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Vol 119 No 1230 ISSN 1175 8716 Should New Zealand continue signing up to the Pethidine
Protocol?

Pethidine is no longer considered a first-line analgesic. The evidence for this view iscritically presented. Clinicians around the World recommend its removal from health-systems or restriction of its use. New Zealand needs to follow these trends.
Pethidine (meperidine) is still widely used in New Zealand by general practitioners,accident and emergency units1, and surgical and maternity suites.2 Ninety-six percentof obstetric facilities in New Zealand have access to intramuscular pethidine.3Pethidine is often a preferred analgesic by both patients and physicians in thetreatment of migraines. In the light of recent evidence, there is a movement globallyto replace pethidine with more efficacious and less toxic opioid analgesics.4 In NewZealand, is pethidine a second-line agent with first-line prescribing practices?5 The initial studies demonstrating the analgesic efficacy of pethidine were mostly casereports and not double blind, randomised, controlled trials in specific populations.4Subsequent comparative studies failed to demonstrate any advantages of pethidineover comparable doses of other analgesics.1,4 There is no conclusive evidence thatpethidine is a superior or safer alternative to morphine.6 In a meta-analysis of the use of intramuscular pethidine (100 mg) for treating acutepostoperative pain, the numbers-needed-to-treat (NNT) to produce at least 50% painrelief was 2.9 (95% confidence interval: 2.3–3.9).7 Pethidine is an effective analgesicfor treating acute pain. But at this dose (100 mg), pethidine produced significantlymore drowsiness and dizziness than placebo, with numbers-needed-to-harm (NNH) of2.9 (2.2–4.4) and 7.2 (4.8–14), respectively.7 Opioids remain the main contributors to acute perioperative pain relief especially inprocedures giving rise to moderate or severe pain. The modern use of basicmultimodal pharmacological analgesia (local anaesthetics, non-steroidal anti-inflammatory drugs [NSAIDs], paracetamol, alpha-2 adrenergic agonists withopioids) minimises doses of opioids needed and provides optimal acute perioperativepain relief in most patients.
Biliary and renal colic
Pethidine is widely used in the treatment of biliary and renal colic and in pancreatitis.
There is an historical belief that morphine causes more biliary spasm than pethidine.6Studies using endoscopic retrograde cholangiopancreatography with direct sphincterof Oddi manometry demonstrated that the sphincter of Oddi is sensitive to all opioids NZMJ 10 March 2006, Vol 119 No 1230 including pethidine.9 Other studies have clearly demonstrated that pethidine is nomore efficacious in treating biliary or renal tract spasm than comparative mu opioids.4 The sphincter of Oddi is equally sensitive to all opioids, at equianalgesic doses.10NSAIDs have been found to have similar efficacy to pethidine in the management ofacute biliary colic with a decreased number of adverse effects.11,12 Similar efficacy was found between pethidine and morphine in the management ofacute renal colic.13 A recent study showed the use of opioids to be associated with ahigher incidence of adverse events, particularly vomiting with pethidine.14 It did notrecommend the use of pethidine in the management of acute renal colic.14 NSAIDsmay be used instead, however.15 Labour pain
Many clinicians use pethidine to help decrease pain during labour. The mostimportant reason for the widespread use of pethidine during dystocia in the activemanagement of the first stage of labour was an increase in uterine contractility foundin many observational studies with pethidine.16 However, recent studies clearly showthe absence of such an "oxytocic effect" with pethidine.16 It is recommended that pethidine should not be used during labour for this specificindication.16 In addition, there are considerable doubts about the analgesiceffectiveness of pethidine and concerns about its potential maternal, foetal, andneonatal adverse effects.17 In one study, intravenous pethidine provided effective painrelief in only 24% of subjects in the first stage of labour.18 Repeated maternaladministration of pethidine results in significant foetal exposure and neonatalrespiratory depression.19 Maternal administration of pethidine with promethazine has a significant effect onfoetal heart rate indices during the active phase of normal labour.20 Pethidine