Whiplash Associated Disorders (WAD): Responses to pharmacological challenges and psychometric tests

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Scandinavian Journal of Pain 3 (2012) 151–163

Contents lists available at SciVerse ScienceDirect

Scandinavian Journal of Pain

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linical pain research

hiplash Associated Disorders (WAD): Responses to pharmacological challengesnd psychometric tests

ats Perssona,b,∗, Jan Sörensenb,c, Björn Gerdleb,c

Clinical Department of Operation and Intensive Care, Pain Unit, County Hospital Ryhov, SE-551 85 Jönköping, SwedenRehabilitation Medicine, Faculty of Health Sciences, SE-581 85 Linköping, SwedenPain and Rehabilitation Centre, University Hospital, SE-58185 Linköping, Sweden

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rticle history:eceived 13 August 2011eceived in revised form 9 January 2012ccepted 30 January 2012

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Objectives: The present study challenges chronic Whiplash Associated Disorders (WAD)-subjects to apharmacological intravenous (i.v.) test with morphine, ketamine, and active placebo (midazolam). Theaim was to describe the short-term responses to drugs and the assumed heterogeneity in the patterns ofresponses. We related the different responder groups to the results from psychometric tests.Methods: The study includes 95 patients, all with chronic WAD and referred to our departments. Theyanswered a questionnaire including the following psychometric instruments relevant for chronic pain:Beck Depression Inventory, Coping Strategies Questionnaire, Multidimensional Pain Inventory, Life Sat-isfaction Checklist, SF36 and EuroQol. The subjects also went through sessions with separate infusions ofmorphine (0.3 mg/kg), ketamine (0.3 mg/kg) and midazolam (0.05 mg/kg). Infusion time was 30 min fol-lowed by a 2-h post-infusion assessment. Assessments were made using a Visual Analogue Scale (VAS)for pain intensity and unpleasantness and by statements of per cent pain relieved. A categorical painrating scale was also used. A positive response was defined as ≥50% decrease of the VAS-level on twoconsecutive assessment points during the test sessions, anything less was a non response. The placeboresponders were defined as those with a positive response to the active placebo infusion.Results: The tests were completed by 94 subjects and 26% of these were placebo responders. Amongthe placebo non responders, 47% responded to morphine, 41% to ketamine, 25% to both drugs and 37%to neither morphine nor ketamine (pain intensity assessments). Similar proportions were found in theassessments of pain unpleasantness and per cent pain relieved. Approximately one in four subjects (27%,pain intensity assessment) did not respond to any of the drugs tested. This relatively high proportion ofnon responders seemed to be worst cases in some aspects of the psychometric tests. Generally, this nonresponder group had a trend to score worse for most items in the psychometric tests with some reachingsignificance in a univariate analysis. This result was confirmed in a multivariate context, although theresults indicated only small differences between the groups. All three substances showed significant painrelief compared to baseline on all assessment points. On most variables, morphine and ketamine weresignificantly more effective compared to the active placebo.Conclusions: There are different subgroups among subjects with chronic WAD with variations in responsesto i.v. morphine, ketamine, and midazolam (active placebo). Subjects with chronic WAD who did notrespond to any of the drugs tested scored badly in some aspects of the psychometric instruments.Implications: The present study confirms one aspect of the heterogeneity in the population with chronic
WAD. The study does not elucidate precise pain mechanisms but taken together with other studies explor-ing other aspects, it stresses the importance of individualizing the assessment and treatment of subjectswith chronic WAD. A common clinical experience is that depression, anxiety and maladaptive copingstrategies often are obstacles for successful medical treatment of chronic pain. The present study sup-
emp
ports this experience and the treatment of chronic WAD
© 2012 Scandinavian Assoc

DOI of refers to article: 10.1016/j.sjpain.2012.02.008.∗ Corresponding author at: Clinical Department of Operation and Intensive Care, Pain U

ax: +46 (0) 36325055.E-mail addresses: [email protected], [email protected] (M. Persson).

877-8860/$ – see front matter © 2012 Scandinavian Association for the Study of Pain. Puoi:10.1016/j.sjpain.2012.01.003

hasizes the need for assessment of psychometric variables when planning
.iation for the Study of Pain. Published by Elsevier B.V. All rights reserved.
nit, County Hospital Ryhov, SE-551 85 Jönköping, Sweden. Tel.: +46 (0) 36325050;

blished by Elsevier B.V. All rights reserved.

dx.doi.org/10.1016/j.sjpain.2012.01.003

http://www.sciencedirect.com/science/journal/18778860

www.ScandinavianJournalPain.com


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1 n Journal of Pain 3 (2012) 151–163

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Table 1Background data of the recruited subjects (n = 95).

Area Variables

Gender/Age Male (n (%)) 39 (41%)Mean age (years (SD)) 36.8 (9.8)

Female (n (%)) 56 (59%)Mean age (years (SD)) 35.4 (9.5)

All subjects (n) 95Mean age (years (SD)) 36.0 (9.6)

Time from impact (mean (SD)) Months 28 (15)

Type of impact (n (%)) From the rear 41 (43%)Obliquely rear 4 (4%)From the side 6 (6%)Other 44 (46%)

Patient position at impact (n (%)) Driver 69 (73%)Passenger front seat 13 (14%)Passenger back seat 7 (7%)Other type of vehicle 6 (6%)

Time to symptoms (n (%)) Immediately 36 (38%)First 24 h 44 (46%)First week 14 (15%)

Use of analgesics (n (%))NSAID/Acetaminophen None 19 (20%)

Sporadic 22 (23%)Daily 42 (44%)

Weak opioids None 40 (42%)Sporadic 17 (18%)Daily 26 (27%)

Strong opioids None 83 (87%)

52 M. Persson et al. / Scandinavia

. Introduction

A sudden acceleration or deceleration due to impact can lead towhiplash trauma and cause acute symptoms (pain and stiffness in

he neck, often described as acute Whiplash Associated Disorder,AD) and a significant subgroup develops chronic pain (chronicAD) [1–3].Apart from cases where the trauma causes verifiable lesions

n the musculoskeletal or neural structures, most patients withhronic WAD do not present with such signs. In the majority ofatients with chronic WAD, the pathogenesis of the persistent pain

s poorly understood as is evident by the different views presentedn the literature [4–6].

When describing and analysing chronic WAD according to aiopsychosocial model [7,8], different studies put various weightn different parts along the “bio”, “psycho”, and “social” axes.or example, emphasising the “bio” side, some researchers stressesions in the zygapophyseal joints [9]; emphasising the “psycho”nd “social” sides, some researchers stress factors such as anxiety,oping, and insurance issues, often as interconnected factors [10].

A possible approach is to view patients with chronic WADs a heterogeneous group even though the basic concept is theio-psycho-social model. Support for this can be found in stud-

es where responses to pharmacological interventions have beennvestigated [11]. Studies focusing on the “psychosocial side” of the

odel also show heterogeneity among patients with chronic WAD12–15].

One way to investigate chronic pain is to study responses toharmacological agents with known targets. This approach haseen done for different patient groups including patients withhronic WAD [11]. Most studies deal with opioid agents and/oretamine and assume the former acts on the central pain pro-essing via the �-receptor and the latter acts as an antagonistn the NMDA-receptor. Clearly, NMDA-receptors play an impor-ant role in central sensitization [16,17]. Several studies concludehat central hyperexcitability (sensitization) and/or disinhibiton ofhe somatosensory system may play a part in the pathogenesisf pain in chronic WAD [18–22], a conclusion that might explainhy patients without detectable or minimal nociceptive input stillerceive debilitating pain.

