Is cue exposure cure exposure?

© 2002 Society for the Study of Addiction to Alcohol and Other Drugs Addiction, 97, 357–360

DOES ‘UNLEARNING’ EVER REALLYOCCUR: COMMENT ON CONKLIN &TIFFANY

Sir—In a previous issue of Addiction, Conklin & Tiffany(2002) presented a compelling argument to re-examinelearning principles governing extinction of conditionedresponses as a means to extinguish reactions to drug use-conditioned cues, which might provoke relapse to substance use. The authors present a meta-analysis oftreatment studies which have used cue exposure methodsto forestall relapse, but even this quantitative analysis isnot needed to conclude that the methods used to datehave failed, miserably.

An informed tour through the recent literature onextinction paradigms in animals yields some insights intowhat forms and structures extinction trials may need toadopt if real extinction of conditioned responding is to beachieved. However, the authors make an exceedinglyimportant point in noting that the bond between condi-tional stimulus and conditioned response may in factremain indelible. Thus, extinction, conceived as ‘unlearn-ing’, may never really occur. Studies of the neural basisof learned fear and defensive responding confirms thispossibility (LaBar et al. 2001).

Extrapolating from conditioning of aversive stimuli toappetitive stimuli, we may never be able to extinguishappetitive responding to drug use cues. Nevertheless,individuals ‘learn’ to cope with cue-induced craving,perhaps in a number of ways—cognitively, by avoiding orsuppressing conditioned craving responses, and behav-iorally, by suppressing drug-seeking actions, physicallyfleeing or avoiding situations where drug use cues arepresent, or by engaging in alternative, drug-free behav-iors. Inhibition of conditioned fear responding is con-trolled to a large extent by higher cortical structures, andthe same is probably true of conditioned appetitiveresponding. Herein lies what I believe to be the realpromise of cue exposure therapies. Higher order learningmust take place in order to control highly automatedconditioned reactions and drug-seeking behaviors inresponse to drug cues. Coping skills training to preventrelapse is designed to do just this. However, coping skillstraining may miss the mark if it is not practised, espe-cially in the cue-laden contexts where drug craving is

experienced and drug use occurs (Rankin et al. 1983). Tobe sure, there are enormous practical challenges inundertaking such in vivo coping/exposure therapy. Asyet, there is no indication that cognitive-imaginalmethods for evoking cue reactivity are sufficiently pow-erful to mimic exposure to real-world drug cues (Niauraet al. 1999). Perhaps media-rich technologies, such asvirtual simulations of drug-using environments, will behelpful in this regard. We must heed Conklin & Tiffany’sadvice on how best to configure cue exposure trials, andlearn to combine this with coping skills training andpractice, if the promise of cue exposure treatment is to berealized.

RAYMOND NIAURA

Centers for Behavioral and Preventive MedicineThe Miriam HospitalCoro Building, Suite 500One Hoppin Street, Providence, Rhode Island 02903USAE-mail: [email protected]

References

Conklin, C. A. & Tiffany, S. T. (2002) Applying extinctionresearch and theory to cue-exposure addiction treatment.Addiction, 97, 155–167.

LaBar, K. S. & LeDoux, J. E. (2001) Coping with danger: theneural basis of defensive behavior and fearful feelings. In:McEwen, B. S. & Goodman, H. M., eds. Coping with theEnvironment: Neural and Endocrine Mechanisms, Vol. IV.Handbook of physiology, Section 7. The Endocrine System, pp.139–154. New York: Oxford University Press.

Niaura, R., Abrams, D., Shadel, W., Rohsenow, D., Monti, P. &Sirota, A. (1999) Cue exposure treatment for smoking relapseprevention: a controlled clinical trial. Addiction, 94, 685–695.

Rankin, H., Hodgson, R. & Stockwell, T. (1983) Cue exposureand response prevention with alcoholics: a controlled clinicaltrial. Behaviour Research and Therapy, 21, 435–446.

IS CUE EXPOSURE CURE EXPOSURE?

Sir—Periodic reviews of a research field are essential to take stock of progress and refocus the priorities for

Letters to the Editor

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future research. Conklin & Tiffany’s (2002) review istherefore a welcome addition to what has become a series of approximately quinquennial reviews of theaddiction cue exposure field (Niaura et al. 1988;Drummond et al. 1990; Drummond et al. 1995;Drummond 2000).

As ever, the Purdue group provides an intelligent,challenging and provocative paper that rightly throwsdown a gauntlet to the cue exposure field. As with previous reviews of this area of research endeavour(Drummond et al. 1990, 1995) Conklin & Tiffany correctly advocate greater linkage between basic andclinical cue exposure research.

