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ORIGINAL ARTICLE

Impact of etiology and duration of pain on pharmacological


treatment effects in painful polyneuropathy
S. H. Sindrup1, J. Holbech1, D. Demant1, N. B. Finnerup2, F. W. Bach3, T. S. Jensen2
1 Department of Neurology, Odense University Hospital, Denmark
2 Danish Pain Research Center, Aarhus University Hospital, Denmark
3 Department of Neurology, Aarhus University Hospital, Denmark

Correspondence Abstract
Søren H. Sindrup
E-mail: soeren.sindrup@rsyd.dk Background: The pharmacological treatments for painful polyneuropa-
thy have not changed much for more than a decade, and less than half
Funding sources of the patients obtain adequate pain relief with first line treatments.
Research reported in this publication is part Therefore, patient-specific factors which could predict drug response are
of the International Diabetic Neuropathy
searched for.
Consortium IDNC research programme,
Methods: We analysed data from four published, randomized,
which is supported by a Novo Nordisk Foun-
dation Challenge Programme grant (Grant controlled trials of drugs in painful polyneuropathy to see if diabetic
number NNF140C0011633). etiology and duration of neuropathic pain had an impact on drug
efficacy. The studies had a cross-over design, and had nearly similar
Conflicts of interest outcome recordings as well as a thorough baseline registration of
F. W. Bach reports to have been compen- symptoms, signs and quantitative sensory testing. 244 patient records of
sated as an investigator in clinical trial spon-
drug effect distributed over treatments with three antidepressants
sored by Pfizer and Gru €nenthal and personal
(imipramine, venlafaxine, escitalopram) and two anticonvulsants
fees from Pfizer. N. B. Finnerup reports per-
sonal fees from Pfizer, Astellas and Nor- (pregabalin, oxcarbazepine) were analysed.
pharma, grants from EU/EFPIA, and grants Results: Diabetes as etiology of polyneuropathy had no impact on the
and personal fees from Gru €nenthal. T. S. effect of antidepressants (imipramine, venlafaxine, escitalopram), but
Jensen reports to be on Advisory Board for there was a significant interaction with treatment effect on
Pfizer, Gru€nenthal and Orion. J. Holbech anticonvulsants with better effects in diabetics (0.86 NRS points,
reports personal fees and study grants from
p = 0.021) with most pronounced interaction for oxcarbazepine (1.47
Pfizer. S. H. Sindrup reports study grants
NRS points, p = 0.032). There was an interaction between duration of
from Pfizer and EU/EFPIA. D. Demant reports
to have no conflicts of interest to declare. neuropathic pain and treatment with antidepressants with better effect
with duration less than 3 years (0.62 NRS points, p = 0.036), whereas
anticonvulsants tended to work best with duration of pain for more
Accepted for publication than 3 years.
15 March 2017 Conclusion: Despite the small sample size and limited number of drugs
included this study suggests that diabetic etiology of polyneuropathy
doi:10.1002/ejp.1048
may impact on the efficacy of anticonvulsants, and duration of
neuropathic pain may impact on the efficacy of antidepressants.
Significance: This study found that duration of pain appears to have an
impact on the effect of antidepressants in neuropathic pain and that
diabetes as etiology for painful polyneuropathy appears to influence pain
relief obtained with anticonvulsants.

1. Introduction
ments is disappointing (Sindrup and Jensen, 2000;
Treatment options for painful polyneuropathy have Finnerup et al., 2010, 2015). The mainstay of treat-
not changed much during the past two decades, and ment for painful neuropathy is still the antidepres-
in general performance of pharmacological treat- sants of tricyclic and balanced serotonin and

© 2017 European Pain Federation - EFICâ Eur J Pain 21 (2017) 1443--1450 1443
Factors in drug response in neuropathic pain S. H. Sindrup et al.

noradrenaline reuptake inhibitor category as well as observations, we retrospectively searched for a


