AnalgesicDrugs Combinations in theTreatment of Different Types of Pain
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Analgesic Drugs Combinations
in the Treatment of DifferentTypes of Pain
Pain Research and Treatment
Guest Editors: Mario I. Ortiz, Mara Asuncin Romero Molina,Young-Chang P. Arai, and Carlo Luca Roman
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AnalgesicDrugsCombinations in theTreatment
ofDifferent Types of Pain
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Pain Research and Treatment
AnalgesicDrugsCombinations in theTreatment
ofDifferent Types of Pain
Guest Editors: Mario I. Ortiz, Mara Asuncion Romero Molina,
Young-Chang P. Arai, and Carlo Luca Romano
-
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Copyright 2012 Hindawi Publishing Corporation. All rights reserved.
This is a special issue published in Pain Research and Treatment. All articles are open access articles distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the originalwork is properly cited.
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Editorial Board
Mustafa alAbsi, USAKarel Allegaert, Belgium
Anna Maria Aloisi, Italy
Fabio Antonaci, Italy
Robert Barkin, USA
M. E. Bigal, USA
Kay Brune, Germany
John F. Butterworth, USABoris A. Chizh, UK
MacDonald J. Christie, Australia
Marina De Tommaso, Italy
Sulayman D. Dib-Hajj, USA
Jonathan O. Dostrovsky, Canada
P. Dougherty, USAChristopher L. Edwards, USA
Jens Ellrich, Denmark
S. Evers, Germany
Maria Fitzgerald, UK
Pierangelo Geppetti, Italy
James Giordano, UK
Hartmut Gobel, GermanyJ. Henry, Canada
Kazuhide Inoue, Japan
Michael G. Irwin, Hong Kong
Robert N. Jamison, USA
Piotr K. Janicki, USA
C. Johnston, Canada
Steve McGaraughty, USABjorn A. Meyerson, Sweden
Gunnar L. Olsson, Sweden
Ke Ren, USA
John F. Rothrock, USA
Paola Sarchielli, Italy
Zeev Seltzer, CanadaDonald A. Simone, USA
Howard Smith, USA
Giustino Varrassi, Italy
Muhammad B. Yunus, USA
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Contents
AnalgesicDrugs Combinations in theTreatment of Different Typesof Pain, Mario I. Ortiz,
Mara Asuncion Romero Molina, Young-Chang P. Arai, and Carlo Luca Romano
Volume 2012, Article ID 612519, 2 pages
Antineuropathic and Antinociceptive Drugs Combination in Patientswith Chronic Low Back Pain:A
Systematic Review, Carlo Luca Romano, Delia Romano, and Marco Lacerenza
Volume 2012, Article ID 154781, 8 pages
Efficacy and Tolerability of Fixed-Dose Combination of Dexketoprofen and Dicyclomine Injection in
Acute Renal Colic, A. Porwal, A. D. Mahajan, D. S. Oswal, S. S. Erram, D. N. Sheth, S. Balamurugan,
V. Kamat, R. P. Enadle, A. Badadare, S. K. Bhatnagar, R. S. Walvekar, S. Dhorepatil, R. C. Naik, I. Basu,S. N. Kshirsagar, J. V. Keny, and S. Sengupta
Volume 2012, Article ID 295926, 5 pages
Morphine and ClonidineSynergize to Ameliorate Low Back Pain in Mice, Maral Tajerian,
Magali Millecamps, and Laura S. Stone
Volume 2012, Article ID 150842, 12 pages
Effects of CombinedOpioids onPainand Mood in Mammals, Richard H. Rech, David J. Mokler,
and Shannon L. Briggs
Volume 2012, Article ID 145965, 11 pages
Combination DrugTherapy forPain following Chronic Spinal Cord Injury,
Aldric Hama and Jacqueline SagenVolume 2012, Article ID 840486, 13 pages
Efficacy and Safety of Duloxetine inPatients with Chronic Low Back Pain Who Used versus Did Not Use
ConcomitantNonsteroidal Anti-Inflammatory Drugsor Acetaminophen: A Post Hoc PooledAnalysis of
2 Randomized, Placebo-ControlledTrials, Vladimir Skljarevski, Peng Liu, Shuyu Zhang, Jonna Ahl,
and James M. Martinez
Volume 2012, Article ID 296710, 6 pages
Effectof Diclofenac withB Vitamins on theTreatment of Acute Pain Originated by Lower-Limb Fracture