However, the pharmacological studies so far have been rela-ively small. Most studies incorporate a test with a placebo agent,ommonly physiological saline, but sometimes benzodiazepinesave been used as an active placebo [23,24] in order to simu-

ate the sedative effects of other agents presuming no analgesicctivity.

In the present study patients with chronic WAD were examinedegarding the responses to different i.v. pharmacological chal-enges: morphine, ketamine, and “active” placebo (midazolam). Theatients also answered a questionnaire including several psycho-etric instruments relevant for chronic pain.The aim of the study was to describe the short term

esponses to drugs and the assumed heterogeneity in responseatterns. Furthermore, we analysed whether the outcomes ofhe pharmacological challenges correlated with the psychometricesults.

. Patients and methods

.1. Patients

Between May 2001 and October 2008, 95 subjects with chronicAD were recruited from patients referred to the Pain Unit, Oper-

tion and Intensive Care Clinic, County Hospital Ryhov, Jönköping,weden and to the Pain and Rehabilitation Centre, University

Missing data 12 (13%)

Hospital, Linköping, Sweden. For background data see Table 1.The study was conducted in accordance with the Declaration ofHelsiniki and approved by the local Ethics Committee (00-283). Allparticipants gave written informed consent.

2.1.1. Inclusion criteriaThe subjects had a well-documented whiplash trauma or a

whiplash-like accident with a minimum of six months and max-imum of five years before inclusion (i.e., WAD grades II–III). Theyhad a persistent pain in the neck – with or without spread of thepain to the head, shoulder, and arm regions – with a pain intensityof ≥40 mm on a 100 mm VAS. The minimum age was set to 18 years.

2.1.2. Exclusion criteriaAll subjects were given a MRI of the cervical spine. If affections of

medulla and/or nerve roots corresponding to neurological signs inthe periphery were discovered, these subjects were excluded fromthe study. If the subjects had neuroorthopedic surgery done on thecervical spine, they were excluded. Subjects were excluded if theyhad a significant chronic pain problem before the trauma. Subjectswith generalized pain after the trauma were also excluded. That is,subjects were only included if their pain was mainly localized tothe neck with or without spread of the pain to the head, shoulder,or arm regions. Subjects were excluded if they had drug addictionproblems, exhibited psychotic behaviour, or were pregnant.

2.1.3. Baseline screeningAll subjects answered a comprehensive questionnaire including

psychometric instruments relevant for chronic pain. The question-naire asked the subjects whether they had been using analgesics
the previous six months. If they answered “yes”, they were askedfor type of analgesic and whether they were using it sporadicallyor daily (Table 1).

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.1.4. Study contextThe present study is a part of a larger project that explores the

requency of cervical zygapophyseal joints as a source for the per-istent pain in subjects with chronic WAD. This larger project alsoested the efficacy of radiofrequency neurotomy of the innervationf the joints.

.2. Methods

.2.1. Pharmacological challenge

.2.1.1. Procedure. Before the test sessions, subjects werenstructed not to take any analgesics at least 8 h before theest. The subjects were placed in a silent room and arrangementsere made to achieve a relaxed supine position in a bed. An

ntravenous cannula was inserted, usually on the back of a hand.sing a syringe pump (Braun Perfusor®, Germany), we infused thectual drug (morphine, ketamine, or active placebo). Infusion timeas 30 min. Assessments were made before and after placement

f the i.v. cannula as well as at 10, 20, and 30 min after the infusiontarted and 10, 20, 30, 45, 60, and 120 min after the infusiontopped.

The subjects marked a 100-mm Visual Analogue Scale (VAS)ith the endpoints labelled “no pain” and “worst imaginable pain”

o indicate intensity of the local pain in the neck. In addition, theubjects were asked to rate the unpleasantness of the pain on a VAS.he subjects also rated their pain on a categorical scale (0 = no pain,= light pain, 2 = moderate pain, 3 = serious pain, 4 = unbearableain). Finally, the subjects stated in percentage the perceivedegree of pain relief in relation to the baseline assessment (seeelow) at the different time points.

.2.1.2. Drugs and dosage. All subjects received all three substancesn three different sessions separated by a minimum of one week.he substances were delivered in a randomized sequence preparedy the hospital pharmacy. A person not involved in delivering the

nfusion or making the assessments prepared the syringe withhe actual drug according to the randomization. The subject andhe nurse responsible for the infusion and the assessments werenaware of the actual drug.

The drugs administered during a 30 min infusion time were asollows:

morphine hydrochloride (0.3 mg/kg, Morfin®, Meda);ketamine hydrochloride (0.3 mg/kg, Ketalar®, Pfizer);midazolam hydrochloride (active placebo, 0.05 mg/kg,Midazolam®, Actavis).

Dosages were chosen with references to earlier studies11,24–26].

.2.1.3. Side-effects. At all assessment points, the subjects weresked to note any side-effects and to classify them in the follow-ng categories: (1) sedation/tiredness, (2) dreams/hallucinations,3) dizziness, (4) nausea/vomiting, (5) itching, (6) paresthe-ias/numbness, and (7) other. They were also asked to estimate thentensity of any side-effects on a 100 mm VAS with endpoints “noide-effect” and “worst imaginable side-effect”.

.2.1.4. Monitoring. For safety reasons, heart rate, blood pressure,
espiratory rates, and pulse oxymetry were continuously mon-tored during the test sessions. The drug delivery and all thessessments were made by anaesthetic nurses who were well-rained in resuscitation methods.
nal of Pain 3 (2012) 151–163 153

2.2.2. Psychometric instrumentsThe study used the validated Swedish versions of the instru-

ments listed below.

2.2.2.1. BDI – Beck Depression Inventory. The Beck DepressionInventory evaluates 21 different aspects of depressive symptomsinto a scale ranging between 0 and 63 [27]. For psychiatric patientsa total score less than 14 indicates minimal or no depression, 14–19a mild depression, 20–28 a moderate, and >28 a severe depres-sion [28]. A screening cut-off point of 10 has been used for medicalpatients [12]. The BDI is considered as an established and well-researched scale [27–29].

2.2.2.2. CSQ – Coping Strategies Questionnaire. CSQ measures theway patients cope with pain. The original version included eighttypes of coping strategies: diverting attention, re-interpreting painsensations, coping self-statements, ignoring pain sensations, pray-ing and hoping, catastrophizing, increased behavioural activities,and pain behaviour. Each strategy is measured according to its fre-quency of use ranging between never (0) and always (6) with amaximum score of 36 for each strategy. Two additional questionsassess the perceived control of and ability to minimize pain [30].The Swedish version, which was used in this study, excludes thelast type of strategy (pain behaviour) [31].