the anticonvulsants gabapentin and pregabalin. possible influence of duration of pain and diabetes as
These treatment options provide adequate pain relief the etiology for polyneuropathy on the treatment
in less than half of the patients. response to the major drug classes in peripheral neu-
It has for decades been discussed if mechanism- ropathic pain as determined in a series of previously
based treatment could improve treatment outcome conducted controlled clinical trials in painful
in neuropathic pain after this concept was intro- polyneuropathy (Sindrup et al., 2003; Otto et al.,
duced by various researchers (Max, 1990; Woolf and 2008; Demant et al., 2014; Holbech et al., 2015).
Mannion, 1999; Holbech et al., 2016). A major
obstacle for implementing the concept in clinical
2. Methods
practice is that we do not have the tools for deter-
mining the molecular mechanisms of pain at play in
2.1 Study design
each patient. A range of different pain mechanisms
have been acknowledged mainly from experiments This was a retrospective analysis of data from four
in animals (Woolf and Mannion 1999), but their randomized, double-blind, placebo-controlled, cross-
individual contribution and interplay in each patient over trials (Sindrup et al., 2003; Otto et al., 2008;
are not easily determined. The pattern of symptoms Demant et al., 2014; Holbech et al., 2015) of almost
and quantitative sensory examination data has been similar design and in which there was a significant
suggested as a tool for determining mechanisms in effect of the study drug. The trials were performed at
neuropathic pain (Baron et al., 2012). Recently, it Odense University Hospital, Aarhus University
was reported from a controlled clinical trial with Hospital and Aalborg University Hospital from 1999
stratification according to sensory phenotype that to 2014. All the included trials met the CONSORT
patients with peripheral neuropathic pain having a Guidelines for randomized, controlled trials and have
phenotype termed irritable nociceptor had a better been reported in detail previously.
pain relief from the sodium channel blocker oxcar-
bazepine than patients without this phenotype
2.2 Patients
(Demant et al., 2014). However, a retrospective
analysis of data from several clinical trials comprising Patients with painful diabetic and non-diabetic
the major drug classes used in painful polyneuropa- polyneuropathy were included in the analysis.
thy found no interaction between sensory phenotype Patients were male and female, aged > 18 years and
and drug efficacy in this pain condition (Holbech had symptoms compatible with polyneuropathy for
et al., 2016). Challenges in this context are both more than 6 months with distal symmetric pain
inability of sensory phenotyping to clearly reflect localisation and sensory disturbance in the area of
mechanisms of pain and the fact that the major drug pain. Polyneuropathy diagnosis had to be confirmed
classes tested do not have selective mechanism of by clinical signs and electrophysiological tests or skin
action targeting specific pain mechanisms. biopsy. In three of the trials (Otto et al., 2008;
Other factors than sensory phenotype could pre- Demant et al., 2014; Holbech et al., 2015), the
dict response of pharmacological treatment in patients had to have a median total pain rating of at
peripheral neuropathic pain. In painful polyneuropa- least 4 on an 0-10-point numeric rating scale
thy, the etiology could be a factor with for example (0 = no pain, 10 = worst possible pain) (NRS) during
pain in diabetic polyneuropathy being more respon- 1 week without pain medication. In one trial (Sin-
sive to treatment than neuropathies of other etiolo- drup et al., 2003), it was sufficient with at least 4 on
gies, as has been indicated in one of our previous the NRS for one of four specific pain phenomena,
trials (Sindrup et al., 2003). Furthermore, in experi- i.e. constant pain (burning, pressing or deep aching),
mental models of neuropathic pain it has been pain paroxysms, touch-evoked pain or pain on pres-
shown that inhibitory GABAergic interneurons in sure. To be included in the analysis, the patients
the dorsal horn of the spinal cord may degenerate needed to have data from at least two treatment
after a relatively short time, i.e. within a few weeks periods (one being a placebo period). Therefore, in
of pain (Moore et al., 2002). Thus, duration of neu- the 3- and 4-armed studies (Sindrup et al., 2003;
ropathic pain could also be a factor, with long-term Holbech et al., 2015), a number of patients were
neuropathic pain being less responsive to drug treat- included based on observations from only two
ment because of degeneration of neurons involved periods. The trials were designed to investigate the
in their mechanism of pain relief. Based on these independent effect of the drugs on peripheral

1444 Eur J Pain 21 (2017) 1443--1450 © 2017 European Pain Federation - EFICâ
S. H. Sindrup et al. Factors in drug response in neuropathic pain

