaning of pethidine injections is far more difficult than for alternative opioids <strong>and</strong>additionally is rarely accomplished without inpatient admission <strong>and</strong> close supervision of dosing. Pain medicinespecialists left to deal with such patients do so needlessly since the patients could – <strong>and</strong> should – have beenmanaged with a less addictive agent in the first instance. The anaesthetists who are frequently the initial prescribersof pethidine are rarely involved in the subsequent management of the patient many weeks or months later <strong>and</strong> soremain unaware of the harm caused by their actions.Expert OpinionAddiction medicine is a field in which there is not the ability to conduct large r<strong>and</strong>omised controlled trials orFramingham-styled longitudinal studies of the type we have grown accustomed to in other fields of medicine <strong>and</strong>so we are heavily reliant on expert opinion. This expert opinion is overwhelmingly to avoid the use of pethidine,owing to the greater risk of addiction. Some anaesthetists express their own counter opinion of pethidine use posingno greater risk of addiction than any other opioid based on their absent recollections of addiction seen in their ownpatients following many years of pethidine prescribing. Such assertions are challengeable on the basis of naivety.Given that the interaction between anaesthetist <strong>and</strong> patient is usually relatively brief <strong>and</strong> at best episodic, it cannot be expected that anaesthetists would consistently conduct a thorough assessment of their patient’s psychosocialhistory capable of uncovering the intimately personal nature of addictive behaviour toward opioids.Medical profession misuseDoctors detected to be self-administering opioids display a preference for the misuse of pethidine over morphine.In the often-cited review of Cadman <strong>and</strong> Bell, pethidine was the main opioid abused by 84% of doctors disciplinedby the <strong>New</strong> South Wales Department of Health. 52 Self-administering doctors brought to the attention of the authoritiesst<strong>and</strong> the greatest chance of successful rehabilitation, however the associated mortality rate is still high at 13%.Far more concerning is the doctors who do not receive treatment for their addiction. For these doctors, particularlyanaesthetists, the anecdotal experience is of a significant number to have their first presentation of opioid abusein the form of a fatality (G Knoblanche, personal communication, May <strong>2011</strong>). Up until the 1980s, pethidine was theabusing anaesthetist’s drug of choice, reflecting that of the medical <strong>and</strong> nursing professions as a whole. 53,54 Then,with the introduction of fentanyl came a change in behaviour of anaesthetists, with fentanyl replacing pethidine asthe most common opioid of abuse by anaesthetists. 55This change in preference to fentanyl away from pethidine by anaesthetists is ascribed to a number of reasons.Firstly, the increased awareness <strong>and</strong> vigilance for aberrant pethidine prescribing makes diversion without drawingsuspicion quite difficult. Secondly, fentanyl is presented in ampoules containing very high doses <strong>and</strong> is indeed oftenadministered in very high doses. Diversion of even small proportional quantities therefore can readily go unnoticed,but are still of sufficient potency to provide reward to the abuser. For example, the intentional diversion of 100 mcgout of a 500 mcg ampoule intended for a patient will have barely detectable consequences for the patient whilstproviding a substantive effect for the abusing anaesthetist. Finally, an anaesthetist under the influence of fentanylis capable of a higher degree of function than if using pethidine. 56 The present-day preference away from pethidineby anaesthetists does not now justify an attitude of complacency. Instead it should be viewed as evidence of theeffectiveness of strategies to date, but strategies that need to be enhanced in order to reduce the rate of pethidineabuse still further.
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