Received: 3 March 2022

| Revised: 3 May 2022

| Accepted: 21 May 2022

DOI: 10.1002/ejp.1988

ORIGINAL ARTICLE

The effect of duloxetine on mechanistic pain profiles,

cognitive factors and clinical pain in patients with painful
knee osteoarthritis—­A randomized, double-­blind,
placebo-­controlled, crossover study

Kristian Kjær-­Staal Petersen1,2 | Asbjørn Mohr Drewes3,4 | Anne Estrup Olesen3,5 |

Nadia Ammitzbøll3,4 | Davide Bertoli3,4 | Christina Brock3,4 | Lars Arendt-­Nielsen1,2,4
1
Center for Neuroplasticity and Pain, Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
2
Center for Mathematical Modeling of Knee Osteoarthritis (MathKOA), Department of Material and Production, Faculty of Engineering and Science,
Aalborg University, Aalborg, Denmark
3
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
4
Mech-­Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
5
Department of Clinical Pharmacology, Aalborg University Hospital, Aalborg, Denmark

Correspondence
Kristian Kjær-­Staal Petersen, Center for Abstract
Neuroplasticity and Pain, Department Background: Duloxetine is indicated in the management of pain in osteoar-
of Health Science and Technology,
thritis. Evidence suggests that duloxetine modulates central pain mechanisms
Faculty of Medicine, Aalborg
University, Fredrik Bajers Vej 7 D3, DK-­ and cognitive factors, and these factors are assumed contributing to the analge-
9220 Aalborg, Denmark. sic effect. This proof-­of-­mechanism, randomized, placebo-­controlled, crossover,
Email: [email protected]
double-­blinded trial evaluated the effect of duloxetine on quantitative sensory
Funding information testing (QST), cognitive factors and clinical pain in patients with osteoarthritis
TaNeDS Daiichi Sankyo Science Center and to predict the analgesic effect.
Europe; The Shionogi Science Program;
Danish Rheumatism Association, Methods: Twenty-­five patients completed this cross-­over study with either 18-­
Grant/Award Number: A6579; Aalborg week duloxetine (maximum 60 mg/daily) followed by placebo or vice-­versa.
University, Grant/Award Number:
Pressure pain thresholds, temporal summation of pain and conditioned pain
771126; Danish National Research
Foundation, Grant/Award Number: modulation were assessed using cuff algometry. The Hospital Anxiety and
DNRF121; Center for Mathematical Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors.
Modeling of Knee Osteoarthritis
Clinical pain was assessed using Brief Pain Inventory and Western Ontario and
(MathKOA) is funded by the Novo
Nordisk Foundation, Grant/Award McMaster Universities Osteoarthritis Index. Linear regression models were used
Number: NNF21OC0065373 to predict the analgesic effect of duloxetine.
Results: Depending on the clinical pain outcome, 40%–­68% of patients were clas-
sified as responders to duloxetine. Linear regression models predicted the an-
algesic effect (predictive value of 45%–­75% depending on clinical pain outcome
parameter) using a combination of pretreatment QST parameters, cognitive fac-
tors and clinical pain. No significant changes were found for QST, cognitive fac-
tors or clinical pain on a group level when comparing duloxetine to placebo.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.

1650 | wileyonlinelibrary.com/journal/ejp  Eur J Pain. 2022;26:1650–1664.

PETERSEN et al.    | 1651

Conclusion: A combination of pretreatment QST, cognitive factors and clinical

pain was able to predict the analgesic response of duloxetine. However, in this
relatively small study, duloxetine did not selectively modulate QST, cognitive fac-
tors or clinical pain intensity when compared with placebo.
Significance: Duloxetine is proposed as a treatment for chronic pain. Pre-­clinical
trials suggest that duloxetine provides analgesia through modulation of descend-
ing pain inhibitory pathways or through improvements in cognitive factors. The
current study demonstrates that pretreatment mechanistic pain profiling, cogni-
tive factors and clinical pain can predict the analgesic effect of duloxetine and
that only a subset of patients might benefit from duloxetine treatment.