The principal contribution of their review is to identify pointers from the animal conditioning field that might both limit and potentially increase the efficacyof cue exposure treatment in humans. They providesound advice on the probable methods to maximizeextinction, and to reduce spontaneous recovery and reinstatement of cue reactivity, focusing on the method-ology of cue exposure. The potential problems of gener-alization and reinstatement have been noted previously(Drummond et al. 1990). However, it is also worth notingthat in practice there does appear to be a degree ofgeneralization from the cue exposure laboratory to the natural drinking environment, and reinstatementappears to be attenuated to some extent by cue exposuretreatment (Monti et al. 1993; Drummond & Glautier1994).

Nevertheless, more needs to be known about the optimal methods of delivering cue exposure treat-ment (Rohsenow et al. 1995). Further, the question ofwhether pharmacological agents (such as naltrexone)block unconditioned responses to drugs as a means ofproviding unreinforced cue exposure, or alternativelyblock conditioned cue reactivity, is intriguing and worth exploring further (Drummond 2000). This hasbeen proposed as a potential benefit of naltrexone inalcohol dependence used in conjunction with cue exposure (Modesto-Lowe et al. 1997; Rohsenow et al.2000).

While Conklin & Tiffany appear essentially to be cue exposure enthusiasts, their meta-analysis of cueexposure treatment studies is both premature andmethodologically unwise.

The principal problem with their meta-analysis is thatof attempting to combine a highly heterogeneous groupof studies. Heterogeneity in this case arises from a myriadof sources including different types of drug misuser(alcohol, cocaine, heroin, nicotine), different settings (in-patient, outpatient), different modes of delivery (individ-ual, group) different cues (imaginal, in-vivo, video, sight,smell, audio, personalized, standardized, priming doses,

non-priming doses), different number and duration ofsessions, different frequency and intensity of sessions anddifferent drug use status (abstinent, continuing use).Many of these studies also used different measures anddifferent methods of statistical analysis. The studies wereof varying methodological quality. Many of the studieswere non-randomized, introducing potential for bias.Further, most of the published cue exposure studiessuffer individually from inadequate statistical powerleading to the potential for Type 1 error. All these factorspoint to the inappropriateness of meta-analysis andexplain in part the significant variance in effect sizesacross studies. Such problems have been noted previouslyin critiques of meta-analysis (Liberati 1995; Blettneret al. 1999; Jadad et al. 2000; Altman 2001).

However, it is of interest that the updated MesaGrande study (Miller & Wilbourne 2002) has for the firsttime identified cue exposure treatment for alcohol dependence as an efficacious treatment, with a moder-ately positive ‘cumulative evidence score’. Further, a newstudy from the Brown group (not yet included in the MesaGrande series) has shown further evidence of treat-ment efficacy of cue exposure in alcohol dependence(Rohsenow et al. 2001).

What we need now is more research testing thehypotheses derived from animal conditioning, applied tothe clinical situation, as has been clearly advocated in therest of Conklin & Tiffany’s paper. When optimal cue expo-sure treatment methods have been identified, we needmore randomized clinical trials of adequate methodo-logical quality, including adequate statistical power. Only then will meta-analysis be a useful means to studytreatment efficacy.

Nevertheless, Conkin & Tiffany are correct to urgecaution in rushing to adopt cue exposure as a routinetreatment approach. Much more needs to be knownabout efficacy, effectiveness and optimal methods ofdelivery. In this context larger trials with improvedmethodology are needed. Anecdotally some of the subjects in our clinical trial of cue exposure in alcoholdependence thought incorrectly that the treatment wascalled ‘cure exposure’ (Drummond & Glautier 1994). On the basis of existing research this ascription wouldappear to be wishful thinking.

D. COLIN DRUMMOND

Department of Addictive BehaviourSt George’s Hospital Medical SchoolUniversity of LondonCranmer TerraceLondon SW17 0REUKE-mail: [email protected]

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References

Altman, D. G. (2001) Systemic reviews in health care: systemicreviews of evaluations of prognostic variables. British MedicalJournal, 323, 224–228.

Blettner, M., Sauerbrei, W., Schlehofer, B., Scheuchenpflug, T. &Friedenreich, C. (1999) Traditional reviews, meta-analysesand pooled analyses in epidemiology. International Journal ofEpidemiology, 28, 1–9.

Conklin, C. A. & Tiffany, S. T. (2002) Applying extinctionresearch and theory to cue-exposure addiction treatments.Addiction, 97, 155–167.