hasrelatively long-acting behavioural and neurological effects in the newborn due to itsslow elimination.21 As a result, breastfeeding is delayed and the mother-infantinteraction is disturbed. There is concern about the routine administration of pethidinein this context.21 In obstetric analgesia in labour, increasing use is made of neuraxial combinations oflocal anaesthetics and opioids (ropivacaine, levobupivacaine, bupivacaine withfentanyl, sufentanil)22,23 and the utilisation of patient controlled epidural analgesia.24Remifentanil has been suggested as an ideal opioid for patient-controlled analgesia(PCA) in labour, but its safety profile has not been established.25,26 Repeated administration of pethidine, in contrast to morphine, affects the sucklinginfant negatively. Safer alternatives to pethidine should be considered in lactatingmothers.25 The use of morphine should be preferred.27 It has been suggested that thecourse of behavioural maturation during certain periods of infancy is influenced bypethidine administration at birth.28 Chronic pain
Recommendations from the Agency for Health Care Policy and Research (AHCPR),an organisation which has defined standards of care for acute and chronic painmanagement, contraindicate the use of pethidine in chronic pain.5,29 Patients reliant on NZMJ 10 March 2006, Vol 119 No 1230 regular pethidine for chronic non-malignant pain, require multidisciplinaryassessment and management. A quality improvement approach using a traditionalplan-do-check-act (PDCA) model can help reduce the inappropriate use ofpethidine.30 Tramadol can be an effective and well-tolerated alternative for the management ofchronic pain of malignant or non-malignant origin, particularly neuropathic pain.
Nausea is the most common adverse effect of tramadol with an incidence of 6.1% fororal administration and 20.7% for patient-controlled analgesia.31 To reduce nauseaand vomiting, a slow intravenous injection (over 1–3 minutes) and initial low dosesfollowed by gradual dose increases (go low, start slow) are used. 31 Tramadolproduces less constipation and dependence than equianalgesic doses of strongopioids.32 Pethidine has molecular pharmacological features of a local anaesthetic (sodiumchannel blocker) in addition to its opioid properties.33 Because of its intermediatelipid solubility, pethidine may have advantages over many other epidural opioids. It isan effective epidural opioid for the treatment of acute pain. Its use has been welldescribed in Australian and New Zealand practice, particularly in the field of obstetricanaesthesia.34 Epidural pethidine is efficacious as an analgesic for post Caesareansection pain control.35 However, the potential for accumulation of norpethidine limitsits use to relatively short durations of treatment.
The use of intrathecal opioids, including pethidine, does not significantly affect thenatural progression of labour, and no adverse foetal outcomes have been reported.36Pethidine has been used as the sole intrathecal agent for spinal anaesthesia37 but hasno real advantages over lignocaine.38 Postoperative shivering consists of muscular tremor and rigidity. Pethidine has beenused to decrease the incidence and intensity of shivering associated with general orspinal anaesthesia.39,40 Other alternatives include clonidine and tramadol. Intravenoustramadol 1 mg/kg has been found to be more effective for the treatment ofpostoperative shivering than pethidine 0.5 mg/kg.41 Pethidine is a phenyl-piperidinic synthetic drug, used in the management of moderateto severe pain. It has been widely used since its introduction in the 1930s.42 In theUnited Kingdom, pethidine became the most commonly used opioid in hospitals.43Pethidine was initially synthesised as an anticholinergic agent but was soondiscovered to have analgesic properties.4 It was introduced as a drug lacking many ofthe adverse effects of morphine such as respiratory depression, urinary retention,constipation, and chemical dependency. None of these claims have beensubstantiated.6 Pethidine, ethyl-1-methyl-4-phenyl-piperidin-4-carboxylate, is a predominantly mu-receptor agonist.34 It can be administered orally or parenterally. Pethidine has aplasma half-life of 2.5-4 hours with a similar duration of analgesic effect (shorter than NZMJ 10 March 2006, Vol 119 No 1230 morphine).34,44 Reported methods of parenteral delivery include bolus injection,continuous infusion, and patient-controlled epidural analgesia.2 Pethidine has poor oral