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Combined Psychophysical Approach to Pharmaco-therapeutic Management of Chronic Pain: A Review

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Abstract and Figures

Pain is a vital symptom which symbolizes the body's response to injury. The pathophysiology of pain from the site of the injury or pathology to its perception in the brain involves multiple pathways and mediators. Therefore it is increasingly being recognized that a single or unidimensional approach may not give the desired improvement in the quality of life of the patient with chronic pain. Chronic pain is often accompanied by psychological components and symptoms such as anxiety, depression and sleep disturbances which also further aggravate and exaggerate the pain, increase the disability days and severely impact quality of life. Therefore, a holistic approach to chronic pain management as seen in distressing neuropathic and musculoskeletal pain conditions like peripheral neuropathy, neuralgias, fi-bromyalgia, and spondylopathies, would require pharmacotherapy at both physical and psychological levels to give the desired improvement in both pain and quality of life of these patients. Drugs like Pregabalin and Gabapentin combined with Antidepressants can not only alleviate pain symptoms but can also improve the psychological component of associated anxiety and depression as well as improve sleep. Therefore such a combination approach can be one of the pharmaco-therapeutic ways of a psycho-physical approach in patients with the above mentioned painful conditions.
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Review Article
The Indian Practitioner q Vol.72 No.5. May 2019
Combined Psychophysical Approach to Pharmaco-therapeutic
Management of Chronic Pain: A Review
Dr Varsha Narayanan*
* Health and Pharmaceutical Consultant, Andheri, Mumbai. Email:
Pain is a vital symptom which symbolizes the body’s response to injury. The pathophysiology of pain from
the site of the injury or pathology to its perception in the brain involves multiple pathways and mediators.
Therefore it is increasingly being recognized that a single or unidimensional approach may not give the
desired improvement in the quality of life of the patient with chronic pain.
Chronic pain is often accompanied by psychological components and symptoms such as anxiety, depres-
sion and sleep disturbances which also further aggravate and exaggerate the pain, increase the disability
days and severely impact quality of life. Therefore, a holistic approach to chronic pain management as seen
in distressing neuropathic and musculoskeletal pain conditions like peripheral neuropathy, neuralgias, -
bromyalgia, and spondylopathies, would require pharmacotherapy at both physical and psychological lev-
els to give the desired improvement in both pain and quality of life of these patients.
Drugs like Pregabalin and Gabapentin combined with Antidepressants can not only alleviate pain symptoms
but can also improve the psychological component of associated anxiety and depression as well as improve
sleep. Therefore such a combination approach can be one of the pharmaco-therapeutic ways of a psycho-
physical approach in patients with the above mentioned painful conditions.
Keywords: Chronic pain, Seratoninergic, GABA, Glutamate, Anxiety, Depression, Pain-disability.
Conicts of Interest: None Declared.
Introduction to pain pathways
Pain is an unpleasant experience associated with
actual or potential tissue injury/damage.
Chronic pain, arbitrarily dened as that lasting lon-
ger than six months, is a clinical, social, and economic
problem, with evidence suggesting that pain and
emotion share common pathways and mechanisms.1
Both serotoninergic and noradrenergic pathways
facilitate the transport of pain impulses. They as-
cend from subcortical areas (brainstem, hypothala-
mus and thalamus) to the whole neocortex and me-
diate emotional and physiological responses to pain.