1 | I N T RO DU CT ION Petersen et al., 2015, 2016, 2021; Petersen, Simonsen,

et al., 2019). Pre-­clinical studies have shown that sero-
Osteoarthritis is prevalent in both high-­ and low-­income tonin and noradrenaline are important neurotransmitters
countries (Safiri et al., 2020). The prevalence of OA in- for the descending pain inhibitory pathways (Bannister
creases with life style changes (Reyes et al., 2016) and age et al., 2017; Lockwood et al., 2019), hence suggesting that
(Berenbaum et al., 2018), and the global prevalence of OA the human proxy for assessing the descending modula-
is expected to continue its rise. tion CPM (Bannister & Dickenson, 2017) may be useful
Pain is the hallmark symptom of OA and the 2019 to study such pain modulatory substances. CPM is the
Osteoarthritis Research Society International guide- human surrogate measure for diffuse noxious inhibitory
lines included duloxetine (a serotonin–­noradrenalin control (Yarnitsky, 2010). Yarnitsky et al., 2012 (Yarnitsky
reuptake inhibitor antidepressant) for the treatment of et al., 2012) suggested an analgesic effect of duloxetine
patients with OA and widespread pain and/or depres- and a normalization in CPM responses in patients with
sion (Bannuru et al., 2019). Seven randomized controlled diabetic neuropathy.
trials have demonstrated analgesic effects of duloxetine It has been suggested that CPM (Yarnitsky et al., 2012)
when compared to placebo in (Blikman et al., 2022; Chen and heat pain thresholds (Kisler et al., 2019) can predict
et al., 2021) although the mechanism-­of-­action in pain is the analgesic effect of duloxetine and thereby explain the
not completely elucidated. underlying mechanistic mode-­of-­action leading to a pos-
Recent evidence suggests that OA clinical pain is in- sible personalized pain management regime. In addition,
creased by cognitive factors such as depression, anxiety cognitive factors are often used to predict treatment re-
and pain catastrophizing (Edwards et al., 2011; Larsen, sponses (Edwards et al., 2011). A recent study found that
Laursen, Simonsen, et al., 2021). As an antidepressant, a combination of preoperative QST, cognitive factors and
for example, duloxetine, improves symptoms of depres- clinical pain predicted chronic postoperative pain after
sion and anxiety in patients with OA (Cipriani et al., 2018; total knee arthroplasty better than each parameter alone
Lunn et al., 2015). Therefore, it is likely that a potential (Larsen, Laursen, Edwards, et al., 2021). This suggests
analgesic effect of duloxetine could be partly mediated that a multidimensional evaluation of patients prior to OA
through these factors. treatment might be advantageous when pursuing a per-
Quantitative sensory testing (QST), for example, sonalized management approach.
pressure pain thresholds (PPTs), temporal summation The primary aim of this proof-­of-­mechanism, ran-
of pain (TSP) and conditioned pain modulation (CPM) domized, placebo-­controlled, double-­blinded, crossover
have been used to assess pain sensitivity in patients with trail was to investigate the effect of an 18-­week duloxetine
OA (Arendt-­Nielsen et al., 2015, 2016; Petersen, 2021; treatment on mechanistic pain biomarkers in patients
Petersen et al., 2016; Petersen, Olesen, et al., 2019; with painful OA and the study was therefore not powered
Petersen, Simonsen, et al., 2019). Accumulating evi- to investigate the potential analgesic effect of duloxetine
dence suggests that severe OA is associated with lower compared to placebo. Secondary aims included (A) the ef-
PPTs, facilitated TSP and impaired CPM (Arendt-­Nielsen fects of duloxetine on cognitive factors and clinical pain
et al., 2015) and that these mechanistic pain biomarkers features and (B) an attempt to predict the analgesic re-
might hold predictive value for pain management with sponse of duloxetine using a combination of pretreatment
different therapies (Edwards et al., 2016; Kjær et al., 2019; QST, cognitive factors and clinical pain.
1652 |    PETERSEN et al.

2 | M ET H ODOLOGY Practice (GCP) Unit of Aalborg University Hospital,

externally audited by the Danish Medicines Agency,
This proof-­of-­mechanism, randomized, placebo-­ and was conducted in accordance with The Helsinki
controlled, double-­blinded, crossover trail compared Declaration, GCP, and all applicable Danish regulatory
QST (PPTs, TSP and CPM) and cognitive factors (anxi- requirements. Informed consent was obtained from all
ety, depression and pain catastrophizing) before and after participants.
18 weeks of duloxetine and placebo. Forty patients were
randomized to one of two equally sized sequences: (1)
duloxetine followed by placebo or (2) placebo followed 2.1 | Study population
by duloxetine. Patients were screened for inclusion (visit
0) and assessed before (visit 1 and visit 3) and after the Patients were recruited through Synexus/C4Pain,
treatments (visit 2 and 4); see Figure 1 for overview. Visit Aalborg, Denmark (a contracting research organization).
2 and 4 were conducted when the patients received the Women and men, 40–­75 years of age, with OA of the
full dose treatment and before the discontinuation period. knee, who agreed to participate and filled in an informed
Randomization was conducted before baseline measure- consent, were included. Patients fulfilling the inclusion
ments at visit 1. Adverse events were assessed at each visit. criteria were invited to a screening visit (visit 0) during
The study was approved by The Danish Medicines which a physical and psychological (for evaluation of sui-
Agency (case number: 2019082317), The North Denmark cidal risk) examination was conducted by a medical doc-
Region Committee on Health Research Ethics (case tor. The screening included x-­ray of the knee, screening
number: N-­20190050), registered at Clini​calTr​ial.gov of medical records and screening of the eligibility criteria.
(clini​caltr​ials.gov identifier: NCT04224584), and in the Patients were asked to discontinue all analgesic pain med-
European Union Drug Regulating Authorities Clinical ication (including non-­steroidal anti-­inflammatory drugs
Trials Database (EudraCT number: 2019–­003437-­42). The [NSAIDs]) during the entire trial, and the patients were
study protocol is published (Ammitzbøll et al., 2021). The instructed to note the use of rescue medication (paraceta-
trial was continuously monitored by the Good Clinical mol) in a trial-­specific diary.

F I G U R E 1 Patients with osteoarthritis were screened (visit 0) and randomized (visit 1) into 18 weeks of duloxetine followed by 18 weeks
of placebo (sequence 1) or 18 weeks of placebo followed by 18 weeks of duloxetine (sequence 2). A 2-­week washout period was conducted
between the two treatments. Patients were assessed before (visit 1 and 3) and after (visit 2 and 4) each treatment. Assessments were
conducted at each of the four visits. HADS: Hospital anxiety and depression scale, BPI: Brief pain inventory, WOMAC: Western Ontario and
McMaster universities osteoarthritis index.
PETERSEN et al.    | 1653

According to the inclusion and exclusion criteria, pa- during the lockdown period, to minimize suspension of
tients who were eligible were invited to visit 1 during subjects, and to increase the willingness of continued
which they were included in the study and randomized. participation.

