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NEWSLETTER OF THE NORTH BRITISH PAIN ASSOCIATION - SPRING 2004

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REPORT FROM WINTERSCIENTIFIC MEETING

Due to shortage of space, this is a fairlysuccinct report of the Winter meeting, whichis in no way a reflection of the quality of thetalks or my note taking. The day was kindlysupported by Pfizer, Napp, MSD and JanssenCilag. The theme was “Pain – AnInflammatory View”. Professor Iain McInnes,

FROM THE EDITOR

Welcome to the Spring 2004 edition of Threshold, brought to you with the support of Pfizer pharmaceuticals. In this issue, as wellas the regular features, there are two articlessubmitted by NBPA members. I am verygrateful to Gail Gillespie, the current GlasgowPain Management Fellow, who has compiledan up to date report on NSAIDs and the newgeneration of COX 2 inhibitors. In addition,Claire Dunlop, Senior CharteredPhysiotherapist at the Astley Ainslie painmanagement programme has written anaccount of the Fourth Congress of theEuropean Federation of the InternationalAssociation for the Study of Pain, held inPrague, which she attended in September2003. Her visit was supported by a travelinggrant from the NBPA and we are delighted tohear that she found the conference so usefuland interesting.I hope you enjoy the rest of this issue.Please send any suggestions or submissionsto me at the address below.Dr Colin P. Rae,Department of Anaesthesia,Stobhill Hospital,133 Balornock Road,Glasgow,G21 3UW.Tel no 0141 201 3005.Fax no 0141 201 4167.Email colin.rae@northglasgow.scot.nhs.uk Website www. nbpa.org.uk or www.nbpa.ac.uk

Professor Iain McInnes and Dr. Donald McMillan Drs Susan Nimmo and Michael Basler Dr Janet Braidwood, Sister Anne Kelly and Dr. Dick Davidson Lamb Professor Iain McInnes, Dr. Mick Serpell and Professor Mary Norval

Professor of Experimental Medicine atGlasgow Royal Infirmary, started with anoverview of the role that inflammation and theimmune system play in various diseaseprocesses. He concentrated initially onrheumatoid arthritis (RA), which as well ascausing a great deal of morbidity, has asignificant 5 year mortality if more than thirty joints are affected. Recent research hasconcentrated on the role of cytokines,interleukins and TNFa in the inflammatoryprocess within rheumatoid joints. He finishedwith the optimistic note that perhapsrheumatoid arthritis will be a curable ratherthan a managed disease, within the nextdecade.Professor Mary Norval, from theDepartment of Medical Microbiology at theUniversity of Edinburgh, followed with avirologists view on post herpetic neuralgia(PHN). She initially reviewed the cause,clinical presentation, epidemiology andpathophysiology of PHN. 200,000 people inthe United Kingdom have PHN at any onetime. Pain usually resolves 4-6 weeks after therash disappears. Approximately 10-15% of patients will develop PHN and more than 50%of PHN cases are in the over 60-age group.Only two risk factors for the development of PHN have been identified; increasing age andthe presence of prodromal symptoms. Thelevel of varicellar antibodies or cytokines doesnot influence the incidence of PHN. Theredoes seem to be a seasonal variation in theincidence of PHN, which might be explainedby ultra violet light suppressing cell-mediatedimmune responses.Dr. Donald McMillan from the UniversityDepartment of Surgery at Glasgow RoyalInfirmary gave the third lecture, “AnInflammatory View of Cancer”. His main areaof research has been into the weight loss andcachexia associated with cancer. He explainedthat you could think of a tumour as a woundthat will not heal. The traditional view is thattumours are associated with an increasedenergy demand and produce toxins that causeanorexia and thus cachexia. The increasedresting energy expenditure may explain thefatigue suffered by cachectic patients. Morerecently, the view is emerging that cancercauses both a chronic inflammatory responseand a release of products which together resultin metabolic abnormalities such as lipolysis,

DATES FOR YOUR DIARY

Winter Scientific Meeting

Friday 5th November 2004

Spring Scientific Meeting

Friday 6th May 2005

NSAIDS and COXIBS- What’s new?