Serotoninergic cell bodies are located in the raphe
nucleus in the brainstem, while noradrenergic neu-
rones arelocated in the locus coeruleus (also in the
brainstem) and these send projections to various parts
of the brain involved in the control of mood, appe-
tite, sexual activity, aention and concentration. Their
pathways descend the spinal cord and act to suppress
nociceptive inputs (gure 1).1
Nociceptive inputs from tissue injury through me-
diators like cytokines, TNF (Tumor Necrosis Factor)
and Substance P etc cause nerve irritation. TRP
(Transient Receptor Potential) channels that detect
noxious stimuli (mechanical, thermal, and chemical
pain) relay that information to nociceptors that gen-
erate an action potential.2 Nociceptors have a certain
threshold and they require a minimum intensity of
stimulation before they trigger a signal. Once this
threshold is reached a signal is passed along the axon
Review Article
The Indian Practitioner q Vol.72 No.5. May 2019
of the neuron into the spinal cord where it causes
changes in the neurotransmier levels, thereby in-
creasing the release of excitatory neurotransmiers
like Glutamate, and decreasing levels onhibitory or
calming neurotransmiers like Gama-amino-butyric
acid (GABA). This modulation of neurotransmiers
modulates and increases pain perception.3
A decrease in GABA levels and increased
Glutamate action also leads to anxiety and reduced
sleep.4,5 Decrease in serotoninergic and noradrener-
gic eect results in mood alterations and depression.
Thus, these psychological symptoms along with sleep
disturbances increase the associated distress and dis-
ability as well as decrease the quality of life, and prog-
nosis of pain.
Serotoninergic and noradrenergic pathways regu-
late emotional and physiological responses in the cor-
tex, and these pathways also descend the spinal cord
to suppress nociceptive inputs, decrease Glutamate,
increase GABA levels and reduce pain perception.5,6
Increased serotoninergic and noradrenergic activ-
ity also reduce anxiety and depression, and also im-
prove sleep, thereby improving pain associated dis-
ability and quality of life. A rational pharmacological
approach would involve modulation of these neu-
rotransmiers and pain channels in order to decrease
pain perception and its psychological impact.
Psychophysical relation and impact of pain
Pain is characterized by both sensory and aective
disturbances, like anxiety, depression, loss of sleep
and impaired social interactions.7,8 More than 40% pa-
tients with musculoskeletal and neuropathic pain suf-
fer from anxiety-depression and sleep disturbances.9,10
Anxiety-depression patients experience the greatest
pain severity, pain-related disability and impaired
quality of life (gure 2).9,11 In a study with 2981 partici-
pants with pain with and without a co-morbid depres-
sive and anxiety disorder, presence of a depressive
(OR = 6.67; P<.001), anxiety (OR = 4.84; P<.001), or co-
morbid depressive and anxiety disorder (OR = 30.26;
P<.001) was associated with the Chronic Pain Grade.12
Greater severity of psychological symptoms, more
disabling and severely limiting was the pain.
Patients with pain are also at increased risk of de-
veloping an anxiety or depression episode for the rst
time. A study from Netherlands showed that 15.5%
Figure 1: Ascending and descending serotoninergic and noradrenergic pathways
Review Article
The Indian Practitioner q Vol.72 No.5. May 2019
patients with pain with no prior psychological history
developed depression or anxiety or both in a 4 year
follow up period.13
Another study found that anxiety disorders were
very prevalent in elderly patients with chronic pain,
and these also correlated signicantly with pain and
depression. In this study, a high prevalence of anxiety
disorders was observed in an elderly female popula-
tion (mean age 85 years), being 53.6% and 68.3%, re-
spectively, for trait and state anxiety.14
It has also been seen that almost 50% of patients
with major depressive disorders also have chronic
painful physical conditions and such patients had a
longer duration of depressive symptoms (7 months
longer) and were more likely to report severe fatigue
(OR = 5.4), insomnia nearly every night (OR = 3.3), se-
vere psychomotor retardation (OR = 3.3), weight gain
(OR = 2.3), severe diculty concentrating (OR = 1.7),
and severe feelings of sadness or depressed mood (OR
= 1.8).15
In a cross-sectional study, a hospital Anxiety and
Depression Scale and the Pain Visual Analogue Scale
were used to evaluate pain.16 A frequency of 68.5% of
anxious symptoms and 51.9% of depressive symptoms
was seen in patients with neuropathic pain. 57.4% of
the patients reported severe pain with a positive corre-
lation between pain severity and anxious and depres-
sive symptoms (p ≤ 0.05) a high frequency of anxious
and depressive symptoms in patients with peripheral
neuropathies. Disturbed sleep further exacerbates and
reduces the prognosis of musculoskeletal and neuro-
pathic pain.17,18
Gabapentinoids for pain and anxiety
Pregabalin and Gabapentin (synthetic Gabapenti-
noids) act as antagonists of voltage gated Ca2+ chan-
nels by binding to the alpha-2-delta sub-unit of
voltage-gated calcium channels of pre-synap-
tic neurons in an excited state, thereby chang-
ing the conformation of the channel and reduc-
ing the release of excitatory neurotransmiers
such as glutamate and substance P.19,20 The con-
sequent reduced stimulation of post-synaptic
neurones is thought responsible fortheiranxio-
lytic, antiepileptic and analgesic eects.