2.2.2.3. MPI – Multidimensional Pain Inventory. The West Haven-Yale Multidimensional Pain Inventory – (WHY)MPI – is a 61-itemself-report questionnaire measuring psychosocial, cognitive, andbehavioural effects of chronic pain [32]. It has three sections. Part1 consists of five scales: Pain severity; Interference (pain relatedinterference in everyday life); Perceived Life Control; Affective Dis-tress; and Social Support (perceived support from a spouse orsignificant others). Part 2 assesses the perception of responses fromsignificant others to displays of pain and suffering and consists ofthree scales: Punishing Responses, Solicitous Responses, and Dis-tracting Responses. Part 3 measures the extent to which patientsengage in various activities and these four scales are combined ina composite scale labelled General Activity index. We only usedthe General Activity index of the items in Section 3. We used theSwedish Language Version (MPI-S) [33].

2.2.2.4. Life Satisfaction Checklist according to Fugl-Meyer et al.(LiSat-11). LiSat-11 estimates life satisfaction in general as well asin eight specific domains: vocational situation, financial situation,leisure situation, contact with friends and acquaintances, sexuallife, Activities of Daily Life, family life, and partnership. Two addi-tional variables estimate the satisfaction with physical and mentalhealth [34]. Each item has six possible answers ranging from 1 (verydissatisfying) to 6 (very satisfying).

2.2.2.5. The SF-36 Health Survey (Swedish version). SF-36 measuresdifferent dimensions of health, including levels of well-being andpersonal evaluation of health. The instrument consists of 36 ques-tions covering eight items or dimensions: Physical functioning;Role limitations due to physical pain; Bodily pain; General health;Vitality; Social functioning; Role limitations due to emotional prob-lems; and Mental health. Each item score is coded, summed, andtransformed to a standardized scale calculated from a specific scorealgorithm ranging from 0 to 100, worst and best possible healthstate, respectively [35].

2.2.2.6. EuroQol. The EuroQol instrument measures the subject’s
perceived state of health [36,37] using five dimensions – mobility,self-care, usual activities, pain/discomfort, and anxiety/depression– coded 1–3 (no problems, some problems, and severe prob-lems). The second part of the instrument concerns a self-estimation

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f today’s health according to a 100-point vertical scale, athermometer”-style scale (EQ-VAS). The endpoints are definednd high values indicate good health and low values indicate badealth.

.3. Definitions, calculations and statistics

.3.1. Pharmacological challengesThe mean of the first two assessments (i.e., before and after

nsertion of the i.v. cannula but before start of the infusion) wasonsidered the baseline assessment. We classified the subjects aslacebo responders, responders, and non responders:

Placebo response criterion: ≥50% VAS decrease (compared to base-line) of the local pain intensity on two consecutive assessmentpoints during the placebo test session.Response criteria: not a placebo responder and ≥50% VAS decrease(compared to baseline) of the local pain intensity on two consec-utive assessment points during test session of active drug.Non response criteria: none of the above.

Similar classifications were made regarding the assessments ofain unpleasantness and percentage pain relief.

A global response was defined as a response to both morphinend ketamine and a global non response as a response to nei-her morphine nor ketamine. Placebo responders and subjects withncomplete data for deciding a placebo response were excluded

hen calculating the proportions for morphine, ketamine, globalesponders, and global non responders.

The following variables were also determined to compare thehree substances:

Area under curve (i.e., the VAS × time (mm min)) for the rating oflocal pain intensity and unpleasantness.Mean pain intensity and unpleasantness decreases (the differ-ence between baseline and the mean of all other assessmentpoints).Mean percentage pain relieve (the mean of all values except thetwo assessments before start of infusion (i.e., baseline)).Efficacy (maximum difference between baseline and a singleassessment point) for the rating of local pain intensity, unpleas-antness and pain on the categorical scale.Efficacy regarding the rating of percentage pain relief (maximumvalue on a single assessment point).

.3.2. Psychometric testsThe mean values for the different scales of all the psychometric

nstruments used were calculated.

.3.3. Correlations pharmacological challenges and psychometricests

The responses to the pharmacological challenges were codednto three groups according to the assessments of pain intensityuring the test sessions. A positive response was defined as ≥50%AS decrease (compared to baseline) of pain intensity on two con-ecutive assessment points:

Placebo responders – positive responders to the placebo infusion;
Active responders – not a placebo responder and positive respon-der to morphine and/or ketamine;Non responders – neither a placebo responder nor an activeresponder.
nal of Pain 3 (2012) 151–163

The mean values of the different scales of psychometric instru-ments were calculated for the different responder groups and thencompared.

2.3.4. Statistical testsAnalyses were made using SPSS for Windows (version 19.0 SPSS

Inc. Chicago, Illinois, USA). Multivariate analyses were performedusing the SIMCA-P+, version 12.0 (Umetrics Inc.). Results in thetext and tables are generally given as mean values ± one stan-dard deviation (SD). Analysis of variance for repeated measures(Friedman’s test) was used followed by two-tailed comparisons(Wilcoxon signed ranks test) to determine which time points dif-fered from the baseline or which drugs differed from the placebo.The Wilcoxon signed ranks test was used for other paired compar-isons. Kruskal–Wallis and The Mann–Whitney U test were used fornon-paired group comparisons.

When investigating the correlations between the different vari-ables, the Principal component analysis (PCA) and Partial leastsquares or projection to latent structures (PLS) were applied. Principalcomponent analysis (PCA) using SIMCA-P+ was used to extract anddisplay systemic variation in the data matrix. PCA can be viewed asa multivariate correlation analysis. Variables loading on the samecomponent are correlated and variables with high loadings butwith different signs are negatively correlated. A component can beconsidered as a group of intercorrelated variables. Variables withhigh absolute loadings and that had a 95% confidence interval notequal to zero were considered significant. Significant variables withhigh loadings (positive or negative) are more important for thecomponent under consideration than variables with lower abso-lute loading. A component consists of a vector of numerical valuesbetween −1 and 1 (referred to as loadings) and obtained significantcomponents are uncorrelated. Variables that have high loadings(with positive or negative sign) on the same component are inter-correlated. Items with high loadings (ignoring the sign) are con-sidered to be of large or moderate importance for the componentunder consideration. A cross validation technique was used to iden-tify nontrivial components (p). This method keeps part of the dataout from the model development to assess the predictive power ofthe model and was used to test the significance of the components.The obtained components are, per definition, not correlated and arearranged in decreasing order with respect to explained variation.R2 describes the goodness of fit – the fraction of sum of squares ofall the variables explained by a principal component.

Partial least squares or projection to latent structures (PLS) wasused for the multivariate regression analysis of group membership– placebo responders, active responders, and non responders (i.e.,PLS-discriminant analysis; PLS-DA) – using the psychological instru-ments and pain-related variables as regressors. The VIP variable(variable influence on projection) indicates the relevance of eachX-variable pooled over all dimensions and Y-variables – the groupof variables that best explain Y. VIP ≥0.8 was considered significant.Coefficients (PLS scaled and centred regression coefficients) wereused to note the direction of the relationship (positive or negative).Multiple linear regression (MLR) could have been an alternativewhen regressing group membership, but it assumes that the regres-sor (X) variables are independent. If such multi-colinearity occursamong the X-variables, the regression coefficients become unsta-ble and their interpretability breaks down. MLR also assumes thata high subject-to-variables ratio is present (5–10). Such require-ments are not required for PCA or PLS; in fact, PLS can handle ratioslower than 1.0. In contrast to MLR, PLS also can handle severalY-variables simultaneously.

Outliers were identified using the two powerful methods avail-able in SIMCA-P+: (1) score plots in combination with Hotelling’sT2 (identifies strong outliers) and (2) distance to model in X-space(identifies moderate outliers).