neuropathic pain. Hence, all concomitant treatments pain symptoms (constant pain, paroxysms,
for neuropathic pain used before inclusion were touch-evoked, pain on pressure) was used. As this
either discontinued or patients on such treatments would lead to an unrealistically low total score for
excluded. Other causes of pain were exclusion crite- some patients (e.g. a patient with 4 on constant pain
ria in all 4 trials. and 0 on the three other pain symptoms would have
a total pain intensity of 1), we used a correction fac-
2.3 Randomization and treatment tor, making the patient’s baseline score = 6 (average
baseline score of total pain in trials using this pain
For patients with ongoing medication for their neu-
measure). At baseline, the cause of polyneuropathy
ropathic pain, treatments were slowly discontinued
was recorded as well as the duration of neuropathic
during a pre-study period of 1 week. After 1 further
pain due to the polyneuropathy.
week for baseline observations, the patients entered
the computer-generated, randomized treatment
2.4.2 Bedside examination
sequence with treatment periods of 4-6 weeks’ dura-
tion. Treatment periods were separated by 1 or A full clinical examination was performed by a neu-
2 week(s) for washout. All trials were double-blind rologist at the time of inclusion. The examination
and trial drugs of identical appearance as placebo, included assessment of muscular function, deep ten-
and trials with two active treatments employed dou- don reflexes, vibration sensation, touch sensation
ble-dummy technique. Drug doses and duration of (hypoesthesia), pin prick sensation (hyperalgesia),
treatment periods are shown in Table 1. Paracetamol temperature sensation and dynamic mechanical allo-
in doses up to 3000 mg was used as escape medica- dynia.
tion, and in one trial (Demant et al., 2014), addi-
tional tramadol 50 mg daily was allowed as escape 2.4.3 Quantitative sensory testing (QST)
medication.
The most painful site on each individual patient was
located, and QST was performed at this site at base-
2.4 Assessments
line. The following was assessed: Pressure pain
thresholds with pressure algometer (Somedic AB,
2.4.1 Symptoms
Stockholm, Sweden) (all trials); mechanical allody-
The data used in the analysis originated from ratings nia by stroking skin with a sponge rubber brush
in diaries. All ratings were entered in diaries in the (Demant et al., 2014; Holbech et al., 2015), or stim-
morning covering the symptoms experienced during ulation with an electronic toothbrush (Sindrup et al.,
the preceding 24 h. Total pain intensity (three trials) 2003); cold-allodynia with Thermoroller at 20 °C
and specific pain symptoms (all trials) were rated (Somedic AB, Stockholm, Sweden) (Demant et al.,
using the 0-10-point NRS throughout all baseline 2014; Holbech et al., 2015); pain by repetitive pin-
and treatment periods. For the one trial (Sindrup prick stimulation using von Frey hair, 2 Hz during
et al., 2003) in which total pain intensity was not 30 s (all trials); cold and warm detection thresholds
scored, the mean score of the four registered specific with a Thermotest (Somedic AB) (all trials). The

Table 1 Studies, drugs, drug doses and duration of treatment periods.

Study Drug Doses (mg/day) Duration treatment periods (weeks)

Holbech et al., 2015 Imipramine 75 (patients aged < 70 years) 5


25 (patients aged ≥ 70 years)
25 (poor metabolisers)
Pregabalin 300 (patients aged < 70 years)
150 (patients aged ≥ 70 years)
Sindrup et al., 2003 Imipramine 150a 4
Venlafaxine 225a
Otto et al., 2008 Escitalopram 20 6
Demant et al., 2014 Oxcarbazepine 2400 (patients aged < 70 years)b 6
1800 (patients aged ≥ 70 years)b
a
Poor metabolisers excluded from study.
b
Dosages adjustable due to side effects, average dose 1684–1846 mg/day.

© 2017 European Pain Federation - EFICâ Eur J Pain 21 (2017) 1443--1450 1445
Factors in drug response in neuropathic pain S. H. Sindrup et al.