Pregabalin is shown to modulate dierent
potassium channels including KATP chan-
nels whose opening produces antinocicep-
tive eects by reducing the neuronal excit-
ability and inhibiting the release of dierent
neurotransmiers including substance P in
the spinal cord contributing to the analgesic
eects.21 Gabapentin is a potent activator of the het-
eromeric KCNQ2/3 voltage-gated potassium chan-
nel, the primary molecular correlate of the neuronal
M-current channel activation which may enhance its
anticonvulsant, anti-nociceptive and anxiolytic ef-
fects.22 Pregabalinand Gabapentinmay increase GABA
in brain, possibly by enhancing rate of synthesis of
GABA from glutamate by glutamic acid decarboxyl-
ase (GAD enzyme) and by inhibiting branched-chain
amino acid transaminase, possibly reducing gluta-
mate concentration without direct eect on GABAA
or GABAB receptors.23,24
Orally Pregabalin has the advantage of faster and
more complete absorption along with predictable
linear pharmacokinetics unlike Gabapentin which
displays non linear pharmacokinetics and vari-
able absorption especially at higher doses, therefore
Pregabalin has faster onset of action, higher predict-
ability, potency and bioavailability as compared to
Many clinical studies have shown the ecacy
and safety of Pregabalin and Gabapentin in chronic
neuropathic pain. In painful Diabetic Peripheral
Neuropathy, Pregabalin 150, 300, or 600 mg/day has
shown reduction in daily mean pain scores, pain and
pain-related sleep interference with higher doses of
Pregabalin produce a faster reduction in pain scores
as compared to lower dosesbut also causing more
somnolence.26,27 Clinical studies of Pregabalin (75-600
mg/day) in older patients above 65 yearswith pain-
ful Diabetic Neuropathy and Post Herpetic Neuralgia
showed signicant reduction inneuropathic pain
compared to that observed in younger patients.28,29
Gabapentin has also shown benecial evidence in
improving pain in diabetic neuropathy and herpetic
Figure 2: Increase in Pain Disability days with associated
psychological symptoms
Review Article
The Indian Practitioner q Vol.72 No.5. May 2019
A study reported that Pregabalin produces relief
in terms of pain perception, disability level, anxi-
ety, depression, sleep quality and quality of life in
Gabapentin refractory neuropathy making it a use-
ful option for these group of patients.31 Pregabalinhas
shown to be eective in a randomized, placebo-con-
trolled trial comprising Asian patients with pain from
cervical spondylosis (CS).32 Pregabalin has addition-
ally also shown ecacyand safety in treating long
standing bromyalgia in some clinical studies.33-35
Combining gabapentinoids with antidepressants
in chronic pain treatment
There is now evidence coming in that adding an
antidepressant (like tricyclic antidepressants TCA
–Amitriptyline or Nortriptyline, or newer ones like
Duloxetine) can help not only to reduce the depres-
sion associated with chronic pain but independently
improve pain severity, pain related disability and
quality of life. From the point of view of pain mecha-
nism discussed earlier in the review, these antidepres-
sants act by reducing the reuptake of serotonin and
noradrenalin.36 These neurotransmiers and their
pathways have been seen to suppress nociceptive in-
puts, decrease glutamate, increase GABA levels and
reduce pain perception and pain associated disability,
along with psychological benets of reducing depres-
sion, and normalizing sleep.5,6 TCAs are the most well
recognized antidepressants that inhibit reuptake of
both serotonin and Noradrenalin while newer ones
like Fluoxetine selectively inhibit only Seratonin up-
take. Duloxetine and Venlafexine also inhibit reuptake