Dr. Gail GillespieSpecialist Registrar in Pain ManagementGlasgow

The discovery of cyclooxygenase (COX)-2provided the rationale for the development of the new class of non-steroidal anti-inflammatory drugs (NSAIDs), the selectiveCOX-2 inhibitors or ‘Coxibs’. Their aim wasto reduce toxicity associated with theadministration of NSAIDs, by virtue of theirCOX-1 sparing effects.

First Generation Coxibs

Rofecoxib and celecoxib were the firstselective coxibs. They are both effectivemeans of acute pain relief.(1) Celecoxib is7.5 times more selective for COX-2 thanCOX-1. Rofecoxib is 35 times more selectivefor COX-2. (2)

Second Generation Coxibs

Recently, other selective coxibs withdifferent COX-1/COX-2 selectivity andpharmacokinetic features have beendeveloped: valdecoxib, parecoxib, etoricoxiband lumiracoxib. Valdecoxib is twice asCOX-2 selective as celecoxib in vitro. Theclinical relevance of this is unclear.Parecoxib, a pro-drug of valdecoxib, is theonly injectable Coxib.Lumiracoxib is the most selective COX-2inhibitor in vitro being 400 times moreselective for COX-2. It is unusual in that it isthe only acidic coxib. Theoretically, thisshould allow high concentrations to penetrateinflammatory sites and thus improve efficacy.This is still to be clarified in vivo.

GI toxicity:

NSAID-associated GI side effects represent25% of all drug side-effects reported to theFDA. 2-4% of chronic NSAID users willdevelop upper GI bleeding, symptomaticulceration or perforation each year. (3) Coxibshave been demonstrated to halve the incidenceof serious upper GI events as compared to non-selective NSAIDs. (4)(5)

Cardiovascular toxicity:

In theory, there are pathophysiologicalmechanisms which could explain whyselective cox-2 inhibition might increasecardiovascular risk: namely, that coxibs may

NEWS FROM COUNCIL

At the last council meeting, several councilmembers intimated their intention to standdown from council. Those stepping down areDr. Ruhy Parris, Secretary, Dr. Alan Semple,Treasurer and Sister Anne Kelly, nursing andEast of Scotland representative. All haveworked hard on behalf of the NBPAmembership over several years. Specialmention must go to Anne who is the longestserving council member and whose ideas,sense of humour and hard work will be sorelymissed. Nominations for replacements will besought at the AGM in May.Council would like to thank BernhardFrank from Newcastle for donating £250 topurchase the NBPA website address fromNewcastle University. At present bothaddresses above will direct you to the NBPAsite.There have been further discussions aboutthe NBPA annual essay competition. It maybe that the prize money will be increased forthe 2005 competition so all interested partiesshould pay attention on May 7th.Many of you will be aware that ProfessorMcEwan has been asked by the ScottishExecutive to survey the current status of PainServices in Scotland. All submissions havebeen sent and we await his report with interest.The Cross Party Working Group onChronic pain at the Scottish Executivecontinues to meet, convened by Dr. JeanTurner MSP. The fact that there is norepresentation from the NBPA on this groupwas highlighted at the last council meeting.Following this, the convenor, Dr. Jean Turnerhas approached council members and askedif representatives could attend, and make apresentation to, the next meeting of the group,towards the end of April. Any developmentsas a result of this will be circulated tomembers.have prothrombotic activity by tipping thebalance in favour of thrombaxane A2 overprostacyclin, resulting in an increase tendencyfor vascular occlusion and tissue ischaemia.The annualized myocardial infarction rate forCoxibs in both the VIGOR(6) and theCLASS(7) trials was higher with roficoxib andcelecoxib than placebo. However, aspirintherapy was withheld in the VIGOR study, andlarger studies using rofecoxib have shown noincrease in MI rates. Therefore, the actual levelof evidence demonstrating an increased risk is weak.It seems that highly selective coxibs mayincrease the risk for cardiothrombotic eventsonly in those at-risk patients who are nottaking aspirin. The best way of safely co-administering aspirin and coxibs in this groupof patients is as yet unknown. Further studiesare required to look specifically at cardiac risk.