and Surgery, Hector A. Ponce-Monter, Mario I. Ortiz, Alexis F. Garza-Hernandez, Raul Monroy-Maya,
Marisela Soto-Ros, Lourdes Carrillo-Alarcon, Gerardo Reyes-Garca, and Eduardo Fernandez-Martnez
Volume 2012, Article ID 104782, 5 pages
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Hindawi Publishing CorporationPain Research and TreatmentVolume 2012, Article ID 612519,2pagesdoi:10.1155/2012/612519
EditorialAnalgesic Drugs Combinations in the Treatment ofDifferent Types of Pain
Mario I. Ortiz,1 Mara Asuncion Romero Molina,2
Young-Chang P. Arai,3 and Carlo Luca Romano4
1 Laboratorio de Farmacologa, Area Academica de Medicina del Instituto de Ciencias de la Salud,Universidad Autonoma del Estado de Hidalgo, Eliseo Ramrez Ulloa 400, Col. Doctores, 42090 Pachuca, HGO, Mexico
2 Fisiopatologia i Tratament del Dolor, IMIM, Parc de Recerca Biomedica de Barcelona (PRBB), c/Dr. Aiguader n 88,
08003 Barcelona, Spain3Multidisciplinary Pain Centre, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan4 Dipartimento di Chirurgia Ricostruttiva e delle Infezioni Osteo-Articolari, I.R.C.C.S. Istituto Ortopedico Galeazzi,
Via Riccardo Galeazzi, 4, 20161 Milano, Italy
Correspondence should be addressed to Mario I. Ortiz,mario i [email protected]
Received 29 April 2012; Accepted 29 April 2012
Copyright 2012 Mario I. Ortiz et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Pain relief can be achieved by a diversity of methods, withdrug use being the basis of analgesic treatment. Clinical useof combinations of analgesic drugs has augmented consider-ably in the last few years. The purpose of combining two ormore drugs with different mechanisms of action is to achievea synergistic interaction [1], yielding a sufficient analgesiceffect with lower doses, and, therefore, reduce the intensityand incidence of untoward effects. At present, many diverseclasses of drugs serve as an efficient complement to nons-teroidal anti-inflammatory drugs (NSAIDs), acetaminophenor opioids, in the management of pain. But we emphasizethat the success of a drug combination depends on thetype of pain that is targeted (acute/chronic, inflammatory,
neuropathic, cancer). Thus, opioids have frequently beenused in combination with acetaminophen or NSAIDs forthe clinical management of both acute and chronic pain.Likewise, the NSAIDs-acetaminophen combination has beenadministered to patients to relief the pain. At the end, theuse of these combinations limits the doses of medication thata patient can receive. However, not all the opioid-NSAID,opioid-acetaminophen, or NSAID-acetaminophen combi-nations are clinically successful in all cases. For example, theassociation of weak opioids, such as dextropropoxyphene,to acetaminophen does not significantly increase pain reliefcompared to acetaminophen alone [2]. The administrationof rectal acetaminophen combined with ibuprofen does not
improve analgesia after adenoidectomy in the immediatepostoperative period compared with either drug alone [3].Likewise, the combination of codeine with paracetamolresults in additional pain relief but may be accompanied byan increase in nausea, dizziness, vomiting, and constipation[4]. Therefore, several other combinations of analgesicagents must be evaluated experimentally or clinically togain insight into their potential clinical use. In this sense,different combinations have been suggested. In the presentspecial issue, a study realized by H. A. Ponce-Monter etal. showed that the diclofenac plus B vitamins combinationwas more effective to reduce the pain than diclofenac alone.Authors conclude that the combination of diclofenac plus
B vitamins could be a safe and inexpensive postsurgicalanalgesic strategy.