of both seratonin and noradrenalin but have a 10 and
30 times higher selectivity for serotonin reuptake.36
Tricyclic antidepressants, together with anti-
convulsants Gabapentinoids like Pregabalin and
Gabapentin, are considered to be rst-line drugs for
the treatment of neuropathic pain as they are known
to have the greatest analgesic ecacy among antide-
pressants with the analgesic and antidepressant ef-
fects occurring independently.37 The analgesic ecacy
of antidepressants in patients with chronic pain and
no concomitant depression, or analgesic eect with-
out any eect on mood in depressed chronic-pain pa-
tients supports their independent analgesic eect, and
the dose required to achieve an optimum analgesic re-
sponse is usually lower than that required to achieve
an antidepressant eect. The Neuropathic Pain Special
Interest Group of the International Association for the
Study of Pain recommended Tricyclic antidepressants,
dual reuptake inhibitors of serotonin and noradrena-
lin , calcium channel a2-d ligands (ie, Gabapentin and
Pregabalin), and topical lidocaine as rst-line treat-
ment options on the basis of the results of randomized
clinical trials.38
Tricyclic antidepressants like Amitriptyline, dual
reuptake inhibitors of serotonin and norepinephrine
like Duloxetine with Pregabalin or Gabapentin have
also been recommended as the initial therapy for
neuropathy patients by National Institute of Health
and Care Excellence.39 Combination of Pregabalin/
Gabapentin with TCA is useful in patients who do
not gain sucient pain relief or tolerate either drug
in high doses, or to improve sleep disturbance in neu-
ropathic pain according to a recent Danish expert rec-
In a Canadian double-blindcrossover trial, 56 pa-
tients with diabetic polyneuropathy or postherpetic
neuralgia, with a daily pain score of at least 4 (scale
0-10), were randomised to daily oral Gabapentin,
Nortriptyline, or their combination with 6 weekly dose
titration towards maximum tolerated dose.41 Mean
daily pain score was 5.4 (95% CI 5.0 to 5.8) at baseline,
and at maximum tolerated dose, pain was 3.2 (2.5 to
3.8) for Gabapentin, 2.9 (2.4 to 3.4) for Nortriptyline,
and 2.3 (1.8 to 2.8) for combination treatment. Pain
with combination treatment was signicantly low-
er than with Gabapentin (-0.9, 95% CI -1.4 to -0.3,
p=0.001) or Nortriptyline alone (-0.6, 95% CI -1.1 to
-0.1, p=0.02). At maximum tolerated dose, the most
common adverse event was dry mouth, which was
signicantly less frequent in patients on Gabapentin
than on Nortriptyline (p<0.0001) or combination treat-
ment (p<0.0001). No serious adverse events were re-
corded during the study.
Two studies evaluate combination eects of
Duloxetine with Pregabalin versus monothera-
py. A study in bromyalgia patients comparing a
Pregabalin-Duloxetine combination with monothera-
py showed daily average pain score at 6 weeks with
Placebo, Pregabalin, Duloxetine, and combination to
be 5.1, 5.0, 4.1, and 3.7, respectively (P < 0.05 for com-
bination vs placebo, and vsPregabalin). 42% patients
reporting moderate or more global pain relief were
18%, 39%, 42%, and 68%, respectively (P < 0.05 for
combination vs placebo, Pregabalin, and Duloxetine).
Fibromyalgia Impact Questionnaire scores were 42.9,
37.4, 36.0, and 29.8, respectively (P < 0.05 for combina-
tion vs placebo, Pregabalin, and Duloxetine) whle SF-
36 scores were 50.2, 55.7, 56.0, and 61.2, respectively
(P < 0.05 for combination vs placebo, Pregabalin, and
Review Article
The Indian Practitioner q Vol.72 No.5. May 2019
Duloxetine). Medical Outcomes Study Sleep Scale
scores were 48.9, 35.2, 46.1, and 32.1, respectively (P <
0.05 only for combination vs placebo, and Duloxetine).