M. Persson et al. / Scandinavian Journal of Pain 3 (2012) 151–163 155

Table 2Number (n) and percentage (%) of responders to placebo, morphine, and ketamine together with global responders and global non responders for three different assessmentmodalities (local pain intensity, pain unpleasantness and percentage pain relief).

Assessment Response Placebo Morphine Ketamine Global responders Global non responders

n % n %a n %a n %a n %a

Local pain intensity Responder 24 26 32 47 28 41 17 25Non responder 69 74 36 53 41 59 25 37Incomplete data 1 1 1

Pain unpleasantness Responder 29 31 29 46 28 44 15 23Non responder 64 69 34 54 36 56 21 33Incomplete data 1 1 1

Per cent pain relief Responder 25 27 27 41 30 45 17 25Non responder 67 73 39 59 37 55 26 39Incomplete data 2 1 1

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among reported side-effects (Table 6). In two subjects who receivedmorphine and in four subjects who received ketamine, the infusionswere discontinued because of side effects.

Table 3Pain intensity and unpleasantness at baseline in patients given different drugs.

Drug Pain intensity VAS Pain unpleasantness VAS

a The percentage of responders to morphine, ketamine, global responders and glo

A p-value ≤ 0.05 was considered to be statistically significant inll tests.

. Results

.1. Pharmacological challenges

.1.1. Drop-outsOne subject withdrew from the study (the informed consent)

efore the tests were carried out and is not included in the analysis.

.1.2. Proportions of placebo responders, responders, and nonesponders.1.2.1. Placebo responders. Depending on the out-ome/assessment variable selected (local pain intensity, painnpleasantness, or percentage pain relief), the proportion oflacebo responders varied between 26 and 31% (Table 2). Amonghe 24 placebo responders (according to the assessment ofain intensity), 15 (63%) also responded to morphine, 17 (71%)esponded to ketamine, and 11 (46%) responded to both drugs.nly two subjects selectively responded to the placebo.

.1.2.2. Responders and non responders to morphine and ketamine.mong the placebo non responders, morphine responders variedetween 41 and 47% and ketamine responders between 41 and5% depending on the assessment variable chosen. Global respon-ers varied between 23 and 25% and global non responders variedetween 33 and 39% (Table 2). 15–22% responded only to morphinend 16–20% only to ketamine.

To summarize according to the assessments of pain intensity,here were 24 placebo responders (26%), 43 active respondersresponding to morphine and/or ketamine but not to placebo, 47%)nd 25 non responders (not responding to any drug, 27%). Threeubjects had incomplete data, so they were not included in thesealculations.

.1.3. Assessment of pain intensity, unpleasantness, and per centain relief over time for the different drugs

There were no differences in the means of the baseline assess-ents (i.e., before the drug administration) of pain intensity

nd unpleasantness between the three sessions (Table 3). Theon responders had a significantly higher baseline assessmentegarding pain unpleasantness (p = 0.047) than the other responderroups. A similar tendency (non-significant; p = 0.080) was noted
or pain intensity.
All three substances significantly reduced pain intensity andain unpleasantness compared to baseline on all assessment pointsuring the test sessions (data not shown). In the initial parts of the

on responders were calculated with the placebo responders excluded.

test sessions, ketamine reduced pain intensity significantly morethan both the placebo and morphine. Morphine was more effec-tive than the placebo on most of the assessment points and inthe later parts of the test sessions morphine was more effectivethan ketamine. A similar pattern was noted for the assessments ofpercentage pain relief.

Morphine was significantly more effective than the placeboregarding VAS-area under curve for pain intensity and unpleasant-ness and regarding mean decrease in pain intensity and in meanper cent pain relief. Morphine also showed a tendency (p = 0.055)to be better than the placebo regarding mean decrease in painunpleasantness (Table 4).

Ketamine was significantly more effective than the placebo formean decrease in pain unpleasantness and in mean per cent painrelief. For the VAS-area under curve and mean decrease in painintensity, ketamine showed no difference compared to the placebo(Table 4).

Morphine showed significance versus ketamine for VAS-areaunder curve for pain intensity (p = 0.018) and a tendency to signifi-cance for VAS-area under curve for pain unpleasantness (p = 0.062).There was also a tendency for morphine to be more effectivethan ketamine regarding mean VAS decrease for pain intensity(p = 0.068).

3.1.4. EfficacyMorphine and ketamine showed significant differences in effi-

cacy when compared to placebo except for morphine’s abilityto decrease pain unpleasantness (Table 5). Ketamine was signifi-cantly more effective than morphine regarding the efficacy for painunpleasantness (p = 0.049) and per cent pain relief (p = 0.037).

3.1.5. Side-effectsSedation/tiredness (all three drugs, most prominent for mida-

zolam), dizziness (morphine and ketamine), nausea/vomiting(morphine), and paresthesias/numbness (ketamine) dominated

Mean (SD) Mean (SD)

Morphine 51.9 (21.3) 48.2 (21.1)Ketamine 50.9 (22.9) 50.4 (22.7)Placebo 52.6 (21.0) 48.9 (23.1)

156 M. Persson et al. / Scandinavian Journal of Pain 3 (2012) 151–163

Table 4Mean values (±one SD) of VAS-area under curve and mean decrease (baseline vs. the mean of all assessments during the test session) in pain intensity and in unpleasantnesstogether with mean per cent pain relief for the three drugs.

Drug VAS area under curve (mm min) Mean decrease Mean per cent pain reliefMean (SD)

Pain intensityMean (SD)

UnpleasantnessMean (SD)



Morphine 5105** (3827) 4624* (3704) 16.6** (17.2) 15.4 (17.5) 36.1*** (32.3)Ketamine 5863 (3386) 5073 (3370) 13.9 (17.1) 16.9** (19.1) 33.7*** (28.0)Placebo 6228 (2901) 5417 (3035) 10.6 (12.2) 11.7 (14.7) 20.8 (21.5)

* Significant difference between morphine or ketamine versus placebo: p < 0.05.** Significant difference between morphine or ketamine versus placebo: p < 0.01.

*** Significant difference between morphine or ketamine versus placebo: p < 0.001.

Table 5Efficacy (mean values (±one SD)) in pain intensity, unpleasantness, categorical rating of pain and percentage pain relief.



Categorical ratingMean (SD)

Per cent pain reliefMean (SD)

Morphine 26.5** (19.7) 25.8 (20.1) 0.96* (0.84) 48.5** (38.8)Ketamine 28.4** (21.2) 31.3*** (22.7) 1.16*** (0.92) 58.5*** (38.2)Placebo 20.6 (17.6) 23.1 (19.5) 0.69 (0.74) 35.5 (32.6)

* Significant difference between morphine or ketamine versus placebo: p < 0.05.** Significant difference between morphine or ketamine versus placebo: p < 0.01.

*** Significant difference between morphine or ketamine versus placebo: p < 0.001.

Table 6Number and percentage (%) of subjects with registered side-effects and with anintensity of more than 50 mm on a 100 mm VAS.