In the present issue, A. Porwal and coworkers showedhow different drug combinations may not be equally effectivein an acute pain model; in a large study population, theyin fact compared diclofenac and dicyclomine injection toa combination of dexketoprofen and dicyclomine for thetreatment of acute renal colic and provided evidence thatthe latter was significantly more effective and tolerable thanthe former drug combination. On the other hand, A. Hamaand J. Sagen, in a comprehensive review of the availablepreclinical and clinical studies, illustrate the pharmacologicaland physiological mechanisms that justify the use of a
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2 Pain Research and Treatment
combined drug therapy for the treatment of neuropathicpain due to spinal cord injury. The authors point out how acombination drug treatment strategy, wherein several pain-related mechanism are simultaneously engaged, may be moreefficacious than treatment against individual mechanismsalone, being possible to reduce the doses of the individual
drugs, thereby minimizing the potential for adverse side-effects.Clinicians should be conscious about the benefits and
risks of the drugs combination in the management of pain.Also, physicians must be aware that NSAIDs can causepotentially serious adverse effects when used in combinationwith other common medications such as anticoagulants,corticosteroids, or antihypertensive agents. Finally, patientsshould be properly counseled on the appropriate and safe useof the combination of analgesics.
Mario I. OrtizMara Asuncion Romero Molina
Young-Chang P. Arai
Carlo Luca Romano
References
[1] R. J. Tallarida, Drug synergism: its detection and applications,Journal of Pharmacology and Experimental Therapeutics, vol.298, no. 3, pp. 865872, 2001.
[2] A. Li Wan Po and W. Y. Zhang, Systematic overview of co-proxamol to assess analgesic effects of addition of dextro-propoxyphene to paracetamol, British Medical Journal, vol.315, no. 7122, pp. 15651571, 1997.
[3] H. Viitanen, N. Tuominen, H. Vaaraniemi, E. Nikanne, andP. Annila, Analgesic efficacy of rectal acetaminophen andibuprofen alone or in combination for paediatric day-caseadenoidectomy, British Journal of Anaesthesia, vol. 91, no. 3,pp. 363367, 2003.
[4] P. Kjaersgaard-Andersen, A. Nafei, O. Skov et al., Codeine plusparacetamol versus paracetamol in longer-term treatment ofchronic pain due to osteoarthritis of the hip. A randomised,double-blind, multi-centre study,Pain, vol. 43, no. 3, pp. 309318, 1990.
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Hindawi Publishing CorporationPain Research and TreatmentVolume 2012, Article ID 154781,8pagesdoi:10.1155/2012/154781
Review ArticleAntineuropathic and Antinociceptive Drugs Combination inPatients with Chronic Low Back Pain: A Systematic Review
Carlo Luca Romano,1 Delia Romano,1 and Marco Lacerenza2
1 Centro di Chirurgia Ricostruttiva, Istituto Ortopedico I.R.C.C.S. Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy2 Centro di Medicina del Dolore, Casa di cura S. Pio X, Fondazione Opera San Camillo, Via F. Nava 31, 20159 Milano, Italy
Correspondence should be addressed to Carlo Luca Romano,[email protected]
Received 8 January 2012; Revised 4 February 2012; Accepted 8 February 2012
Academic Editor: Young-Chang P. Arai
Copyright 2012 Carlo Luca Romano et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Purpose. Chronic low back pain (LBP) is often characterized by both nociceptive and neuropathic components. While variousmonotherapies have been reported of only limited efficacy, combining drugs with different mechanisms of action and targetsappears a rational approach. Aimof this systematic review is to assess the efficacy and safety of different combined pharmacologicaltreatments, compared to monotherapy or placebo, for the pharmacological treatment of chronic LBP. Methods. Published papers,written or abstracted in English from 1990 through 2011, comparing combined pharmacological treatments of chronic LBPto monotherapy or placebo were reviewed.Results. Six articles met the inclusion criteria. Pregabalin combined with celecoxibor opioids was shown to be more effective than either monotherapy. Oxycodone-paracetamol versus previous treatments andtramadol-paracetamol versus placebo were also reported as effective, while morphine-nortriptyline did not show any benefit overany single agent.Conclusions. In spite of theoretical advantages of combined pharmacological treatments of chronic LBP, clinicalstudies are remarkably few. Available data show that combined therapy, including antinociceptive and antineuropathic agents ismore effective than monotherapy, with similar side effects.
1. Introduction
Successful treatment of chronic pain depends on identifi-cation of the involved mechanism and use of appropriatetherapeutic approaches. Woolf et al. [1] proposed that painsymptoms and syndromes should be classified into two
broad mechanism-based pain categories: tissue-injury pain(nociceptive) or nervous-system-injury pain (neuropathic).