Moderate-severe drowsiness was more frequent dur-
ing combination vs placebo. Combining Pregabalin
with a serotonin – Noradrenaline dual uptake inhibi-
tor anti-depressant for bromyalgia can improve mul-
tiple clinical outcomes vsmonotherapy.
A multicentre, study (N=804) in diabetic peripher-
al neuropathic pain showed patients’ pain reduction
measured by BPI-MSF (Brief Pain Inventory Modied
Short Form) to be -2.35 for combination and -2.16 for
high-dose monotherapy: P = 0.370) with most second-
ary end points also consistently favoured combination
therapy. 4350% response rates were 52.1% for com-
bination and 39.3% for high-dose monotherapy (P =
0.068). Both drugs and their combination were well
tolerated. Although not signicantly superior to high-
dose monotherapy, combination therapy was consid-
ered to be eective, safe, and well tolerated.
In an open randomized study of 56 women with
chronic pelvic pain, patients were randomized to re-
ceive Gabapentin (n = 20), Amitriptyline (n = 20), or
a combination of both drugs (n = 16) with upward
dose to maximum tolerable dose or until sucient
pain relief. At 6 months, average change in pain
scores for Gabapentin, Amitriptyline and combi-
nation groups were -6.1, -5.1 and -6.3 showing that
pain relief was signicantly beer in patients receiv-
ing Gabapentin either alone or in combination with
Amitriptyline than in patients receiving monotherapy
with Amitriptyline.44
Chronic pain is the leading reason for morbidity
and disability in medical care as well as an increased
economic burden. Chronic neurological and muscu-
loskeletal pain, have a psychological component in
addition to the physical, which increases pain related
disability, and lowers prognosis and quality of life.
There is a signicant relationship between depression
and pain symptoms, and patients with a long history
of pain disorders also have increased depression and
anxiety symptoms with the intensity of pain correlat-
ing with the intensity of psychopathological symp-
toms - both with mood lowering and with anxiety
symptoms.45 This is essentially due to sharing of com-
mon mechanisms, mediators and pathways. Therefore
management of pain requires both a physical and
psychological approach. Combining gabapentinoids
with antidepressants which have dual action of in-
hibiting reuptake of both serotonin and noradrena-
lin can help as an eective and multiprong approach
in chronic pain. Studies have shown beer results in
pain management with such combinations as com-
pared to monotherapy, and this approach has also
been recommended in some consensus and guidelines
as reviewed in this article. More studies on such com-
bination approaches will add further insights to the
management of chronic pain in diverse conditions and
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Background Due to its high morbidity and prevalence, the potential relationships of depression/anxiety symptoms in neck pain (NP) are not well demonstrated. Objectives This study aimed to conduct a comprehensive estimation of controlled trials of psychological problems and to test hypotheses concerning whether NP was statistically relative to anxiety/depression symptoms. Methods Chinese literature databases such as the China National Knowledge Infrastructure (CNKI), VIP Information (VIP), Chinese Biomedicine (CBM), and Wanfang Data (WANFANG) were scientifically searched for reports published until February 5, 2018. Controlled trials incorporating NP patients with anxiety/depression versus healthy people were contained. Two researchers screened each article and extracted data, respectively, and blinded to the findings of each other. Meta-analysis was conducted by the Cochrane Collaboration's RevMan 5.3 and Stata 14.0 (Stata Corp LP, USA) software. Results We identified 13 eligible studies involving 2339 patients and 3290 healthy people. Compared with healthy control participants, the findings indicated that depression/anxiety symptoms were more common or severe in NP patients (respectively, SMD = 0.89; 95% CI = (0.58, 1.20); P < 0.01 and SMD = 0.92; 95% CI = (0.65, 1.20); and P < 0.01), results from the pooled data demonstrated no statistical significance between depression/anxiety symptoms and gender in NP patients (resp., SMD = 0.16; 95% CI = (−0.18, 0.51); P=0.35 and SMD = −0.08; 95% CI = (−0.42, 0.27); and P=0.67), and the combined data of the incidence of depression or anxiety symptoms revealed significant difference between NP patients and healthy persons (resp., RR = 4.81; 95% CI = (3.30, 7.01); P < 0.01 and RR = 3.29; 95% CI = (2.16, 5.00); and P < 0.01). In addition, we did not find articles that met the inclusion criteria, which compared NP patients with other physical illnesses in terms of anxiety/depression symptoms. Conclusions This meta-analysis suggests that anxiety/depression symptoms are associated with high morbidity in NP patients. We consider these reports support the viewpoint that nonspecific mechanisms mediate mental disturbances in NP. This study may have clinical value for NP, offering an underlying target for the prevention and treatment of anxiety/depression.