Drummond, D. C. (2000) What does cue reactivity have to offerclinical research? Addiction, 95, S129–S144.

Drummond, D. C., Cooper, T. & Glautier, S. P. (1990) Condi-tioned learning in alcohol dependence: implications for cue exposure treatment. British Journal of Addiction, 85,725–743.

Drummond, D. C. & Glautier, S. (1994) A controlled trial ofcue exposure treatment in alcohol dependence. Journal ofConsulting and Clinical Psychology, 62, 809–817.

Drummond, D. C., Tiffany, S. T., Glautier, S. P. & Remington, B.(1995) Addictive Behaviour: Cue Exposure Theory and Practice.Chichester: John Wiley.

Jadad, A. R., Moher, M., Browman, G. P., Booker, L., Sigouin, C.,Fuentes, M., Stevens, R. (2000) Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BritishMedical Journal, 320, 537–540.

Liberati, A. (1995) Meta-analysis: statistical alchemy for the21st century: discussion. A plea for a more balanced view of meta-analysis and systematic overviews of the effect ofhealth care interventions. Journal of Clinical Epidemiology, 48,81–86.

Miller, W. R. & Wilbourne, P. L. (2002) Mesa Grande: a method-ological analysis of clinical trials of treatments for alcohol usedisorders. Addiction, 97, 265–277.

Modesto-Lowe, V., Burleson, J. A., Hersh, D., Bauer, L. O. &Kranzler, H. R. (1997) Effects of naltrexone on cue-elicitedcraving for alcohol and cocaine. Drug and Alcohol Dependence,49, 9–16.

Monti, P. M., Rohsenow, D. J., Rubonis, A. V., Niaura, R. S., Sirota,A. D., Colby, S. M., Goddard, P. & Abrams, D. B. (1993) Cueexposure with coping skills treatment for male alcoholics: apreliminary investigation. Journal of Consulting and ClinicalPsychology, 61, 1011–1019.

Niaura, R. S., Rohsenow, D. J., Binkoff, J. A., Monti, P. M.,Pedraza, M. & Abrams, D. B. (1988) Relevance of cue reactiv-ity to understanding alcohol and smoking relapse. Journal ofAbnormal Psychology, 97, 133–152.

Rohsenow, D. J., Monti, P. M. & Abrams, D. B. (1995) Cue expo-sure treatment in alcohol dependence. In: Drummond, D. C.,Tiffany, S. T., Glautier, S. P. & Remington, B., eds. AddictiveBehaviour: Cue Exposure Theory and Practice, pp. 169–196.Chichester: John Wiley.

Rohsenow, D. J., Monti, P. M., Hutchison, K. E., Swift, R. M.,Colby, S. M. & Kaplan, G. B. (2000) Naltrexone’s effects onreactivity to alcohol cues among alcoholic men. Journal ofAbnormal Psychology, 109, 738–742.

Rohsenow, D. J., Monti, P. M., Rubonis, A. V., Gulliver, S. B., Colby,S. M., Binkoff, J. A. & Abrams, D. B. (2001) Cue exposure withcoping skills training and communication skills training foralcohol dependence. 6- and 12-month outcomes. Addiction,96, 1161–1174.

ESTIMATING PREVALENCE OFPROBLEMATIC DRUG USE:COMMENTS ON FRISCHER ET AL .

Sir—The paper by Frischer et al. (2001) is a useful con-tribution to the study of drug epidemiology, not only inthe United Kingdom but also other countries. The prin-ciples outlined can be applied, with refinements, to laterperiods in the United Kingdom.

It is necessary to make a few observations on the estimates presented in the paper of drug users at risk ofoverdose-related deaths obtained by using the mortalitymultiplier method. It appears a gremlin got into theworks in that the calculation for the high estimate (p. 1470) should have read 2417 rather than 2150.However, the estimated number itself was correct for theapproach adopted.

While accepting completely the authors’ caveats withregard to the limitations of this particular technique, ithas to be pointed out that there were some omissionsfrom their calculations. First, it is stated that the estimategiven is for the United Kingdom; this is not so. The figurequoted of 2150 deaths in 1996 for the United Kingdomactually relates to England and Wales only (EMCDDA1998). The number of deaths in Scotland is given as 267,but no figure is offered for the number of deaths inNorthern Ireland. Secondly, the definition of drug-relateddeath used for Scotland is different to that used forEngland and Wales.