2.2 | Inclusion criteria and 2.4 | Blinding and randomization

exclusion criteria
The study drug was encapsulated in a gelatin capsule
Patients diagnosed with unilateral or bilateral OA of the (DBCaps® from Capsugel, size: AAEL, colour HPMC
knee according to the American College of Rheumatology Swedish Orange Opaque) with identical size, colour
criteria based on clinical and radiographic evidence and weight to ensure blinding. The study drug was pro-
(Altman et al., 1986) were recruited. In addition, patients duced and labelled by the Hospital Pharmacy at Aarhus
provided written informed consent and abided by the University Hospital, Aarhus, Denmark. The blind-
study restrictions. Prior to enrolment, the patients dis- ing and randomization procedures were conducted by
played a Kellgren and Lawrence grade of I, II or III at the the Hospital Pharmacy at Aarhus University Hospital.
index knee, reported worst pain intensity within the last Patients are block-­randomized (four patients at a time)
24 h as 5.0 to 10.0 cm (assessed on a 0–­10 cm visual ana- to either sequence 1 (e.g., duloxetine followed by pla-
logue scale [VAS] anchored at 0 cm: no pain and 10 cm: cebo) or sequence 2 (e.g., placebo followed by duloxetine).
worst pain imaginable) and agreed to maintain the same Patients, study personnel and study management were
activity level throughout the course of the study. blinded until the end of the trial. Procedures for unblind-
Enrolment was restricted to people aged 40 years or ing were initiated if the patient safety was at risk.
older because knee pain in younger patients is often due
to trauma rather than to naturally occurring OA. Patients
were screened for suicidal risk using the Columbia-­Suicide 3 | ASSESSMENTS
Severity Rating Scale (Posner et al., 2011), and patients at
risk were excluded to ensure patient welfare. Interactions Mechanistic pain profiles, cognitive factors and clinical
with other drugs are potentially a bias. Therefore, patients pain were assessed at visits 1, 2, 3 and 4.
having specific medical conditions other than OA or tak-
ing specific medications other than the allowed were ex-
cluded. Patients taking certain psychoactive medications, 3.1 | Mechanistic pain profiling
abusing drugs or alcohol or having other dependencies
were excluded because of the potential confounding fac- Deep tissue pain sensitivity was evaluated by cuff pres-
tors of these medications/substances on the results. sure stimuli using a computer-­controlled cuff algometer
(Cortex Technology and Aalborg University), including a
13-­cm wide tourniquet cuff (VBM) and an electronic VAS
2.3 | Treatments (Aalborg University) for the recording of the pain inten-
sity. The cuff was placed at the head of the gastrocnemius
Treatment periods included a 2-­week titration period muscle of the lower leg at the index knee. The electronic
(week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), continuous VAS (sliding resistor) was 10 cm long and
a 14-­week full treatment period (week 3–­16 [70 days]: sampled at 10 Hz; 0 cm: no pain and 10 cm: worst pain
60 mg/daily) followed by a 2-­week discontinuation period imaginable. Cuff algometry is a reliable assessment for
(week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/ PPTs, TSP and CPM (Graven-­Nielsen et al., 2017; Imai
daily). The treatment periods were separated by at least et al., 2016) and has often been utilized in studies with
2 weeks (washout period). See Figure 1 for overview. OA patients (Izumi et al., 2017; Kjær et al., 2019; Petersen
The patients were instructed to take one capsule of et al., 2016; Petersen, Simonsen, et al., 2019).
study drug orally with approximately 200 ml of water at The pressure of the cuff was increased by 1 kPa/s and
room temperature after breakfast in the morning of each the patient was instructed to rate the pain intensity con-
dosing day. tinuously on the electronic VAS until the tolerance level
This study was initiated before the COVID-­19 pan- was reached. At this point, the patient was instructed to
demic, and all subjects were randomized prior to the press a stop button. The pressure pain detection thresh-
lockdown in Denmark. The original protocol aimed for old (cPDT) was defined as the pressure at which the VAS
10 weeks of full treatment of duloxetine and placebo, but score exceeded 1 cm as in previous studies (Kristensen
this was increased to 14 weeks to allow for study visits et al., 2021; Larsen, Laursen, Edwards, et al., 2021;
1654 |    PETERSEN et al.

Petersen, Simonsen, et al., 2019). The pain tolerance (WOMAC) (Bellamy et al., 1988), a patient-­rated instru-
threshold (cPTT) was defined when the patient pressed ment that measures OA symptoms. The questionnaire
the stop button. The measurements were conducted once contains five pain questions, two stiffness questions and
on both the ipsilateral and contralateral lower leg to the 17 physical function questions (24 questions in total).
most affected knee. Each question utilizes a 5-­point scale from 0 (none) to
Ten short-­lasting stimuli (1 s each) at the level of the 4 (extreme). Both the WOMAC pain scale and the total
cPTT were given at the lower leg with a 1 s break between WOMAC score were used in the analysis.
stimuli. The participants were instructed to continuously
rate the pain intensity of the sequential stimuli using the
electronic VAS and not return to zero during the breaks. 3.4 | Sample size
For each cuff stimulus, a VAS score was extracted. TSP
was calculated as the absolute difference between the Wang et al., 2019 [2] demonstrated an effect size of 0.55
last three stimuli and the first three stimuli as in previous when assessing the worst pain within the last 24 h for
studies (Petersen, Olesen, et al., 2019; Staffe et al., 2019). a 10-­week treatment of duloxetine compared with pla-
The CPM magnitude was assessed as the absolute cebo in a parallel design with patients with moderate-­to-­
changes in cPDT with and without a cuff conditioning severe OA. We hypothesized that the analgesic effect of
stimulus. The conditioning stimulus was applied to the duloxetine acted through modulation of serotonin and
contralateral lower leg, and the cPDT was assessed on the noradrenaline, which would act on the descending pain
ipsilateral lower leg as described above. The conditioning inhibitory pathways and thereby provide modulation
stimulus was applied as a constant stimulus with an in- in QST. Therefore, a sample equation with 85% power
tensity of 70% of the pain tolerance level on the contralat- and a significant level at 0.05 using a crossover design
eral leg (Graven-­Nielsen et al., 2017; Petersen, Andersen, yielded 32 patients, which we assumed would be suf-
et al., 2018; Petersen, Simonsen, et al., 2019). The CPM ficient to detect a modulation in the QST parameters.
effect was calculated as the absolute difference in condi- Forty patients were enrolled to account for potential
tioned and unconditioned cPDT (i.e., cPDTconditioned dropouts.
minus cPDTunconditioned).