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Background Current Danish treatment algorithms for pharmacological treatment of neuropathic pain (NeP) are tricyclic antidepressants (TCA), gabapentin and pregabalin as first-line treatment for the most common NeP conditions. Many patients have insufficient pain relief on monotherapy, but combination therapy had not been included in guidelines until recently. Based on clinical empiricism and scientific evidence, a Delphi consensus process provided a consolidated guidance on pharmacological combination treatment of NeP. Methods A two-round virtual internet-based Delphi process with 6 Danish pain specialists was undertaken. In the first round, questions were answered individually and anonymously, whereas in the second round, the panel openly discussed first round’s summary of outcomes. Combinations of pharmacological pain treatments, that is, pregabalin/gabapentin, TCAs, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors, opioids, other antiepileptics and cutaneous patches, were assessed based on both scientific and clinical practice experiences. The Centers for Disease Control and Prevention (CDC) grading system was used for evidence rating. Results Combination of pregabalin/gabapentin with TCA is useful in patients who do not gain sufficient pain relief or tolerate either drug in high doses, or to improve sleep disturbance. Also, combination of pregabalin/gabapentin and SNRIs is reasonably well documented and experienced by some experts to result in sufficient pain relief and fewer side effects than monotherapy. Good evidence on efficacy was found for the combination of pregabalin/gabapentin or TCAs and opioids, which was also frequently used in clinical practice. The evidence for combining TCAs and SNRIs is insufficient, although sometimes used in clinical practice despite the risk of serotonin syndrome. For localized NeP, combination therapy with cutaneous patches should be considered. There was insufficient scientific evidence for any pharmacologic combination therapies with selective serotonin reuptake inhibitors – as well as for other potential combinations. Conclusions The study revealed that combination therapy is widely used in clinical practice and supported by some scientific evidence. However, further studies are needed.
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Background: Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000. Objectives: To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain in adults. Search methods: For this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries. Selection criteria: We included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. Data collection and analysis: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. Main results: We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%). Authors' conclusions: Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.
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Objectives: to evaluate the frequency of anxiety disorders in older elderly persons with chronic pain and identify associated factors. Method: a descriptive, analytical and cross section study of the "Projeto Longevos" ("Long-Lived Elderly Persons Project") was carried out, featuring elderly persons living in the community who were aged 80 or over. Older elderly persons with chronic pain were selected, and data regarding their sociodemographic characteristics and factors related to pain was gathered, especially with regard to the multidimensional nature of pain, according to the "Geriatric Pain Measure-p" (GPM-p). Self-perception of health was also recorded and functionality assessments were carried out, along with the screenings for depression and anxiety disorders, according to the Geriatric Depression Scale and the State-Trait Anxiety Inventory, respectively. Associations were analyzed by Pearson correlation, the ANOVA Test and Tukey multiple comparisons. Results: the sample was composed of 41 elderly persons with a mean age of 85.7 years, most of whom were female, white, widowed and had a low education. A high prevalence of anxiety disorders was observed, being 53.6% and 68.3%, respectively, for trait and state anxiety. A significant, but not high, correlation was found between the anxiety trait and chronic pain according to the GPM-p (r=31.5%; p=0.048), and there was a significant and high correlation between the same type of anxiety and depression (r=61.3%; p<0.001). Conclusion: anxiety disorders were very prevalent in older elderly persons with chronic pain, and these correlated significantly with pain and depression, which could justify the need for varied multidisciplinary therapeutic measures against the persistent pain conditions of the elderly.