oxcarbazepine trial differed by having used the stan- In the general linear statistical model including all
dardised QST protocol of the German Research Net- patients and all drugs the treatment effect was 0.91
work on Neuropathic Pain (Rolke et al., 2006). NRS points (95% CI 0.66-1.15 NRS points,
p < 0.001) and baseline severity had an impact of
2.5 Data analysis 0.18 NRS points (95% CI 0.02-0.34 NRS points,
p = 0.024).
Due to the retrospective nature of the study, the
The impact of diabetes as etiology for neuropathy
data analysis should mainly be regarded as explo-
on drug effect is detailed in Table 2 and illustrated in
rative. The overall effect of diabetes and duration of
(Fig. 1). For antidepressants, there were no differ-
neuropathic pain on drug effect on pain was anal-
ences in effect between diabetics and non-diabetics.
ysed using a general linear model with pain as
The anticonvulsants as a group reduced pain signifi-
dependent variable, drug and the interaction
cantly more in diabetics than in non-diabetics, and
between drug and diabetes or duration of pain as
for the individual anticonvulsants this was also the
factors, baseline pain as co-variate, period as fixed
case for oxcarbazepine, whereas the results for pre-
effect, and patient as random effect. Mean differ-
gabalin failed to reach statistical significance. The fre-
ences with 95% confidence intervals of pain reduc-
quency of lancinating pain was higher and the
tion on drugs between diabetics and non-diabetics as
frequency of gain of sensation, preserved thermal
well as between short and long duration of pain
sensation, pinprick hyperalgesia and pain summation
were determined. The drug effect was not corrected
on repetitive pinprick lower in diabetics as compared
for placebo effect, since the effect of placebo did not
to non-diabetics (Fig. 2).
differ systematically between the groups (diabetics
The impact of duration of neuropathic pain on
vs. non-diabetics: 0.15 NRS points, p = 0.580; short
drug effect is detailed in Table 3 and illustrated in
pain duration vs. long: 0.22 NRS points, p = 0.407).
Fig. 3. For the total group of antidepressants, there
Differences in frequency of patient characteristics
between the groups were tested by use of Fisher’s
exact test and p values presented are not corrected
for multiple comparisons. ALL DRUGS

ANTIDEPRESSANTS
Impramine
3. Results
Venlafaxine
The dataset comprised in total 244 observations of Escitalopram
patient characteristics and the effect of drugs and ANTICONVULSANTS
placebo in painful polyneuropathy with 86 being on Pregabalin
imipramine, 32 on venlafaxine, 41 on escitalopram, Oxcarbazepine
56 on pregabalin and 29 on oxcarbazepine. Diabetes
–4 –2 0 2 4
was the etiology for neuropathy in 81 patients and Difference DM vs. non-DM (mean, 95% CI)
88 had duration of neuropathic pain less than
3 years. Other causes of polyneuropathy were alco- Figure 1 Mean differences in pain reduction with 95% confidence
hol (n = 33), drug-induced (n = 12), idiopathic intervals between diabetics and non-diabetics for different drug
groups and drugs. Positive values indicate better effect in diabetics.
(n = 86), and other (n = 32).

Table 2 Interaction between drug effect and diabetes as etiological diagnosis of painful polyneuropathy.

Total n Diabetes n Drug Effect Δ NRS points (95% CI)a p Drug-DM-Interaction Δ NRS points (95% CI)a p

All drugs 244 81 0.86 (0.57:1.15) <0.001 0.15 ( 0.31:0.61) 0.521


Antidepresants 159 60 1.09 (0.71:1.48) <0.001 0.20 ( 0.78:0.38) 0.498
Imipramine 86 27 1.14 (0.67:1.61) <0.001 0.15 ( 0.93:0.62) 0.701
Venlafaxine 32 14 1.14 (0.05:2.23) 0.040 0.48 ( 2.01:1.06) 0.543
Escitalopram 41 19 0.90 (0.13:1.66) 0.020 0.07 ( 0.94:1.06) 0.904
Anticonvulsants 85 21 0.49 (0.09:0.89) 0.016 0.86 (0.13:1.58) 0.021
Pregabalin 56 14 0.41 ( 0.03:0.86) 0.069 0.78 ( 0.06:1.61) 0.067
Oxcarbazepine 29 7 0.58 ( 025:1.42) 0.169 1.47 (0.12:2.81) 0.032
a
Estimated by general linear model (GLM) with total numeric rating scale score (NRS) of pain as dependent variable, treatment and interaction
between treatment and diabetes etiology (DM) as factors, baseline pain as co-variate, and period as fixed effect, and patient as random effect.

1446 Eur J Pain 21 (2017) 1443--1450 © 2017 European Pain Federation - EFICâ
S. H. Sindrup et al. Factors in drug response in neuropathic pain

was a significantly better effect in patients with ALL DRUGS


duration of pain less than 3 years, but this was not ANTIDEPRESSANTS
significant for the individual antidepressants. Oxcar- Impramine
bazepine reduced pain less in patients with short Venlafaxine
duration of pain, whereas there was no difference Escitalopram
for pregabalin or for pregabalin and oxcarbaxepine
ANTICONVULSANTS
taken together. The frequency of preserved thermal
Pregabalin
sensation was higher in patients with short duration
Oxcarbazepine
of pain than in patients with longer duration of pain
–4 –2 0 2 4
(Fig. 4). None of the other characteristics differed
Pain duration < 3 years vs. > 3 year (mean, 95% CI)
between the two groups.
Figure 3 Mean differences in pain reduction with 95% confidence
intervals between patients with short duration of pain (<3 years) and
4. Discussion long duration of pain (≥ 3 years) for different drug groups and drugs.
This retrospective analysis of data from drug trials Positive values indicate better effect with short duration of pain.
found that the anticonvulsants oxcarbazepine and
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Figure 4 Frequency of different patient characteristics in patients


Figure 2 Frequency of different patient characteristics in diabetics with short duration of pain (black columns) and long duration of pain
(black columns) and non-diabetics (white columns). Statistically signifi- (white columns). Statistically significant difference (p = 0.017) marked
cant differences (p-value range from <0.001 to 0.006) marked with *. with *.