3.5 | Statistical analysis

3.2 | Cognitive factors
Repeated measures analysis of variances (RM-­ANOVAs)
Anxiety and depression symptoms were assessed using with factors time (before and after treatments) and
the Hospital Anxiety and Depression Scale (HADS) (36), drug (placebo or duloxetine) were conducted for all
which applies a subscale for anxiety and a subscale for de- mechanistic pain profiling methods, cognitive factors
pression. The HADS ranges from 0 to 21; 0 to 7 indicate and clinical pain parameters to investigate significant
no symptoms of anxiety/depression, 8 to 10 indicate prob- differences. Additionally, paired sample t-­tests were
able symptoms of anxiety/depression and 11 to 21 indi- used to evaluate absolute and percentage changes in
cate potential symptoms of anxiety/depression (Zigmond clinical pain for each treatment. The Bonferroni post
& Snaith, 1983). hoc test was utilized to adjust for multiple compari-
The Pain Catastrophizing Scale (PCS) consists of 13 sons. Responders to treatment were classified based on
items focusing on thoughts and feelings in connection a 30% and 50% pain reduction in clinical pain compar-
with pain (Sullivan et al., 1995). The questions are rated ing before and after treatments and compared using the
on a 4-­point scale ranging from 0 (not at all) to 3 (very Fisher's exact Test.
much). Several linear regression models were used to predict
the analgesic effect (dependent variables: mean change
in BPI worst pain, BPI average pain, WOMAC pain and
3.3 | Clinical pain intensity WOMAC total score) of duloxetine and placebo using
the mechanistic pain profiles, cognitive factors and clin-
Clinical pain intensity was assessed using the Brief Pain ical pain prior to treatment. Backward elimination was
Inventory (BPI). The worst pain and average pain within applied to the linear regressions to identify independent
the last 24 h were evaluated using a 10 cm VAS anchored predictors using cut-­offs for statistical independence and
at 0 cm: no pain, and 10 cm: worst pain imaginable. inclusion of 0.05 and exclusion of 0.157, respectively, ac-
Additionally, clinical pain was assessed using the cording to Akaike's information criterion for prognostic
Western Ontario and McMaster Osteoarthritis Scale models (Heinze & Dunkler, 2017). The standardized beta
PETERSEN et al.    | 1655

coefficient (normalized beta coefficients to a standard de- 4.2 | Non-­responder analysis

viation for easier comparisons between different variable)
will be reported for each independent parameter. A higher No significant differences were found comparing patients
standardized beta coefficient indicates a stronger associa- who completed the trial and patients who did not com-
tion to the dependent variable. plete the trial regarding baseline pain severity (independ-
Statistical tests were conducted using the IBM SPSS ent t-­test: p = 0.96), age (independent t-­test: p = 0.83),
Statistics software version 26 (IBM). A value of p < 0.05 body mass index (independent t-­test: p = 0.60), Kellgren
was considered a significant finding. All data are pre- and Lawrence grading (independent t-­test: p = 0.77) or
sented as means ± standard deviation (SD) unless other- gender distribution (Chi-­square: p = 0.15).
wise specified.

4.3 | Adverse events

3.6 | Availability of data and materials
Significantly more adverse events occurred during the
The data used and analysed are available by contacting duloxetine treatment (average: 2.28, SD: 1.54) compared
the corresponding author on reasonable request. with placebo treatment (1.40, SD: 1.32, paired-­sample t-­
test: p = 0.03). The most common adverse events during
the duloxetine treatment were gastroenterological (58% of
4 | R E S U LTS patients), neurological (44% of patients), dry mouth and
nausea (40% of patients) and fatigue (28% of patients). The
4.1 | Patient flow most common adverse events during the placebo treat-
ment were neurological (36% of patients), gastroentero-
The first patient was assessed at the first visit on 18 logical (24% of patients), dry mouth and nausea (24% of
December 2019, and the last patient was assessed at the patients) and fatigue (16% of patients).
last visit on 1 July 2021. Administration of the study drug One serious adverse event occurred during the dulox-
was postponed for two patients in sequence 1, and two etine treatment period where one patient experienced se-
patients in sequence 2 due to the COVID-­19 lockdown of vere headache, palpitations and difficulty breathing, and
Denmark. Later, these four patients withdrew their con- the patient was hospitalized for 1 day to ensure safety.
sent and hence were never administrated any study drug. Later it was discovered that this patient had a medical his-
In sequence 1, three patients discontinued the study tory of cardiovascular problems and had received bypass
in treatment period 1 (duloxetine treatment) due to side surgery 4–­5 years prior to the current study. This patient
effects: one patient experienced psychological issues, one did not withdraw the consent and continued in the study.
patient experienced constipation, and one patient experi-
enced impaired ejaculation.
In sequence 2, two patients discontinued the study 4.4 | Modulation of pain mechanisms
in treatment period 1 (placebo treatment) due to side ef-
fects: one patient experienced signs of liver cirrose (with Significant changes over time were observed for cPDT as-
dark urine), and one patient experienced dizziness. sessed at the ipsilateral side (F[1,24] = 13.112, p = 0.001)
Additionally, one patient experienced a loss of libido in and CPM (F[1,24] = 7.407, p = 0.013), but no drug effect
treatment period 2 (duloxetine treatment). was seen for cPDT (F[1,24] = 1.110, p = 0.303) and CPM
Twenty-­five patients completed all the visits and had (F[1,24] = 1.954, p = 0.177). No time or drug effect was
full data for the analysis, see Table 1 for demographic in- seen for cPDT at the contralateral side, cPTT at the ipsi-
formation on the patients who completed the trial and lateral and contralateral side, and TSP (F[1,24] < 0.080,
Figure 2 for CONSORT diagram. p > 0.190). See Figure 3.