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Lines of evidence coming from many branches of neuroscience indicate that anxiety disorders arise from a dysfunction in the modulation of brain circuits which regulate emotional responses to potentially threatening stimuli. The concept of anxiety disorders as a disturbance of emotional response regulation is a useful one as it allows anxiety to be explained in terms of a more general model of aberrant salience and also because it identifies avenues for developing psychological, behavioral, and pharmacological strategies for the treatment of anxiety disorder. These circuits involve bottom-up activity from the amygdala, indicating the presence of potentially threatening stimuli, and top-down control mechanisms originating in the prefrontal cortex, signaling the emotional salience of stimuli. Understanding the factors that control cortical mechanisms may open the way to identification of more effective cognitive behavioral strategies for managing anxiety disorders. The brain circuits in the amygdala are thought to comprise inhibitory networks of γ-aminobutyric acid-ergic (GABAergic) interneurons and this neurotransmitter thus plays a key role in the modulation of anxiety responses both in the normal and pathological state. The presence of allosteric sites on the GABAA receptor allows the level of inhibition of neurons in the amygdala to be regulated with exquisite precision, and these sites are the molecular targets of the principal classes of anxiolytic drugs. Changes in the levels of endogenous modulators of these allosteric sites as well as changes in the subunit composition of the GABAA receptor may represent mechanisms whereby the level of neuronal inhibition is downregulated in pathological anxiety states. Neurosteroids are synthesized in the brain and act as allosteric modulators of the GABAA receptor. Since their synthesis is itself regulated by stress and by anxiogenic stimuli, targeting the neurosteroid-GABAA receptor axis represents an attractive target for the modulation of anxiety.
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Chronic pain is commonly co-morbid with a depressive or anxiety disorder. Objective of this study is to examine the influence of depression, along with anxiety, on pain-related disability, pain intensity, and pain location in a large sample of adults with and without a depressive and/or anxiety disorder. The study population consisted of 2981 participants with a depressive, anxiety, co-morbid depressive and anxiety disorder, remitted disorder or no current disorder (controls). Severity of depressive and anxiety symptoms was also assessed. In separate multinomial regression analyses, the association of presence of depressive or anxiety disorders and symptom severity with the Chronic Pain Grade and location of pain was explored. Presence of a depressive (OR = 6.67; P<.001), anxiety (OR = 4.84; P<.001), or co-morbid depressive and anxiety disorder (OR = 30.26; P<.001) was associated with the Chronic Pain Grade. Moreover, symptom severity was associated with more disabling and severely limiting pain. Also, a remitted depressive or anxiety disorder showed more disabling and severely limiting pain (OR = 3.53; P<.001) as compared to controls. A current anxiety disorder (OR = 2.96; p<.001) and a co-morbid depressive and anxiety disorder (OR = 5.15; P<.001) were more strongly associated with cardio-respiratory pain, than gastro-intestinal or musculoskeletal pain. These findings remain after adjustment for chronic cardio respiratory illness. Patients with a current and remitted depressive and/or anxiety disorder and those with more severe symptoms have more disabling pain and pain of cardio-respiratory nature, than persons without a depressive or anxiety disorder. This warrants further research.