Table 3 Interaction between drug effect and duration of painful polyneuropathy.

Drug Effect Δ NRS Drug-Duration-Interaction Δ NRS


Total n Pain < 3 years n points (95% CI)a p points (95% CI)a p

All Drugs 244 88 0.82 (0.52:1,11) <0.001 0.24 ( 0.21:0.69) 0.299


Antidepresants 159 58 0.79 (0.41:1.17) <0.001 0.62 (0.04:1.20) 0.036
Imipramine 86 31 0.90 (0.42:1.38) <0.001 0.54 ( 021:1.28) 0.156
Venlafaxine 32 13 0.46 ( 0.58:1.50) 0.390 1.17 ( 0.35:2.69) 0.133
Escitalopram 41 14 0.77 (0.06:1.47) 0.033 0.47 ( 0.57:1.51) 0.377
ANTICONVULSANTS 85 30 0.88 (0.45:1.32) <0.001 0.51 ( 1.18:0.15) 0.131
Pregabalin 56 18 0.65 (0.17:1.13) 0.008 0.13 ( 0.92:0.66) 0.744
Oxcarbazepine 29 12 1.43 (0.56:2.30) 0.001 1.21 ( 2.36:-0.06) 0.040
a
Estimated by general linear model (GLM) with total numeric rating scale score (NRS) of pain as dependent variable, treatment, and interaction
between treatment and duration of pain as factors, baseline pain as co-variate, and period as fixed effect, and patient as random effect.

© 2017 European Pain Federation - EFICâ Eur J Pain 21 (2017) 1443--1450 1447
Factors in drug response in neuropathic pain S. H. Sindrup et al.

pregabalin either worked or tended to work better in could be included in this analysis may also call for a
diabetics than in non-diabetics, and that antidepres- change of how clinical trial results are reported. Thus,
sants had a better effect on patients with short than it could be requested that single patient data, which
longer duration of neuropathic pain. To our knowl- are needed for doing analyses as the present, should
edge, this is the first systematic analysis of such rela- always be made available as an appendix to publica-
tions in painful polyneuropathy. Two previous post- tions.
hoc analyses of data from controlled trials in painful There is no obvious explanation for the present
diabetic neuropathy found no impact of neuropathy findings of our retrospective analysis, but one possi-
duration and the effect of duloxetine or pregabaline bility is that the differences in effect are related to dif-
(Ziegler et al., 2007; Marchettini et al., 2016). These ferences in molecular or cellular mechanisms of pain
studies separated duration of neuropathy by 2 years depending on diabetic etiology of neuropathic pain
and focused on duration of neuropathy and not and duration of pain. The difference in phenotype
directly on duration of neuropathic pain. Further- profile with respect to symptoms and signs between
more, the latter study mainly searched for differ- diabetics and non-diabetics found in this analysis
ences in predictors of response between the imply that this could indeed be the case. However, as
antidepressant duloxetine and the anticonvulsant mentioned in the introduction, there is no well-
pregabalin. In line with our findings the latter study established relation between symptoms and signs and
reported that the treatment effect size was higher in molecular mechanisms of pain. Lancinating pain,
patients with more severe pain at baseline (Marchet- here seen with higher frequency in diabetics, has
tini et al., 2016). been attributed to a sodium channel mechanism
The present study has several substantial limita- (Baron et al., 2012), which could be targeted by the
tions. First of all, based on the retrospective character sodium channel blocker oxcarbazepine and thus
of the study, it can only be hypothesis-generating. explain why oxcarbazepine apparently works better
Minor differences in study design and outcomes may in diabetics. Tricyclic antidepressants, such as imipra-
impact on the results and pooling the data, and ana- mine, also have sodium channel-blocking effect, but
lyzing them together may therefore be problematic. tricyclic antidepressants probably mainly work
Grouping of drugs as antidepressants and anticonvul- through monoaminergic mechanisms, and this may
sants is arbitrary, since with respect to mode of action mask a difference in effect between diabetics and
drugs may differ within groups and drugs may have non-diabetics due to its sodium channel-blocking
similarities between groups. The study also miss data effect. It is in line with common thinking that pre-
on the important first line drugs for neuropathic served thermal sensation is more frequent in patients
pain, i.e. the antidepressant duloxetine and the anti- with short duration of pain, but it is surprising that
convulsant gabapentin, and this may impact on con- we at the same time observed less effect of especially
clusions for drug groups One of the trials (Holbech oxcarbazepine. Preserved small fibre function has
et al., 2015) used relatively low drug doses, since this been found to be a factor for the effects of oxcar-
was part of the design in this drug combination trial. bazepine in peripheral neuropathic pain (Demant
However, this may not have had a major impact on et al., 2014). Similarly, the better effect of antidepres-
the pertinent subgroup comparisons which are not sants with short duration of pain cannot easily be
between drugs, but between groups based on patient explained in these terms, i.e. when we look at the
characteristics. The most important limitation of the symptom and sensory sign profile differences
present study is that the number of observations is between patients with short versus long duration of
small, which reduces the statistical power. This pain. In another retrospective analysis of trial data it
becomes even more important when we analyze data was found that imipramine reduces pain significantly
from single drugs. We may therefore overlook impor- more in patients with gain of sensory function and
tant differences and there is also a risk of spurious that pregabalin had a better effect in patients with
findings when the numbers are very small as for preserved large fibre function (Holbech et al., 2016).
example with oxcarbazepine in diabetics. Further- In a post hoc analysis of data from a study of prega-
more, the limited study population does not allow for balin and duloxetine combination some inter-pheno-
analysis with statistical models which include correc- type differences in response between treatments
tion for co-variates. In all, the results should be inter- were reported (Bouhassira et al., 2014).
preted cautiously. Taken together, the study The slightly better effect of antidepressants with
limitations calls for a very cautiously interpretation of short duration of pain could be explained by the
the results. The low number of observations that mechanisms of pain and the action of