T A B L E 1 Baseline data from patients Age (mean ± SD) (years) 65.12 (7.18)
completing the trial
BMI (mean ± SD) (kg/m2) 27.94 (3.73)
Pain severity (mean ± SD) (VAS) 6.64 (1.55)
Gender (females/males) 18/7
Kellgren and Lawrence grading (mean ± SD) 2.10 (0.77)
Abbreviations: BMI, Body Mass Index; SD, Standard deviation; VAS, Visual analogue scale.
1656 |    PETERSEN et al.

FIGURE 2 CONSORT diagram of patient flow.

4.5 | Modulation of cognitive factors treatment. Model 1 contained all QST methods, cognitive
factors and clinical pain data, whereas Model 2 was devel-
No significant different time or treatment effects were oped using the backward elimination.
found for HADS (F[1,24] < 0.93, p > 0.35) and PCS Depending on the outcome measure, the predictive val-
(F[1,24] < 3.92, p > 0.060). A trend towards a significant ues ranged from 21.3% (WOMAC pain) to 70.3% (BPI aver-
time effect was found for PCS (p = 0.06), but the compar- age pain) for Model 1 and 45.7% (WOMAC total) to 75.4%
ing treatments were not different (p = 0.39), see Figure 4. (BPI worst pain) for Model 2 for the duloxetine treatment,
see Table 4. These models indicate that reducing the num-
ber of predictors increased the predictive value (i.e., from
4.6 | Analgesic effect on clinical pain Model 1 to Model 2) and find that a combination of QST
measures, cognitive factors and clinical pain data consis-
No drug effects were seen for the BPI subscale for worst pain tently predicted the analgesic effect of duloxetine.
(F[1,24] > 0.001, p = 1.00), the BPI subscale for average pain Additionally, depending on the outcome measure, the
(F[1,24] = 0.600, p = 0.45), WOMAC pain (F[1,24] = 0.019, predictive values ranged from 4.8% (WOMAC total) to
p = 0.89) and WOMAC total (F[1,24] > 0.001, p = 0.99); nei- 20.5% (WOMAC pain) for Model 1 and 22.0% (BPI worst
ther for absolute nor percentage differences. See Table 2. pain) to 41.8% (WOMAC pain) for Model 2 for the pla-
cebo treatment, see supplementary Table 1. These models
consistently demonstrated that significant independent
4.7 | Responders predictors of the analgesic placebo response were pre-
treatment clinical pain data.
Number of patients who had a reduction in clinical pain
by 30% or 50% are presented in Table 3.
5 | DISC USSION

4.8 | Predicting analgesic response to Depending on the clinical pain outcome parameter,
duloxetine and placebo 40%–­68% of patients received at least 30% clinical pain
reduction and 24%–­48% of patients received at least 50%
Multiple linear regression was constructed to predict clinical pain reduction during the duloxetine treatment.
the analgesic response to the duloxetine and placebo Depending on the clinical pain outcome parameter,
PETERSEN et al.    | 1657

F I G U R E 3 Quantitative sensory testing data before (dark blue) and after (light blue) 18 weeks' treatment with either placebo or
duloxetine. QST was assessed using ipsilateral (a) and contralateral (b) cuff pain detection thresholds, ipsilateral (c) and contralateral (d)
cuff pain tolerance thresholds, (e) temporal summation of pain and (f) conditioned pain modulation. The data presented illustrate means
and standard deviations.

pretreatment mechanistic pain profiles, cognitive fac- 5.1 | Predicting the analgesic
tors and clinical pain predicted the analgesic response effect of duloxetine
of duloxetine by 45% to 75%, indicating that patients
with high pain sensitivity, higher scores on pain cata- Accumulating evidence suggests that QST parameters
strophizing, anxiety and/or depression and higher can predict OA treatment responses to, for example,
clinical pain may potentially benefit more from dulox- total joint replacement surgeries (Izumi et al., 2017;
etine treatment. The trial demonstrated no significant Kurien et al., 2018; Larsen, Laursen, Edwards,
changes in stand-­alone mechanistic pain biomarkers, et al., 2021; Petersen et al., 2015, 2016; Petersen,
cognitive factors or clinical pain comparing 18 weeks of Simonsen, et al., 2018), NSAIDs (Arendt-­Nielsen
duloxetine with placebo in patients with painful knee et al., 2016; Edwards et al., 2016; Petersen, Olesen,
osteoarthritis. et al., 2019; Petersen, Simonsen, et al., 2019), or exercise
1658 |    PETERSEN et al.

F I G U R E 4 Cognitive factors assessed before (red) and after (pink) 18 weeks' treatment with either placebo or duloxetine. Cognitive
factors assessed using (a) the hospital anxiety and depression score and (b) the pain catastrophizing scale. The data presented illustrate
means and standard deviations.

T A B L E 2 Differences in treatment responses to duloxetine and placebo treatments and calculated analgesic effects presented as absolute
and percentage differences

Duloxetine Placebo p-­value

Before After Before After Time Drug

Time effects of treatments
BPI worst pain 5.56 (2.29) 3.08 (2.71) 4.92 (2.55) 3.96 (2.48) p < 0.001 1.000
BPI average pain 4.42 (1.95) 2.42 (2.02) 4.00 (2.23) 3.25 (2.09) p < 0.001 0.447
WOMAC pain 8.56 (2.97) 6.44 (3.79) 8.29 (3.58) 6.83 (3.82) p = 0.002 0.890
WOMAC total 36.56 (13.91) 28.28 (19.58) 36.58 (18.01) 30.00 (16.68) p < 0.001 0.994

Mean difference p-­value

Absolute differences comparing treatments
BPI Worst pain 2.48 (3.38) 1.28 (2.49) 1.20 (4.74) 0.218
BPI average pain 1.96 (2.85) 0.96 (2.41) 1.00 (4.20) 0.246
WOMAC pain 2.12 (4.14) 1.84 (4.12) 0.28 (6.255) 0.825
WOMAC total 8.28 (18.96) 8.48 (14.91) 0.20 (27.93) 0.972