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Introduction: Pain is defined "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Pain is a sensation of the body, and is always an unpleasant emotional experience. The role of psychology is auxiliary and supplemental to medicine. This is an aid addressed to the patient, physician and patient's caregivers: professional caregivers, family members and significant others. At each stage of the diagnostic and therapeutic process, psychology offers help, both from the cognitive and practical aspects. Objective: The objective of the article is to present important psychological aspects of studies concerning pain, and the psychological methods and techniques of pain treatment. State of knowledge: Pain is the leading reason for patients seeking medical care and is one of the most disabling, burdensome, and costly conditions. Pain accompanies many diseases, each one of which generates unique/separate diagnostic, therapeutic and research problems. DEPRESSION AND RELATED PSYCHICAL DISORDERS: There is a significant relationship between depression and pain symptoms, as well as between pain and suicidal thoughts. Patients with a long history of pain disorders also have increased depression and anxiety symptoms, as well as suicidal thoughts. Patients with more severe depression and anxiety symptoms also have an increase in pain problems. The intensity of pain correlates with the intensity of psychopathological symptoms - both with mood lowering and with anxiety symptoms and worry. Active pain coping strategies strive to function in spite of pain, or to distract oneself from pain, are associated with adaptive functioning. Passive strategies involve withdrawal or relinquishing control to an external force or agent and are related to greater pain and depression. Pain catastrophizing is a negatively distorted perception of pain as awful, horrible and unbearable. Catastrophizing is strongly associated with depression and pain. Studies in which functional magnetic resonance imaging (fMRI) was used showed that pain catastrophizing, independent of the influence of depression, was significantly associated with increased activity in brain areas related to anticipation of pain, attention to pain, emotional aspects of pain and motor control. Pain behaviour is a conditioned pain. Care and concern on the part of others, secondarily enhance a patient's pain behaviours, which lead to an increase in the intensity of the pain experienced. A history of early life adversity (ELA) - rejection, neglect, physical or sexual abuse is related to the development of irritable bowel syndrome (IBS) in adulthood. Ovarian hormones have been shown to modulate pain sensitivity. IMAGING OF THE HUMAN BRAIN IN CHRONIC PAIN: Acute pain and chronic pain are encoded in different regions of the brain. Chronic pain can be considered a driving force that carves cortical anatomy and physiology, creating the chronic pain brain/ mind state. Cognitive-behavioural methods of pain treatment in domains of pain experience, cognitive coping and appraisal (positive coping measures), and reduced pain experience are effective in reducing pain in patients.
Neuropathic pain is associated with sleep disturbances, and in turn poor sleep quality leads to increased pain sensitivity, so it is essential to assess sleep alongside neuropathic pain. Responses to drugs are inconsistent and identifying the best treatment option that will reduce pain and improve sleep quality remains challenging for clinicians. Anticonvulsants such as pregabalin and gabapentin improve neuropathic pain and have a positive effect on comorbid sleep disturbances. Opioids and antidepressants are effective in reducing pain but can exacerbate sleep disturbances. Funding: Pfizer, Italy.
This double-blind randomized controlled trial demonstrates improved outcomes with a pregabalin-duloxetine combination over either single drug for fibromyalgia.
Patients with pain may be at increased risk of developing a first episode of depressive or anxiety disorder. Insight into possible associations between specific pain characteristics and such a development could help clinicians to improve prevention and treatment strategies. The objectives of this study were to examine the impact of pain symptomatology on depression and anxiety onset and to determine whether these associations are independent of subthreshold depressive and anxiety symptoms. Data from the Netherlands Study of Depression and Anxiety, collected between 2004 and 2011, were used. A total of 614 participants with no previous history and no current depression or anxiety at baseline were followed up for 4years. Onset of depressive or anxiety disorder was assessed at 2- and 4-year follow-up by Composite International Diagnostic Interview. Baseline pain characteristics were location, duration, and severity, as assessed by chronic pain grade. Onset of depressive or anxiety disorder occurred in 15.5% of participants. Using Cox survival analyses, onset of depression and anxiety was associated with 6 pain locations (neck, back, head, orofacial area, abdomen, and joints; hazard ratio [HR]=1.96 to 4.02; P<.05), increasing number of pain locations (HR=1.29; P<.001), and higher severity of pain (HR=1.57; P<.001). By contrast, there was no association with duration of pain symptoms (HR=1.47; P=.12). Independent of subthreshold affective symptoms, only joint pain and increasing number of pain locations were still significantly associated with depression and anxiety onset. Clinicians should be aware that regardless of affective symptoms, pain, particularly at multiple locations, is a risk indicator for developing depressive and anxiety disorders