1448 Eur J Pain 21 (2017) 1443--1450 © 2017 European Pain Federation - EFICâ
S. H. Sindrup et al. Factors in drug response in neuropathic pain

antidepressants. In experimental models of neuro- analysis of trial data or it could be considered to


pathic pain, it has been shown that there is a loss of restrict inclusion to short duration of pain when drugs
GABAergic neurones in the superficial layers of the working via pain modulation are studied.
dorsal horn of the spinal cord (Moore et al., 2002). In conclusion, etiology of painful polyneuropathy
These inhibitory interneurons are supposed to be with respect to diabetes may impact on the pain-
important as relay neurons for the descending mod- relieving effect of some anticonvulsants, and dura-
ulation exerted by opioids, cannabinoids and tion of neuropathic pain may impact on the effect of
monoamines (Lau and Vaughan, 2014). GABAergic some antidepressants. This could have implications
neurones in the spinal cord do have monoaminergic for the choice of treatment strategy in clinical prac-
receptors (Wang et al., 2009). So, the less effect of tice and may also be considered in the planning of
antidepressants with long duration of pain may clinical drug trials.
reflect that with time the effect of monoamines will
decrease due to loss of GABAergic neurones in the
dorsal horn of the spinal cord. Acknowledgements
Taken together, it is suggested that the differences The studies that provided data for this analysis were sup-
in effect may be related to differences in pain mech- ported by grants from H. Lundbeck, Pfizer, Takeda Pharma
anism or pain modulation, but the molecular or cel- and the IMI EuroPain collaboration.
lular nature of these differences remains obscure.
Furthermore, the limitations of the present analysis
should be kept in mind. Author contributions
What are the clinical implications of these find- All authors contributed to the idea and concept of this
ings? The effect size of anticonvulsants in painful study and all authors contributed to one or more of the
polyneuropathy in the present analysis is smaller clinical trials which formed the background for the present
than that of antidepressants, and if it is largely dri- analysis. SHS and JH performed the statistical analysis of
ven by effect in diabetics one could argue that the data and SHS wrote the first version of the manuscript.
antidepressants could be the first choice in non-dia- All authors commented on the analysis and the manu-
betic polyneuropathy. The impact of duration of pain script, and approved the final version of the manuscript to
on effect of antidepressants should be kept in mind be published.
and considered as a reason for low efficacy of these
drugs with long duration of pain. If the reason is
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