Mean difference p-­value

Percentage differences comparing treatments
BPI Worst pain 33.69 (59.51) 16.98 (52.31) 15.37 (78.86) 0.340
BPI Average pain 36.84 (65.75) 2.08 (111.95) 34.77 (123.51) 0.266
WOMAC pain 21.02 (44.31) 21.30 (46.95) 0.28 (58.96) 0.981
WOMAC total 20.02 (48.21) 23.29 (35.34) 3.27 (58.66) 0.783
Abbreviations: BPI, Brief Pain Inventory; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

interventions (Hansen et al., 2020; O'Leary et al., 2018). after total knee replacement surgery better than each of
Similarly, it seems evident that cognitive factors are as- the factors alone (Larsen, Laursen, Edwards, et al., 2021).
sociated with treatment outcomes in patients with OA Similarly, the current study demonstrated that a com-
(Brander et al., 2007; Edwards et al., 2011; Escobar bination of mechanistic pain biomarkers, cognitive
et al., 2007; Forsythe et al., 2008; Kendell et al., 2001). factors, and clinical pain consistently predicted the an-
A recent study demonstrated that a combination of pre- algesic response of duloxetine, and this is independent
operative mechanistic pain biomarkers and assessment of the outcome parameters. Composite outcomes merge
of cognitive factors predicted chronic postoperative pain two or more relevant clinical outcomes into a single
PETERSEN et al.    | 1659

T A B L E 3 Number of patients achieving at least a reduction of

assessed pain mechanisms. However, it also argues for the
30% or 50% in clinical pain after duloxetine and placebo treatment.
The numbers in the parentheses represent the percentage of the
importance of combining different outcome parameters as
full cohort end-­points in clinical trials.
Pre-­clinical evidence suggests that serotonin and nor-
Duloxetine Placebo p-­value adrenalin are important neurotransmitters for the de-
Based on 30% responder criteria scending pain inhibitory pathways (Bannister et al., 2015;
BPI Worst pain 16 (64%) 11 (44%) 1.000 Bannister & Dickenson, 2017; Lockwood et al., 2019). This
BPI Average 17 (68%) 7 (28%) 0.640 has been used to explain the mode-­of-­action of duloxe-
pain tine since duloxetine modulates these neurotransmitters.
WOMAC pain 10 (40%) 11 (44%) 0.697 Yarnitsky et al., 2012 (Yarnitsky et al., 2012) demon-
WOMAC total 11 (44%) 7 (28%) 1.000
strated, in a non-­placebo controlled study, an analgesic
effect of duloxetine in patients with diabetic neuropathy
Based on 50% responder criteria
and found duloxetine to improve CPM. Similarly, Kisler
BPI Worst pain 11 (44%) 6 (24%) 1.000
et al., 2019 (Kisler et al., 2019) demonstrated that duloxe-
BPI Average 12 (48%) 5 (20%) 0.645 tine improved CPM in patients with migraine. The current
pain
study is the first study to evaluate the effect of duloxetine
WOMAC pain 6 (24%) 5 (20%) 0.070 on QST parameters in patients with knee OA. As our data
WOMAC total 8 (32%) 4 (16%) 1.000 are, for the single outcome parameters, did not support
Abbreviations: BPI, Brief Pain Inventory; WOMAC, Western Ontario and the previous suggested mechanistic actions the explana-
McMaster Universities Osteoarthritis Index. tion could be that the QST methodologies utilized in the
previous studies (Kisler et al., 2019; Yarnitsky et al., 2012)
measure and Gewandter et al., (Gewandter et al., 2021) are different from those in the current study. Furthermore
recently highlighted that composite outcomes, rather our study is a GCP-­monitored, randomized, placebo-­
for example, clinical pain intensity, should be utilized controlled, crossover, double-­blinded trial utilizing QST
in clinical pain trials, since the composite outcomes are methodology with good-­to-­excellent reliability (Graven-­
more clinical relevant when addressing multifactorial Nielsen et al., 2017; Imai et al., 2016). The data from the
disorders such as chronic pain. The current trial sup- current study are also similar to other OA studies (Kurien
ports that a multidimensional assessment of relevant et al., 2018; Larsen, Laursen, Edwards, et al., 2021; Petersen,
pain parameters prior to treatment is needed to ensure a Olesen, et al., 2019; Petersen, Simonsen, et al., 2019) with
stronger prediction of treatment outcomes. Hence, this the same QST methodology used. Studies using this QST
may be an avenue to pursue in the attempt to develop methodology have demonstrated that the QST parameters
personalized pain management regimes. are modifiable by, for example, exercise-­based therapy in
both OA (Holm et al., 2021) and non-­OA patient cohorts
(Heredia-­Rizo et al., 2019). Additionally, the previous
5.2 | Modulation of mechanistic studies utilized treatment periods of 4 weeks (Yarnitsky
pain profiles et al., 2012) and 8 weeks (Kisler et al., 2019), which are
shorter than the current study. It is, however, important
It has been argued that pain intensity and pain duration are to acknowledge that inter-­individual variability is a valid
associated with lowering of pressure pain thresholds, fa- concern for QST assessments (Kennedy et al., 2016) and it
cilitation of TSP and impairment of CPM (Arendt-­Nielsen is difficult to conclude if the variability of modulation in
et al., 2010; Arendt-­Nielsen & Graven-­Nielsen, 2011; mechanistic pain profiles is due to methodological differ-
Petersen, 2021), which are often seen in patients with se- ences, due to the relatively low number of trials published
vere OA when compared with healthy pain-­free subjects within this area, or due to the relative small sample sizes.
(Arendt-­Nielsen et al., 2015). Based on this, studies have ar-
gued that pain relief from, for example, total joint replace-
ment or NSAIDs is associated with normalization of QST 5.3 | Modulation of cognitive factors
parameters in patients with OA (Arendt-­Nielsen et al., 2016;
Graven-­Nielsen et al., 2012; Kosek & Ordeberg, 2000), Duloxetine is a treatment for major depression, and stud-
but conflicting evidence does exist (Petersen et al., 2015; ies have demonstrated that a subsample of patients with
Petersen, Simonsen, et al., 2019). The current study did not severe knee OA demonstrates signs of depression and anxi-
find significant analgesic effects (by assessing single param- ety (Larsen, Laursen, Simonsen, et al., 2021). Therefore, it
eters) comparing duloxetine and placebo treatments, and would be logical to assume that the analgesic effect of du-
this could be associated with the lack of modulation of the loxetine was due to improvement in signs of depression and
1660 |    PETERSEN et al.