bioavailability, and is metabolised extensively by the liver.1 Inrecent years, the use of pethidine has diminished because of the toxicity of one of itsseveral metabolites. A long-term oral or systemic pethidine administration can giverise to an accumulation of the hepatically formed metabolite, normeperidine. Thisactive metabolite is neurotoxic due to its ability to increase serotonin (andnoradrenaline) in the central nervous system.10 Toxicity usually results from excessive intrasynaptic serotonin.45 Such elevations arelikely to occur with high doses of pethidine, prolonged administration of pethidine,decreased excretion of normeperidine in patients with impaired renal function, andincreased hepatic metabolism of pethidine in patients receiving medications thatinduce hepatic enzyme systems.46 The opioids, tramadol, methadone and dextromethorphan and propoxyphene, appearto be weak serotonin re-uptake inhibitors, and have all been involved in serotonintoxicity reactions (discussed later).45 Normeperidine is half as potent an analgesic as pethidine, but is two to three timesmore potent as a convulsant.47,48 The intensity of the central nervous system excitationis highly correlated with the plasma concentration of normeperidine.47 Symptomsrange from irritability, restlessness and agitation, to myoclonias, tremors, jerking,confusion, and convulsions.49 Due to normeperidine's extended half-life (14–21hours), accumulation of normeperidine can occur in any patient receiving repeateddoses of pethidine.10 The presence of active metabolite norpethidine with its increasedelimination half-life in patients with poor renal or hepatic function makes the routineuse of pethidine ill advised in these patients.50 Another impurity may be present in pethidine. It is N-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), a synthetic substance derived from the hydrolyticdegradation of an ester group.2 MPTP is a very toxic compound, implicated as thecause of severe and irreversible Parkinsonian symptoms. This impurity causes thedestruction of nigrostriatal dopamine neurones, leading to symptoms that closelyresemble those present in human idiopatic Parkinson's disease.2 Despite extensivepurification of pethidine, the drug may still contain traces of MPTP.
The most frequently reported adverse effects with pethidine are drowsiness,somnolence, dizziness, lightheadedness, nausea, and vomiting.7 In a recent evaluation,the usage patterns and frequency of adverse drug reactions with pethidine—centralnervous system effects (confusion, anxiety, nervousness, hallucinations, twitching,and seizure)—were documented in approximately 14% of patients.51 Patients using patient-controlled (PCA) pethidine were at particularly high risk ofexperiencing adverse drug reactions based on cumulative doses and duration oftreatment.51 There is a significant association between pethidine (odds ratio 2.5, p <0.01), and delirium in elderly hip-fractured patients.52 Thus, pethidine should not be NZMJ 10 March 2006, Vol 119 No 1230 used in this group of patients. In addition, hypotension, tachycardia, and erythemamay occur with pethidine due to release of histamine from mast cells.49 Pethidine has vagolytic (atropine-like) effects on heart rate53 giving rise totachycardias and arrhythmias in patients after myocardial infarction or withsupraventricular tachycardias.6 The use of morphine would be preferable in the acutecoronary syndrome. For premedication in children, profound anticholinergic effectsfollow the intravenous administration of pethidine with atropine or glycopyrrolate.54Such combinations are not suitable for clinical purposes.
The serotonin syndrome is caused by excess serotonin (5-hydroxytryptamine; 5-HT)availability in the central nervous system at the 5-HT1A-receptor.55 It is characterisedby a constellation of symptoms (confusion, fever, shivering, diaphoresis, ataxia,hypereflexia, myoclonus, or diarrhoea).55 Pethidine has the potential to induce aserotonin syndrome when used together with other agents. The syndrome may resultfrom coadministration of pethidine with dextromethorphan, pentazocine, tramadol,tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), andmonoamine oxidase inhibitors (MAOIs).53 Even the combined use of moclobemidewith pethidine should be avoided.56 Several fatal reactions have been reported with the coadministration of pethidine withthe MAOIs.6 Pethidine should not be used within a 14-day period of stopping aMAOI.6 Furthermore, commonly