Side-effect Drug

Morphinen (%)

Ketaminen (%)

Placebo (midazolam)n (%)

Sedation/tiredness 33 (35) 21 (22) 45 (48)Dreams/hallucinations 1 (1) 8 (9) 1 (1)Dizziness 25 (27) 46 (49) 4 (4)Nausea/vomiting 23 (24) 8 (9) 0 (0)

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.1.6. Influence of pre-study use of analgesicsSome data were missing (13%, Table 1) regarding the pre-study

se of analgesics.

.1.6.1. NSAID (Non-Steroid Anti-inflammatory Drug)/acetamino-hen. There were no differences in the proportions of the respon-er groups depending on variations in the pre-study use ofSAID and/or acetaminophen. Gender proportions, age, duration of

ymptoms, and baseline assessments of pain intensity and unpleas-ntness did not significantly variate with the use of these drugsdata not shown).

Similarly, there were no significant influences on the effect oforphine, ketamine, and midazolam regarding VAS-area under

urve and efficacy (data not shown). With respect to the mean VASecrease during the test sessions, those reporting no pre-study usef NSAID/acetaminophen showed a significantly lower value fororphine (p = 0.044). For ketamine and midazolam, there were no

ifferences.

.1.6.2. Weak opioids (tramadol, dextropropoxyphen, codeine).here were no differences in the proportions of the responderroups depending on variations in the pre-study use of weak opi-ids. Similarly, there were no influence on gender, age, duration ofymptoms and baseline assessments of pain unpleasantness (data
ot shown). Those reporting daily use of weak opioids had a signif-
cantly higher baseline assessment of pain intensity (p = 0.028).The pre-study use of weak opioids did not affect the mean

AS decrease or efficacy of the three substances used in the

pharmacological tests. Those reporting daily use of weak opioidshad a larger VAS area under curve in the ketamine test (p = 0.033)but not in the morphine or midazolam tests.

3.1.6.3. Strong opioids. No subject in the study sample reported anypre-study use of strong opioids.

3.1.7. Influence of the sequence of infusionsWe compared the groups where the placebo infusions were

given in the first session (n = 32), second session (n = 30), and thirdsession (n = 31). The analysis showed no significant differenceswith respect to gender, age, duration of symptoms, and baselineassessments of pain intensity and unpleasantness (data not shown).VAS area under curve, mean VAS decrease, efficacy, and mean andmaximum per cent pain relief for all three substances did not sig-nificantly depend on where the placebo infusions were placed inthe sequence. There were no significant impacts of the placebosequence on the proportions of the responder groups (data notshown).

Similar analyses were made for morphine and ketamine wherewe grouped the whole sample according to where the drugs wereplaced in the sequence of infusions. As with the placebo infusion,morphine and ketamine did not significantly influence the mainresults of the study (data not shown).

3.2. Group belonging in the pharmacological challenges versuspain intensities, pain unpleasantness, and psychometric tests

There were few and relatively small differences between thethree groups of subjects (i.e., placebo responders, active responders,and non responders). We found significant group differences for thefollowing variables:

Pain unpleasantness at baseline (Placebo: 44 ± 22; Active respon-ders: 46 ± 17; Non responders: 58 ± 23; p = 0.047);CSQ – Coping self statements (Placebo: 19 ± 5.6; Active respon-ders: 18.7 ± 6.6; Non responders: 14.9 ± 6.9; p = 0.045);
CSQ – Increased activities (Placebo 14.2 ± 4.8; Active responders:14.3 ± 6.1; Non responders: 10.2 ± 5.0; p = 0.009);CSQ – Ability to decrease pain (Placebo: 3.1 ± 0.9; Active respon-ders: 2.7 ± 0.9; Non responders: 2.2 ± 0.9; p = 0.006);

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General activity index of MPI (Placebo: 3.1 ± 0.8; Active respon-ders: 2.6 ± 0.6; Non responders: 2.3 ± 0.8; p = 0.003); andLiSAT-11 – Life as a whole (Placebo: 4.1 ± 1.5; Active responders:3.8 ± 1.3; Non responders: 3.3 ± 1.1; p = 0.046).

Hence, the non responder group displayed the worse situationor these significant aspects. Generally, similar trends were notedor most items of the non-significant variables (data not shown).ence, no significant group differences were found for BDI, for sixf nine subscales of the CSQ, for eight of nine subscales of the MPI,nd for ten of eleven items in the LiSAT-11. None of the subscalesf SF36 and EuroQol showed any significant differences.

A PCA was made to confirm the significant results and therends mentioned above. One multivariate outlier was identifiednd excluded from the subsequent analysis. Placebo response,ctive response, and Non response were coded as dummy variables

1 = fulfilled the criteria and 0 = did not fulfil the criteria) and werencluded in the analysis together with pain-related variables andhe different psychometric instruments. PCA identified four sig-ificant components (p1–4) (groups of intercorrelated variables)hat together explained 44% of the variation in the data matrixR2 = 0.44). Two components (p1 and p2) included one of the threeummy variables (Fig. 1a and b). According to p1 (Fig. 1a), pain

ntensity and unpleasantness, CSQ-catastrophizing, BDI, and theajority of the variables of the first section of MPI and EQ5D (except

he health scale) were positively intercorrelated (in Fig. 1a withegative loadings). In addition, the Non response dummy variable

ntercorrelated positively weakly and significantly to this group ofariables. This group of variables correlated negatively with thebsolute majority of variables of LiSAT-11 and SF36. In other words,on response was (weakly) associated with high pain intensity andther symptoms and with low life satisfaction and health. Hence,he patterns of loadings in Fig. 1a confirmed the non-significantrends observed when separately scrutinizing each item of the painariables and the psychometric instruments.

The Non response dummy variable showed a higher absoluteoading on the second component p2 (Fig. 1b). This component

ainly showed a negative intercorrelation between certain aspectsf CSQ and Non response, generally confirming in a multivariateontext the significant differences reported from the univariatenalyses above.

It was not possible to predict group belonging (Placebo respon-ers, Active responders, and Non responders) using PLS-DA. Hence,he above mentioned significant differences were relatively small.

. Discussion

.1. The main results

This study confirms the heterogeneity of a group of subjectsith chronic WAD when it comes to responses to pharmacolog-

cal challenges with morphine, ketamine, and midazolam (activelacebo).

The study displays a large group of subjects not responding tony of the drugs used in the tests (Non responders, 27%).

The Non responder group seems to be the worst cases on a groupevel in some aspects of the psychometric instruments used in thetudy.

.2. The relevance of pharmacological challenge of chronic paintates

.2.1. Different purposes of intravenous pharmacological testsOur study displays heterogeneity in a group of subjects with

hronic WAD. With the method and definitions used, we are able to

nal of Pain 3 (2012) 151–163 157

draw some conclusions about the heterogeneity, but we can neithermake any predictions on the outcome of long-term therapy withthe drugs tested nor conclusions regarding specific pain processingmechanisms.

Since the early 1990s, the literature has seen an expansion ofreports concerning intravenous (i.v.) pharmacological tests includ-ing a multitude of drugs and different pain states. The purposes ofthe tests differ. Some studies try to elucidate whether results froman i.v. drug test can predict the outcome of a long-term drug ther-apy [23,38–42]. Other studies use pharmacological tests to predictthe outcome of surgical or other invasive procedures [43,44]. A thirdfocus is to use i.v. drug tests, presuming known targets of the drugs,to analyse pain pathophysiology in experimental pain [24,45–48]as well as in clinical pain states [25,49–52] and in combinations(induced experimental pain in subjects with a chronic pain state)[11,26,53].