Overall:

The results of clinical trials have shownthat coxibs have a comparable clinical efficacyand renal toxicity and an improved GI safetyversus nonselective NSAIDs. Whether thedifferent pharmacodynamic andpharmacokinetics features of the variouscoxibs will produce detectable differences inefficacy and toxicity remains to be evaluatedin appropriate comparative randomizedclinical studies.Bandolier describes the ‘Oxford leaguetable of analgesics in acute pain’.This is a table based on the number-needed-to-treat (NNT) that was constructedfrom information gathered from systematicreviews of randomized double-blind placebo-controlled trials.Outcome was 50% or more pain relief over4-6hrs using validated standardized painmeasurements.Although it is useful as a guide, we mustbe circumspect in the conclusions drawn fromthis league table. The main problem is thatthe size of the trial will impact on the accuracyof the results. Small trials or data sets will notyield accurate estimations of efficacy.

References:

(1)Single dose oral celecoxib for post-operativepain. Cochrane database of SystematicReviews1, 2003 Barden J et al.(2)Cox-2 inhibitors: today and tomorrow.American Journal of the Medical Sciences.323(4):181-9, 2002 Apr.(3)Best Practice & Research, ClinicalAnaesthesiology vol.17 No.1, p91-1102003. Schug S et al.(4)Rofecoxib for rheumatoid ArthritisCochrane Database of Systematic Reviews1, 2003 Garner S et al(5)Celecoxib was similar to naproxen forrheumatoid arthritis with fewer endoscopiculcers. ACP journal club 132(3)p96 2000(6)Bombardier C, Laine L, Reicin A, et al.Comparison of upper gastrointestinaltoxicity of rofecoxib and naproxen inpatients with rheumatoid arthritis.VIGORStudy Group. N Engl J Med 2000; 343:1520–8.(7)Silverstein FE, Faich G, Goldstein JL, et al.Gastrointestinal toxicity with celecoxib vsnonsteroidal anti-inflammatory drugs forosteoarthritis and rheumatoid arthritis: theCLASS study: A randomized controlledtrial.Celecoxib Long-term Arthritis SafetyStudy. JAMA 2000; 284: 1247–55.protein loss and anorexia. The systemicinflammatory response is the same whateverthe type of tumour and is at a level equivalentto the response following major surgery. Theimportant difference is that the response issustained. It has been demonstrated that thegreater the C reactive protein level (a markerof the inflammatory response), the poorer theprognosis of the patient.The afternoon session, chaired by NicolaStuckey, was an afternoon of contrasts. Itbegan with an excellent lecture by ProfessorDaniel McQueen of the Department of Pharmacology at the University of Edinburghand NBPA council member. He gave afascinating overview of COXs 1-3 and theirrole in the inflammatory response, coveringthe mechanism of action of familiar and newagents.As an experiment, the day finished with adebate. The motion was “This house believesthat the bio-psychosocial model has outlivedits use”. Speaking for the motion wasProfessor Marie Johnston from Aberdeen andagainst Dr. David Craig from Glasgow. Thediscussion was lively although the speakershad trouble disagreeing on some aspects of thediscussion, the general feeling being that thebiopsychosocial model had not outlived itsuse.

REPORT FROM PRAGUE

Clare Dunlop, Senior CharteredPhysiotherapistPain Management ProgrammeAstley Ainslie HospitalPAIN IN EUROPE IV“Europe Against Pain, Don’t Suffer inSilence”

The fourth Congress of the EuropeanFederation of the International Association forthe Study of Pain Chapters was held in Praguein the Czech Republic, from September 2nduntil September 6th

2003. The conferenceconsisted of plenary lectures and a variety of seminars throughout each day. I will expandupon a few of the sessions that I enjoyed themost.

“Pain and Anxiety”

was a plenary sessionpresented via a telephone link from Canada.The speaker focused on presenting thedifferences between fear and anxiety. Fear isoriented in the

present

and is designed toprotect one from immediate threat, whereasanxiety is oriented in the

future

and occurs inresponse to anticipated threats. Fear motivates

defensive

behaviours, but anxiety motivates

preventive

behaviours. Both these responsesare protective, and they trigger each other ina mutually reinforcing fashion. Anxietyincreases the chances that immediate threatwill be perceived, leading to fear. Fear forcesrecognition of the stimulus (and somethingassociated with it) as a threat which may/maynot occur, therefore provoking anxiety.Interestingly, early estimates from researchsuggest that 7-25% of chronic pain patientshave a diagnosable anxiety disorder (11%social phobias, 25% specific phobias, and40% PTSD).