T A B L E 4 Multiple linear regression models aiming to establish the adjusted predictive value (R2) for baseline parameters predicting
analgesic response to duloxetine treatment. Model 1 contains all baseline parameters, whereas Model 2 was constructed using backwards
selection and aimed to identify independent predictors (bold numbers in Model 2 are significant independent predictors)

Standardized β-­values

Model 1 BPI worst pain BPI average pain WOMAC pain WOMAC total
2
Adjusted R 61.8% 70.3% 21.3% 25.3%
cPDT (ipsi) 0.021 −0.168 −0.084 −0.274
cPDT (contra) −0.103 −0.404 −0.529 −0.701
cPTT (ipsi) −0.013 0.411 0.114 0.718
cPTT (contra) −0.192 −0.223 −0.043 −0.303
TSP −0.215 −0.033 −0.102 −0.069
CPM 0.080 −0.026 0.153 −0.039
BPI Worst pain 0.996 0.158 0.134 −0.001
BPI Average pain −0.047 0.665 −0.030 0.080
WOMAC pain 0.091 0.301 0.879 0.250
WOMAC total −0.315 −0.286 −0.235 0.644
HADS −0.610 −0.441 −0.530 −0.675
PCS −0.038 0.006 0.072 0.045

Standardized β-­values

Model 2 Worst pain Average pain WOMAC pain WOMAC total

2
Adjusted R 75.6% 75.3% 48.6% 45.7%
cPDT (ipsi)
cPDT (contra) −0.342 −0.491 −0.538
cPTT (ipsi)
cPTT (contra) −0.237
TSP −0.240*
CPM
BPI Worst pain 0.999
BPI Average pain 0.743
WOMAC pain 0.787
WOMAC total −0.255 0.781
HADS −0.611 −0.441 −0.515 −0.650
PCS
Abbreviations: BPI, Brief Pain Inventory; contra, contralateral side to the most osteoarthritic affected knee; cPDT, cuff pain detection threshold; CPM,
conditioned pain modulation; cPTT, cuff pressure pain tolerance threshold; HADS, Hospital Anxiety and Depression Score; ipsi, ipsilateral side to the most
osteoarthritic affected knee; PCS, Pain Catastrophizing Scale; TSP, temporal summation of pain; WOMAC, Western Ontario and McMaster Universities
Osteoarthritis Index.

anxiety. Bjelland et al., 2002 (Bjelland et al., 2002) reviewed of anxiety and depression scores but that duloxetine acts
the studies on the validity of the HADS questionnaire to a purely analgesic substance. However, this was not sup-
identify anxiety and depression and found a cut-­off point ported by the current trial.
of 8/21 on each subscale to identify anxiety and depression.
The current study demonstrated average HADS anxiety
and depression scores below 8/21. Therefore, this cohort 5.4 | The analgesic effect of duloxetine in
might not have been ideal for the antidepressant proper- osteoarthritis
ties of duloxetine. In contrast to this, Chappell et al., 2009
(Chappell et al., 2009) argued that the analgesic effect of Seven studies have consistently demonstrated signifi-
duloxetine for OA pain is not dependent on improvements cant clinical analgesic effects of duloxetine for OA pain
PETERSEN et al.    | 1661

(Abou-­Raya et al., 2012; Chappell et al., 2009, 2011; De duloxetine when compared to placebo and this should be
Tommaso et al., 2007; Frakes et al., 2011; Uchio et al., 2018; considered when interpreting the results.
Wang et al., 2019) with a daily dose varying from 60 mg/ The current study does indicate that mechanistic pain
daily (Abou-­Raya et al., 2012; Uchio et al., 2018; Wang profiling, cognitive factors and clinical pain can predict the
et al., 2015) up to 120 mg/daily (Chappell et al., 2009, analgesic response of duloxetine and therefore it would be
2011; Frakes et al., 2011). Similar to the current study, the interesting to conduct exploratory analysis of subgroup of
previous studies included patients with KL grade I-­III, patients responding and not responding to the duloxetine
moderate-­to-­severe pain intensity levels, and OA duration treatment. This is analysis is not possible in the current
for a minimum of 3 years (Chen et al., 2021). The treat- study due to the low sample size but should be conducted
ment outcomes of the different trials varied, but four trials in future studies.
utilized a combination of the BPI and WOMAC to assess
the analgesic effect (Chappell et al., 2009, 2011; Frakes
et al., 2011; Wang et al., 2019), which is similar to the cur- 6 | CONC LUSION
rent trial.
Recent studies have included an enrichment strat- This proof-­of-­mechanism, randomized, placebo-­
egy for recruiting patients based on higher scores on the controlled, double-­blinded, crossover GCP-­monitored trial
PainDetect Questionnaire (De Tommaso et al., 2007) or the found that 40%–­68% of patients received at least 30% pain
Central Sensitization Inventory (Koh et al., 2019), which reduction, and 24%–­48% of patients received at least 50%
have demonstrated analgesic effects when compared clinical pain reduction by the duloxetine treatment, which
to placebo. However, a recent RCT utilized PainDetect was depending on the clinical pain outcome parameter
Questionnaire for an enriched patient population but did to assess the analgesic effect. Depending on the clinical
not demonstrate significant analgesic effects of duloxetine pain outcome parameter, pretreatment mechanistic pain
when compared to placebo (Rienstra et al., 2021). The profiling, cognitive factors and clinical pain predicted the
current study did not implement an enrichment strategy, analgesic response of duloxetine with a prediction value
which could, in part, explain the lack of analgesic effect in of 47%–­75%. No group-­level significant changes in single,
the current trial. stand-­alone clinical pain parameters, mechanistic pain bi-
The current study was not powered towards demon- omarkers, or cognitive factors were found when 18 weeks
strating an analgesic effect but rather to demonstrate an of duloxetine was compared to placebo in patients with
effect on the mechanistic pain profiles. Previous studies painful knee osteoarthritis. This trial demonstrates that
have demonstrated approx. 1 point mean difference in an- only a subsample of patients with severe OA gained an an-
algesic effect scores when comparing duloxetine and pla- algesic benefit of duloxetine and that these patients could
cebo using the BPI pain score (Chappell et al., 2009, 2011; be stratified based on mechanistic pain profiling, cogni-
Frakes et al., 2011; Uchio et al., 2018; Wang et al., 2015), tive factors and clinical pain parameters and hence may
which is similar to the current trial. give indications for developing personalized pain manage-
ment regimes.