A systematic review found weak or no evidence for the utility ofi.v. infusion tests [54]. However, this review focused on evidence forthe tests ability to predict the outcome of a long-term drug therapy.The shortcomings of these studies were related to more than justmethodological flaws. For instance, some drugs used for i.v. testsdo not have an analogous available drug for long-term therapy orthere might be side-effects not seen in the i.v. test but seen aftersome time during the long-term treatment.

4.2.2. Cutoff pointsOne aspect for consideration is where to set the cutoff point for

the dichotomy response and non response to a pharmacologicalchallenge. We chose the 50% paradigm, i.e., a response was definedas a ≥50% pain decrease on two consecutive assessments during thetest session compared to baseline; anything less was considered anon response. Farrar et al. studied the subject by reanalysing formerclinical trials [55,56]. They tried to define the degree of change inabsolute pain rating scales (e.g., an 11-point pain intensity ratingscale, NRS) that best corresponded to significant clinical improve-ment estimated by some global assessment (by the patient). Theyfound, on average, that a reduction of approximately two points(on an 11-point NRS) or a reduction of approximately 30% rep-resented a significant clinical difference. However, these studiesconcerned the cutoff point for significant clinical improvement inlong-term treatment of chronic pain. Our study has another target:trying to display different patterns of responses to an i.v. pharma-cological challenge in a group with a specified chronic pain state.Cohen et al. designed a cutoff point to a 67% pain relief, which gavethe best prediction by an i.v. ketamine test for the outcome of anoral dextromethorphan treatment in neuropathic pain [39]. Theyused the same cutoff point in similar studies regarding fibromyalgiapatients [40] and in opioid-exposed patients with persistent pain[41]. Again, this cutoff point was designed for another purpose thanwhat is relevant for our study. To our knowledge, no similar data-driven studies exist that define the cutoff points for i.v. drug teststo elucidate patterns of responses on a group level. We find it rea-sonable to believe that the 30% cutoff point might be too weak andthe 67% cutoff too strong for our purpose. Hence, we chose the 50%paradigm although it is an arbitrary designation to some extent.

4.2.3. Pain intensity and pain unpleasantnessIn our study, there were small differences (on a group level)

between the two assessment modalities – pain intensity andpain unpleasantness – both regarding the baseline assessmentsand the proportions of different responses to the substances.Hence, it can be questioned whether it is possible to distinguish
between the intensity/sensory and the unpleasantness/affectivefactors in the perception of pain. An alternative is that thesetwo factors are separable but strongly correlated. Traditionally,the pain experience has been analysed in the following three

158 M. Persson et al. / Scandinavian Journal of Pain 3 (2012) 151–163

Fig. 1. a: Loadings of the first component. The columns of variables with significant loadings are red. The non response dummy variable (labelled as Nonglobal), painintensity and unpleasantness, CSQ-catastrophizing, BDI and the majority of the variables of the first section of MPI and of EQ5D were positively intercorrelated (all hadnegative loadings). These variables correlated negatively with the absolute majority of variables of LiSAT-11 and SF36 (i.e., these had positive loadings). Hence, non responsew ctionT varias brevia

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as associated with high pain intensity and other symptoms and with low life satisfahe columns of variables with significant loadings are red. The non response dummyigns) with certain aspects of CSQ (but not CSQ-catastrophizing; see Fig. 1a). For ab

ays: sensory/discriminative, affective/motivational, and cogni-ive/evaluative. Fields argues that there are primary and secondarynpleasantnesses [57]. The first is stimulus bound and hence shoulde analysed as a sensory/discriminative component of pain. In ournderstanding, one could, for example, ask whether there is anyain that is not unpleasant. The secondary unpleasantness “[. . .] is
higher level process to which contextual features contribute pow-rfully resulting in an emotional experience[. . .]” [57]. The questionan be raised regarding what kind of unpleasantness we measure,specially in a pharmacological short-term drug test. We also used
and health. For abbreviations, see Appendix A. b: Loadings of the second component.ble (labelled as Nonglobal) mainly showed a negative intercorrelation (i.e., differenttions, see Appendix A.

a placebo substance (benzodiazepine) that could have influencedthe affective pain component.

4.2.4. The possible influence of pre-study use of analgesicsUnfortunately, data were missing regarding the use of pre-study

analgesics. However, we did not find any significant influence onthe major results of the study. No subject in the sample reportedany pre-study use of strong opioids, which, of course, would haveinfluenced the analysis.

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We find it difficult to explain why those reporting no use ofSAID and/or acetaminophen have a significant lower mean VASecrease during the morphine test (p = 0.044). Without any ratio-ale we interpret this as a random result.

Those subjects reporting a daily pre-study use of weak opioidsad a significantly higher baseline assessment of pain intensityp = 0.028). As the subjects were instructed not to take any anal-esics for at least 8 h before the test sessions, this result mighteflect the absence of their daily used analgesic at the baselinessessment. Together with the short-acting pharmacokinetic pro-le of ketamine, this could also explain why subjects who usedeak opioids on a daily basis had a larger VAS area under curveuring the ketamine infusion.

.2.5. Alternatives in study designThere are some possible alternatives when designing a phar-

acological study like the present one. For instance, a study canonsider the pharmacokinetic profiles of the drugs and adjust theimetable for assessments of effect accordingly. For the sake of sim-licity and for optimizing the blinding procedure, we chose a designith a fixed timetable and fixed points of time for assessment of

ffect, a strategy that covered most of the elimination half life forhe drugs tested. The differences between pharmacokinetic pro-les of the drugs were reflected in the results with the short actingetamine proving more effective in reducing pain in the beginningf the test sessions and morphine proving more effective in the laterarts. Morphine was also more prominent in reducing the VAS areander curve, whereas ketamine seemed to be more prominent infficacy parameters.

.3. The placebo effect/response

.3.1. The placebo effect per seThe placebo effect is indeed a complex phenomenon. Recent

ears have seen an expansion of research into the mechanismsf the placebo effect, especially regarding pain (experimental andlinical). One of the main results of this research is the knowledgehat a placebo response is a real psychobiological phenomenonhere the central nervous system is involved not only on the psy-

hological level but also on a physiological level. It represents aink between a complex mental activity and the body [58]. Theres not one specific mechanism responsible for the placebo effectnd there is not a single placebo effect, but many. There are differ-nt mechanisms for different medical conditions and interventions58]. When it comes to pain, data indicate that the placebo effectorks in part through the opioid-related endogenous pain modula-

ory descending circuits and in part through the dopamine-relatedircuits for reward [59,60]. The placebo effect regarding pain isobust and strong. In one study, the placebo was as effective ashidden i.v. injection of 8 mg morphine [61]. Several studies have

ound the magnitude of the placebo analgesic effect to be aroundout of 10 on a visual analogue scale. When viewing the placebo

esponders selectively, the effect is even more impressive: 3.3–5ut of 10 [60]. Some data indicate that the placebo effect workinghrough the endogenous opioid system also has the capability to beelectively directed to local parts of the body; i.e., it works under aomatotopical structure [62]. Other data indicate that the placeboight work on a spinal as well as a supra-spinal level with impact

n the mechanisms we think are responsible for central sensitiza-ion; i.e., the placebo effect might mimic the effect we assign toetamine [63].