“Hypervigilance to Pain : An Experimental Approach”

looked at thedifferences between vigilance andhypervigilance.

Vigilance

is to sustainattention to weak external signals (visual orauditory) in a monotonous situation.

Hypervigilance

is a perceptual habit of scanning the body for somatic sensations.Intense chronic pain causes a chronicinterruption of attention, with no other stimulito compete with it. Patients can end up in asituation called

Attentional Stuckness

whichmeans that once pain is detected, it is difficultto switch attention back to other demands inthe environment. Patients (especially thosewho catastrophise about the pain) have greatdifficulty disengaging from it.

“Pain Related Fear Amplifies Pain inChronic Pain Patients”

was a presentation of findings from a study that found that inducingpain anticipation (by instruction) led tosignificantly lower levels of behaviouralperformance and an increase in pain intensityand anxiety in the experimental group. Theyalso noticed that behavioural performance washighly correlated with the amount of fear/ avoidance beliefs. It was concluded that painanticipation and fear/avoidance beliefsmotivate avoidance behaviour and amplifypain experience. Inducing pain anticipationmay result in a selective attentional biastowards pain related information and/orpronounce the experience of pain viacognitive/emotional appraisal. An importantmessage for the clinical situation is to

avoid

advice that could trigger anticipation of pain.

“Hypervigilance Mediates the Association Between Fear and Pain”.

Experimental results showed that individualswith high pain related fear detected low-intensity, ambiguous somatosensory stimulifaster, had more difficulty in disengaging frompotentially threatening somatic stimuli, andhad decreased attentional capacity forcognitive task performance compared tocontrols. With high fear patients, distractionwas shown

not

to affect pain tolerance orintensity in an experiment carried out withiced water. The overall conclusion was thatlevels of pain related fear were associated withpain intensity. There was evidence that highfear patients show increased attention to pain.

“New Treatments of Rheumatoid Arthritis”

was a plenary session. In RA it hasbeen found that damage in joints is much morewidespread than was first thought, therefore,treatment is now based on early suppressionof disease activity (and prevention of irreversible joint damage) as soon as possibleafter diagnosis, irrespective of the kind ornumber of drugs indicated. It has become clearthat the cytokines TNFa and IL1 play animportant role in the inflammatory process of R.A. Treatments have been specificallydeveloped to block these proinflammatorycytokines. When given intravenously, theonset of action is almost immediate with thenew drugs, the mechanism of action is knownand focused, and the frequency of adversereactions in the short term is low. Any long-term adverse reactions are unknown as yet.

“Chronic Pain: Neuroplasticity in LimbicStructures”

was a talk about how the memoryof pain could be more damaging than its’initial experience. The central nervous systemseems to have the ability to acquire and storememories of aversive events. Behaviouralresponses resulting from aversive memorieswill diminish over time to become extinct, aslong as reinforcement of the memories isabsent. Long term changes in the nervoussystem may aggravate sensory discriminativeand aversive dimensions of pain, and thesemay outlast the primary cause for the pain.

“Psychosocial Determinants of PainChronification”

emphasised the importanceof paying attention to the complexity anddynamics of the pain experience. It has beendemonstrated in the past that severalpsychosocial factors contribute to thechronification of pain. They interact with thesomatic/nociceptive dimensions and maymodify appraisal, coping and behaviour.Psychosocial factors were addressed in termsof 5 dimensions:1.Physiological/disease perspective2.Narrative perspective3.Individual dimensions4.Social/anthropologicaldimensions5.BehaviourIf clinicians take into account the wholepain experience, the patient’s understandingcan improve, as well as the quality of thetherapist/patient relationship.

League Table of Coxibs

The full version of this league table, including individual trial size,can be found at www.jr2.ox.ac.uk