Data are now available from the General RegisterOffices for England and Wales, Scotland and NorthernIreland on a consistent basis for each year from 1994 to1999 (see Table 1) using the Office for National Statistics’‘standard’ definition. This comprises the ICD-9 codesgiven below:

292 Drug psychosis.304 Drug dependence.305.2–9 Non-dependent abuse of drugs.E850-858 Accidental poisoning by solid or liquid

substances—drugs, medicaments, and biologicals.E950.0–5 Suicide and self-inflicted poisoning by solid

or liquid substances—drugs and medicamentsE980.0–5 Poisoning by solid or liquid substances,

undetermined whether accidentally or purposelyinflicted—drugs and medicaments.

E962.0 Assault by poisoning—drugs and medicaments.

This definition may be over-inclusive in the sense thatit covers a number of deaths (chiefly suicides) where ‘prescription only’ and ‘over-the-counter’ medicines areimplicated. However, a considerable proportion of drug-dependent individuals commit suicide (for example seeOyefeso et al. 1999; Vingoe et al. 1999; Neale 2000). Few

360 Letters to the Editor


cases are reported in the United Kingdom of deaths codedto 292 or E962.0.

Applying the same range of mortality rates as Frischeret al. (2001), i.e. 1%, 1.5% and 2%, estimates for theUnited Kingdom and its constituent countries have beenobtained and are presented in Table 1 for both 1996 andthe most recent year available. A substantially higheroverall UK rate is derived for 1996. The table demon-strates how the problem of deaths associated directlywith drug use has grown in just 3 years.

The methodology can be applied at both national andsubnational levels. In order to do so, however, it is neces-sary to know the appropriate mortality rates to use. For instance, based on the existing mortality rates per100 000 population (5.52 for England and Wales, 9.6 forScotland and 3.18 for Northern Ireland), it is probablethat the figures presented here for Scotland would behigher and those for Northern Ireland lower. Accountalso has to be taken of regional variations within acountry (Jackson & Cole 2000; Uren 2001).

The use of the mortality multiplier technique can beapplied to different types of users classified by frequencyof use, method of consumption, drugs of use, etc. How-ever, as Frischer et al. (2001) have demonstrated, it is justone of a battery of methods that can be brought to bearon this area of research.

Note

The views expressed are those of the author, and are notnecessarily those of St George’s Hospital Medical Schoolor of the Home Office.

JOHN MARTIN CORKERY

Honorary Senior Research FellowCentre for Addiction StudiesDepartment of Addictive Behaviour and PsychologicalMedicineSt George’s Hospital Medical SchoolCranmer TerraceLondon SW17 0RE, UK

References

European Monitoring Centre for Drugs and Drug Addic-tion (EMCDDA) (1998) 1998 Extended Annual Report on the State of the Drugs Problem in the European Union.Luxembourg: Office for Official Publications of the EuropeanCommunities.

Frischer, M., Hickman, M., Kraus, M., Mariani, F. & Wiessing, L.(2001) A comparison of different methods for estimating theprevalence of problematic drug misuse in Great Britain.Addiction, 96, 1465–1476.

Jackson, G. W. L. & Cole, S. K. (2000) Drug-related Deaths inScotland in 1999. Occasional Paper no. 1. Edinburgh: GeneralRegister Office (Scotland).

Neale, J. (2000) Suicidal intent in non-fatal illicit drug overdose.Addiction, 95, 85–93.

Oyefeso, A., Ghodse, H., Clancy, C. & Corkery, J. M. (1999)Suicide among drug addicts in the UK. British Journal ofPsychiatry, 175, 277–282.

Uren, Z. (2001) Geographical variations in deaths related todrug misuse in England and Wales, 1993–9. Health StatisticsQuarterly, 11, 25–35.

Vingoe, L., Welch, S., Farrell, M. & Strang, J. (1999) Heroin over-dose among a treatment sample of injecting drug misusers:accident or suicidal behaviour? Journal of Substance Use, 4,88–91.

Table 1 Prevalence estimates of drug users at risk of overdose-related death, UK, 1996 and 1999.

1996 1999

Estimated EstimatedNumber Mortality population Number Mortality population of deaths rate at risk of deaths rate at risk

England & WalesLow 2721 0.020 136050 2943 0.020 147150Central 0.015 181400 0.015 196200High 0.010 272100 0.010 294300

ScotlandLow 460 0.020 23000 492 0.020 24600Central 0.015 30667 0.015 32800High 0.010 46000 0.010 49200

Northern IrelandLow 40 0.020 2000 50 0.020 2500Central 0.015 2667 0.015 3333High 0.010 4000 0.010 5000

United KingdomLow 3221 0.020 161050 3485 0.020 174250Central 0.015 214753 0.015 232333High 0.010 332100 0.010 348500

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Is cue exposure cure exposure?