5.5 | Limitation
AUTHOR CONTRIBUTION
All patients were enrolled before the COVID-­19 lock-­
down in Denmark (March 13, 2020), but the treatment pe- KKP, AMD, AEO and LAN conceptualized the design of
riods were conducted during the COVID-­19 pandemic and the study, wrote the protocol and initiated the trial. KKP,
lock-­down. Studies have demonstrated that COVID-­19 AMD, DB, CB and NA implemented the protocol, commu-
negatively impacted anxiety, depression, and psychologi- nicated with the Regulatory Authorities and conducted
cal stress in the general population and in different patient the study. KKP analysed the data and wrote the first draft
groups (Jin et al., 2021; Momenimovahed et al., 2021), of the manuscript, and all authors critically revised the
which could have impacted the results. manuscript and approved the final version.
A total of 32 patients should complete this trial to
reach a power of 85%. Forty patients were enrolled to en- ACKNOWLEDGEMENTS
sure a sufficient margin of error in case of dropouts, but Center for Neuroplasticity and Pain (CNAP) is supported
only 25 patients completed the study. Therefore, the cur- by the Danish National Research Foundation (DNRF121).
rent analysis is underpowered, and the results should be The Aalborg University Talent Management Programme
cautiously interpreted. Additionally, the current trial was (j.no. 771126), The Danish Rheumatism Association
not powered to investigate a potential analgesic effect of (grant number: A6579), The Shionogi Science Program
1662 |    PETERSEN et al.

Bannister, K., & Dickenson, A. H. (2017). The plasticity of descend-

and the TaNeDS Daiichi Sankyo Science Center Europe ing controls in pain: Translational probing. The Journal of
grant are acknowledged for providing the opportunity Physiology, 595, 4159–­4166.
to conduct the study. The authors declare no conflict of Bannister, K., Lockwood, S., Goncalves, L., Patel, R., & Dickenson,
interest. Project nurses Kristina Lykkegaard Andersen, A. H. (2017). An investigation into the inhibitory function of
Isabelle Myriam Larsen and Marianne Harlis at Synexus, serotonin in diffuse noxious inhibitory controls in the neuro-
Aalborg, are kindly acknowledged for their expert knowl- pathic rat. European Journal of Pain, 21, 750–­760.
edge, their quick introduction into the world of clinical Bannister, K., Patel, R., Goncalves, L., Townson, L., & Dickenson, A.
H. (2015). Diffuse noxious inhibitory controls and nerve injury:
trials and for their technical assistance in developing the
Restoring an imbalance between descending monoamine inhi-
protocol. bitions and facilitations. Pain, 156, 1803–­1811.
FUNDING INFORMATION Bannuru, R. R., Osani, M. C., Vaysbrot, E. E., Arden, N. K., Bennell,
Center for Neuroplasticity and Pain (CNAP) is supported K., Bierma-­Zeinstra, S. M. A., Kraus, V. B., Lohmander, L. S.,
by the Danish National Research Foundation (DNRF121). Abbott, J. H., Bhandari, M., Blanco, F. J., Espinosa, R., Haugen,
The Aalborg University Talent Management Programme I. K., Lin, J., Mandl, L. A., Moilanen, E., Nakamura, N., Snyder-­
(j.no. 771126), The Danish Rheumatism Association Mackler, L., Trojian, T., … McAlindon, T. E. (2019). OARSI
guidelines for the non-­surgical management of knee, hip, and
(grant number: A6579), The Shionogi Science Program,
polyarticular osteoarthritis. Osteoarthritis and Cartilage, 27,
and the TaNeDS Daiichi Sankyo Science Center Europe
1578–­1589.
grant funded the study. Bellamy, N., Buchanan, W. W., Goldsmith, C. H., Campbell, J., &
CONFLICT OF INTEREST Stitt, L. W. (1988). Validation study of WOMAC: A health status
The authors declare no conflict of interest. instrument for measuring clinically important patient relevant
outcomes to antirheumatic drug therapy in patients with os-
ORCID teoarthritis of the hip or knee. The Journal of Rheumatology,
Kristian Kjær-­Staal Petersen https://orcid. 15, 1833–­1840.
Berenbaum, F., Wallace, I. J., Lieberman, D. E., & Felson, D. T.
org/0000-0003-4506-000X
(2018). Modern-­day environmental factors in the pathogenesis
of osteoarthritis. Nature Reviews Rheumatology, 14, 674–­681.
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