This knowledge about the placebo effect raises the follow-
ng question: How should we interpret the placebo response in
pharmacological drug test? In addition to an active placebomidazolam), we tested morphine and ketamine and the placeboffect might mimic them both. However, we find it reasonable to

nal of Pain 3 (2012) 151–163 159

exclude the placebo responders when analysing the proportions ofthe other responder groups, but bearing in mind that among theplacebo responders there might be some with “true” morphine-responsiveness, some with “true” ketamine-responsiveness, andsome with a combination of the two. In the present study, only twoout of 24 placebo responders (pain intensity) selectively respondedto the placebo substance.

4.3.2. MidazolamThe present study obtained a higher proportion of placebo

responders (26%, pain intensity) compared to an earlier study ofWAD-subjects, which had a proportion of approximately 10% whensaline was used as a placebo [11]. On the other hand, the fre-quency of side-effects, especially sedation and tiredness, indicatesthat our placebo infusions to some extent mimicked the infusionsof the other substances, which was why we used midazolam as aplacebo substance. The frequency of sedation and tiredness wasmore prominent for midazolam infusion than for morphine andketamine (Table 6), indicating that the dosage of midazolam wastoo high. This finding suggests that future studies may want toconsider reducing the dosage.

A possible confounding factor in the analysis of the placeboresponse could be where the placebo infusions were placed in thesequence – first, second, or third infusion. However, we found thatwhere the infusions were administered in the sequence had nomajor impact.

We used midazolam as an active placebo substance assumingthat it has no inherent analgesic activity. However, the absence ofanalgesic effects of benzodiazepines (BZ) is not a straightforwardmatter. It is fairly well documented that BZ has analgesic effectswhen administered intrathecally [64,65], whereas the effects withsystemic administration have been more controversial. Severalclinical reports indicate analgesic effects in chronic pain syndromessuch as cancer pain, phantom limb pain, and myofascial pain [66].Knabl et al. [67] speculate that the controversy regarding sys-temic BZ might be due to studies not distinguishing between acutepain and chronic pain states with hyperalgesia. They state thatintrathecal BZ can have antihyperalgesic effect in the absence ofany antinociceptive effect on acute pain [68].

4.4. The different responder groups

4.4.1. MorphineMorphine is the prototypical �-receptor agonist presumed

to exert its main analgesic effect through a blockade or inhi-bition/modulation of an on-going nociceptive input to the paintransmission system [69]. Clinically, it is well known that there is ahigh degree of inter-individual variation of sensitivity for the anal-gesic effect as well as for side-effects. This variation might be dueto genetic variations in the expression and distribution of receptorsubtypes [70].

In the present study, 32 of 69 (47%, pain intensity, placeboresponders excluded) responded to the morphine infusion accord-ing to the assessments of pain intensity. This result is similar towhat a smaller study of chronic WAD subjects found [11]. We findit reasonable to interpret these results taken together as showingthat at least a subgroup of subjects with chronic WAD has opioidsensitive pain.

4.4.2. KetamineKetamine exerts its analgesic effect mainly through a non-

competitive blockade of the NMDA-receptor in the central nervous
system even though at higher doses it may interact with �-opioidreceptors and suppress sodium channels [71]. The importance ofthe NMDA-receptor for a nociceptive or neuropathic input to ini-tiate central sensitization is well documented [17,72,73]. It is also

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ell documented that at least a subgroup of patients with chronicAD shows signs of a central sensitization [20–22].We used a subanaesthetic low-dose ketamine infusion

0.3 mg/kg), which presumably would rule out any significant anal-esic effect other than the NMDA-receptor blockade. Of 69 subjects,8 (41%, pain intensity, placebo responders excluded) respondedo ketamine. This result might indicate the presence of a centralensitization in a subgroup of patients with chronic WAD.

.4.3. Global respondersOf 69 subjects, 17 (25%, pain intensity, placebo responders

xcluded) responded to both morphine and ketamine.Some studies indicate the importance of a peripheral nocicep-

ive input for initiating and maintaining a central sensitization inhronic pain [74–76]. It is reasonable to believe that there are vari-tions in the degree of on-going nociceptive input as well as in theegree of central hypersensitivity among subjects with pain suchs chronic WAD. In the present study some individuals respondedrimarily to morphine, some to ketamine, and some to both drugs.

.4.4. Non respondersAn intriguing result of our pharmacological tests is the rela-

ively high frequency of non responders (25 out of 69, 37%, placeboesponders excluded). This finding is in line with a smaller study ofubjects with chronic WAD that showed a frequency of global nonesponders of 33% [11]. These figures for global non respondersoncerning chronic WAD are higher than in comparable studiesegarding other pain states: one study on patients with fibromyal-ia syndrome showed a frequency of 17% [25] and one study onow-back pain showed 25% global non responders [43].

Hence, one of four subjects in a relatively large group of subjectsith chronic WAD did not reach 50% pain relief when chal-

enged with an active placebo infusion, an infusion of morphine0.3 mg/kg), or an infusion of ketamine (0.3 mg/kg), otherwise doc-mented to have a potency for a high analgesic effect. So far we cannly speculate about this result:

We tested three substances. There might be other targets in thepain processing system not reached by our drugs but relevant,e.g., for central hyperexcitability (sensitization).A subgroup of patients with chronic WAD might be extremelybiased to the psychosocial side of the biopsychosocial pain model,making these patients out of reach for any significant pain reliefprovided by analgesic drugs.Assessment considerations must be addressed. We placed sub-jects with a chronic pain state in a rather odd experimentalsituation, compared to daily life, and asked them for a minute-by-minute estimation of pain intensity, unpleasantness, and percent pain relief. All this was done during a drug infusion with side-effects probably obscuring the capability of correct estimates tosome extent.

The non responders had a significantly higher baseline assess-ent of their pain unpleasantness compared to the other groups

p = 0.047). There was also a weak trend (p = 0.080) for higher base-ine in pain intensity in the non responder group.

In addition to the tendency for the non responder group subjectso rate their baseline pain higher than the other responder groups,he non responders seem to be the worst cases in at least somespects of the psychometric tests used in this study. This findingould be in line with clinical experience when it comes to treatinghronic pain: patients with scores indicating depression, anxiety,
aladaptive coping strategies, etc. seem less disposed to respond
ositively to a single medical intervention such as a drug treatment.We can only speculate about the reasons why non responders

eem to score badly in the psychometric tests. The biopsychosocial

nal of Pain 3 (2012) 151–163

model is now widely accepted as a model for understanding chronicpain disorders. The underlying neuromatrix for pain is a complexneurophysiological system mediating all the factors inherent inthe model, leading to the final pain experience and behaviour. Theascending somatosensory input from the periphery is modulatedin the matrix and descending pathways from the matrix have thepotential to facilitate or inhibit the peripheral input at different lev-els of the central nervous system. The complexity increases whenconsidering the plasticity of the neuromatrix, i.e., an on-going noci-ceptive or neuropathic input in the system tends to change thematrix in different ways. Furthermore, we have the question ofthe reversibility of these plastic changes. Finally, we can considerpossible genetic variations in how the matrix performs the painprocessing mechanisms. In the context of this complexity we haveto consider the i.v. infusion of a pain-reducing drug as a rathercoarse intervention. It is understandable that some individuals witha chronic pain disorder have other dominating factors in the matrixthan those targeted by the drug, leaving the pain experience moreor less unaffected by the drug intervention. For some individuals,some of these other factors might be reflected in the psychometrictests.