used drugs (such as theophylline, tricyclicantidepressants, and the fluoroquinolones) can potentiate the seizure potential ofpethidine.9 Pethidine possesses a high potential for abuse. Pethidine, similar to other opioidsproduces euphoria in some patients, providing the motivation for abuse, which can bedetrimental even with occasional use.57 Treatment of acute migraine headaches withpethidine is potentially ineffective and may lead to abuse.58 Pethidine addiction by medical personnel, however, seems to be an occupationalhazard.6,59 In New South Wales, from 1985 to 1994, 79 doctors had their drugauthorities withdrawn for opioid addiction.55 Pethidine was the main drug used (66doctors or 84%).60 Other opioids (morphine, fentanyl, sufentanil) can also give rise tosubstance-use disorders amongst physicians.61 Fentanyl and sufentanil are the opioids of choice for anaesthetists.62 In all of thesecases, toxicological investigations are difficult as half-lives of the compounds areshort, and the circulating concentrations weak.62 Pethidine is a widely used opioid by virtue of its familiarity and low cost.63 But itlacks potency, has a short duration of action (half life 3–4 hours), and a narrowtherapeutic index .43 Equianalgesic doses of pethidine when compared to morphine are as follows:pethidine 100 mg intramuscularly/intravenously (or 400 mg orally) is equianalgesic to NZMJ 10 March 2006, Vol 119 No 1230 morphine 10 mg intramuscularly/intravenously (or 30 mg orally).64 In controlledtrials, its analgesic efficacy has rarely proven superior to alternative opioids.1 Inaddition, clinical evidence shows that pethidine has no advantages over other opioidsfor the treatment of biliary or renal colic or of pancreatitis.42 The metabolism of pethidine gives rise to a neurotoxic metabolite norpethidine thataccumulates due to its longer half-life.6 Therefore, pethidine should only be used forshort intervals to treat acute pain (24–48 hours).65 It should not be used with renaldysfunction. Another disadvantage is that it is vagolytic. The use of pethidine iscomplicated by dangerous drug interactions that include serotonergic crises. It is notindicated in the management of chronic pain.
Pethidine is no longer considered a first-line analgesic. It has no unique clinicaladvantages over other stronger opioids (morphine, oxycodone).4 Its poor efficacy,toxicity, and multiple drug interactions have resulted in many clinicians around theWorld recommending that pethidine be removed from health-systems or that its usebe restricted.42 Surely, it is time for clinicians in New Zealand to re-evaluate itswidespread use? Author information: Edward A Shipton, Academic Head and Chair, Department of
Anaesthesia, Christchurch School of Medicine, University of Otago, Christchurch
Correspondence: Professor EA Shipton, Department of Anaesthesia, Christchurch
School of Medicine, PO Box 4345, Christchurch. Fax: (03) 357 2594; email:
ted.shipton@cdhb.govt.nz
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11. Dula DJ, Anderson R, Wood GC. A prospective study comparing i.m. ketorolac with i.m.
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NZMJ 10 March 2006, Vol 119 No 1230

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Primary prevention of breast cancer: state of the art in 2012 Fabienne Liebensa*, Birgit Carlya, Pino Cusumanob, Virginie Lienarta, Serge Rozenberga a ISALA Breast Unit and Prevention Center, OBGYN department, CHU Saint Pierre, Brussels, ULB-VUB. bBreast Unit, CHC Saint Joseph and CHU Sart Tilman, Liège, ULg *Corresponding author: Fabienne Liebens MD, ISALA Breast Unit and Prevention Center, CHU Saint Pierre, 290 rue Haute, 1000 Bruxelles.

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Critical Care Medicine Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit Juliana Barr, MD, FCCM1; Gilles L. Fraser, PharmD, FCCM2; Kathleen Puntillo, RN, PhD, FAAN, FCCM3; E. Wesley Ely, MD, MPH, FACP, FCCM4; Céline Gélinas, RN, PhD5; Joseph F. Dasta, MSc, FCCM, FCCP6; Judy E. Davidson, DNP, RN7; John W. Devlin, PharmD, FCCM, FCCP8; John P. Kress, MD9; Aaron M. Joffe, DO10; Douglas B. Coursin, MD11; Daniel L. Herr, MD, MS, FCCM12; Avery Tung, MD13; Bryce R. H. Robinson, MD, FACS14; Dorrie K. Fontaine, PhD, RN, FAAN15; Michael A. Ramsay, MD16; Richard R. Riker, MD, FCCM17; Curtis N. Sessler, MD, FCCP, FCCM18; Brenda Pun, MSN, RN, ACNP19; Yoanna Skrobik, MD, FRCP20; Roman Jaeschke, MD21

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