4.5. Methodological aspects

In addition to the uncertainties mentioned in other parts of thisdiscussion, this study may have other limitations that need to beconsidered.

4.5.1. Sample biasThe sample in the study was recruited from patients referred

to a second or third level of health care institutions for manage-ment of chronic pain. Hence, those managed in primary care wereexcluded. This could put into question how representative the sam-ple is for the whole population of chronic WAD. The estimate ofthe population itself is poorly defined in the literature: differentstudies show different results regarding incidence and prevalenceof chronic WAD as well as regarding the recovery rate from acuteWAD [2,3,77]. This context of what is considered to be chronic WADadds further uncertainty regarding the relevance of a single sample.

4.5.2. Inclusion/exclusion criteriaSome chronic WAD patients develop a generalized muscu-

loskeletal disorder including spontaneous pain in all four quadrantsof the body. Studies trying to reveal a relationship between chronicWAD and fibromyalgia show contradictory results [78–80]. Wedecided to exclude from the study those with generalized pain andrestricted the sample to those with localized pain in the neck withpossible referred pain to the head and/or upper extremities. Thereason for this exclusion criteria was that we planned to evaluatethe effect of diagnostic blocks of zygapophyseal joints and the effi-cacy of radiofrequency neurotomy of the innervation of these joints.The results of this will be considered in future papers. However, thisexclusion criteria might imply a further restriction in the relevanceof the sample in relation to the population of chronic WAD.

4.5.3. Pain mechanismsIn recent years, pain research has focused on genetic variability.

Genetic variations are considered to have an impact on the dis-position to develop a chronic pain state and how the neuromatrixresponsible for processing a nociceptive or neuropathic input isworking. Genetic variability is also believed to be of importancewhen it comes to responses to medical interventions such as anal-
gesic drugs. Hence, this variability is a factor to consider whentrying to understand precise pain mechanisms and their treatmentin the individual patient as well as in defined groups of chronic painstates. In an ideal world, we know these precise pain mechanisms

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hen meeting the individual patient or when dealing with a groupf patients with a defined chronic pain state. We can target thisnown mechanism in our treatment and restrict our samples forlinical research to those with pain mechanisms apt to respond tohe intervention we are investigating. Today, in the clinic as wells in clinical research, we seldom have this precise knowledge ofain mechanisms. Most often we deal with syndromes with poorlyefined mechanisms for chronic pain: failed back surgery, low backain, general myofascial pain, fibromyalgia, temporo-mandibularisorders, CRPS, etc. The underlying variability in pain syndromes

eads to poor treatment results. Some impact of the variability cane reduced in clinical research by expanding sample sizes, but treat-ents are sometimes probably ruled out simply because of poorly

efined pain mechanisms in the sample.Chronic WAD is a pain syndrome with poorly defined pain

echanisms, presumably involving a great deal of variability.hen challenging patients with an i.v. infusion of morphine,

etamine, and midazolam (active placebo), we do not knowhether the variations in responses reflect variations inherent in

he concept of chronic WAD or simply reflect genetically deter-ined dispositions. However, we do know that at least some of

he subjects with chronic WAD have signs of central sensitizationn their pain processing system [18,21,22]. We also know that theMDA-receptor, the main target for ketamine, is of major impor-

ance in the development of central sensitization [16,17]. We doave data that suggests that morphine and ketamine have differentargets for their pain reducing effects [46] and we have data display-ng synergistic effects of morphine and ketamine [24,47,48], whichlso implies that there are different targets for the substances.ence, the present study does not reveal precise pain mechanismsut does reveal one aspect of the heterogeneity in the populationf subjects suffering from chronic WAD.

.6. Conclusions

The population with chronic WAD contain subgroups withariations in pain-reducing effects of morphine, ketamine, andidazolam (active placebo) when studied with an i.v. pharmaco-

ogical challenge. That is, our study confirms the heterogeneitynherent in a group of subjects with chronic WAD. The studyevealed that many subjects did not respond to any of therugs used. This non responder group proved to be theorst cases in some aspects of the psychometric instrumentssed.

onflict of interest statement

None.

cknowledgements

This study was supported by the Medical Research Council ofoutheast Sweden. We wish to express our thanks to the painurses, study nurses, and assistant nurses and to the logistic per-onnel in our institutions – without them there had been no study.

ppendix A. Abbreviations of Fig. 1a and b

lacebores Placebo respondersctiveResp Active respondersonglobal Non responders

ADduratio Duration of pain
asePaini Baseline pain intensityaseUnplea Baseline pain unpleasantness
SQ43 Coping Strategies Questionnaire/perceived control of painSQ44 CSQ/ability to minimize pain

[

nal of Pain 3 (2012) 151–163 161

Appendix A (Continued )CSQ DA CSQ Diverting attentionCSQ RS CSQ Reinterpreting pain sensationsCSQ CSS CSQ Coping self-statementsCSQ IS CSQ Ignoring pain sensationsCSQ PH CSQ Praying and hopingCSQ CAT CSQ CatastrophizingCSQ IBA CSQ Increased Behavioural activities

BDIindex Beck Depression Inventory index

LSQ01 life Life Satisfaction Checklist (LiSat-11) Satisfaction with lifeas a whole

LSQ02 work LiSat-11 Satisfaction with vocational situationLSQ03 econ LiSat-11 Satisfaction with financial situationLSQ04 leis LiSat-11 Satisfaction with leisure situationLSQ05 frie LiSat-11 Satisfaction with contacts with friends and

acquaintancesLSQ06 sexl LiSat-11 Satisfaction with sexual lifeLSQ07 ADL LiSat-11 Satisfaction with Activities of Daily LifeLSQ08 fami LiSat-11 Satisfaction with family lifeLSQ09 marr LiSat-11 Satisfaction with partnershipLSQ10 phys LiSat-11 Satisfaction with physical healthLSQ11 psyc LiSat-11 Satisfaction with mental health

MPI1a Multidimensional Pain Inventory (MPI) Pain severityMPI1b MPI Interference – pain related interference in everyday

lifeMPI1c MPI Perceived Life ControlMPI1d MPI Affective DistressMPI1e MPI Social Support – perceived support from spouse of

significant othersMPI2a MPI Punishing ResponsesMPI2b MPI Solicitous ResponsesMPI2c MPI Distracting ResponsesMPIGA MPI General Activity Index

EQ5D1 mob EuroQol mobilityEQ5D2 ADL EuroQol self-careEQ5D3 acti EuroQol usual activitiesEQ5D4 pain EuroQol pain/discomfortEQ5D5 anx EuroQol anxiety/depressionEQ5D7VAS EuroQol VAS – self estimation of perceived health

SF36 PF SF36 Physical functioningSF36 RP SF36 Role limitations due to physical painSF36 BP SF36 Bodily painSF36 GH SF36 General HealthSF36 VT SF36 VitalitySF36 SF SF36 Social functioningSF36 RE SF36 Role limitations due to emotional problemsSF36 MH SF36 Mental healthSF36 pcs SF36 Physical scoreSF36 mcs SF36 Mental score

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Whiplash Associated Disorders (WAD): Responses to pharmacological challenges and psychometric tests

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