Even if there is increasing knowledge that different mech-anisms of pain require appropriate treatments and oftenpolypharmacotherapy, and although drug combination isfrequently empirically adopted in the clinical practice [25],prospective studies concerning the relative efficacy and safetyof therapeutical drug associations to treat various painfulconditions are still remarkably few [610] and, as recentlyreported, more preclinical, clinical, and translational studiesare needed to improve the efficacy of combination drug therapythat is an integral part of a comprehensive approach to themanagement of chronic pain [11].
Although many patients have self-limited episodes ofacute low-back pain (LBP) and do not seek medical care [12],this condition is among the five most common reasons forall physician visits in the USA [13,14]. Among those whodo seek medical care, pain, disability, and return to worktypically improve rapidly in the first month [15]; however, up
to one-third of patients report persistent back pain of at leastmoderate intensity one year after an acute episode [16,17].
Medications are the most frequently recommended inter-vention for low back pain [14,18]. In one study, 80% of pri-mary care patients with low back pain were prescribed at leastone medication at their initial office visit, and more than one-third were prescribed two or more drugs [5]. The most com-monly prescribed medications for low back pain are nons-teroidal anti-inflammatory drugs (NSAIDs), skeletal musclerelaxants, and opioid analgesics [5,19,20]. Benzodiazepines,systemic corticosteroids, antidepressant medications, andantiepileptic drugs are also prescribed [21]. Monotherapiesof chronic LBP with NSAIDs, acetaminophen and tricyclic
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2 Pain Research and Treatment
Potentially relevant publications identified and screened for retrieval
(monotherapy, mixed target population, and/or acute lowbackpain)
Papers excluded on the basis of title and abstract
(n = 96)
(n = 112)
Full-text articles evaluated (n = 16)
Excluded (n = 5)Reviews ( n = 2)
Acute lowback pain ( n = 3)
Total included studies (n = 6)
Figure1: Flow diagram of inclusion and exclusion of articles for combined pharmacological interventions for chronic low back pain.
antidepressants, opioids, tramadol, benzodiazepines, and ga-bapentin (for radiculopathy) have all been found to provideonly a limited pain relief, ranging from 10 to 20 points on a100-point visual analogue pain scale [22].
Chronic LBP has been shown to be the result of neu-ropathic as well as nociceptive pain mechanisms and hastherefore been classified as a mixed pain syndrome [2325].Nonspecific nociceptive pain is the result of an inflammatoryresponse to tissue injury, while neuropathic pain describescutaneous projected pain arising from the lumbar spineand/or nerve roots (radicular pain or radiculopathy) [3,4].The multifactorial nature of chronic LBP has often beenunderrecognized and undertreated. Thus, recent studies havedemonstrated that approximately 2055% of patients withchronic LBP have a >90% likelihood of a neuropathic paincomponent and, in an additional 28% of patients, a neuro-pathic pain component is suspected [5,26,27]. The presenceof a neuropathic pain component is associated with moresevere pain symptoms and higher healthcare utilization costs[28].
Based on this evidence, it has been suggested that antide-pressants and/or anticonvulsants in combination with eitheropioids, traditional nonsteroidal anti-inflammatory drugs,or muscle relaxants could be useful in the treatment of thiscondition [27,29,30]. The aim of this systematic review isto evaluate evidence for the effectiveness of pharmacological
combination therapy in chronic LBP, with specific referenceto the management of nociceptive and neuropathic paincomponents.
2. Materials and Methods
Published papers written in English or including an Englishabstract, published from 1990 through 2011 and reportingthe results of a combined pharmacological treatment ofchronic lowback pain (LPB), compared with monotherapyor placebo, were reviewed. To this aim, we searched inter-national databases, including EMBASE, PubMed/Medline,Google Scholar, SCOPUS, CINAHL, Cochrane Central Re-
gister of Controlled Trials, Cochrane Database of Sys-tematic Reviews, http://www.google.com/, and http://www.yahoo.com/. Inclusion criteria were the following:
(a) papers written or with an abstract in English;
(b) papers concerning the results of management ofchronic low-back pain (symptoms duration >6months);
(c) treatment using a combination of two or more drugs,versus monotherapy or placebo.
Two investigators, CR and ML, searched and reviewedindependently the literature and classified the references
found in terms of whether they should be included on basisof the title and the abstract of the paper. In addition tooriginal study reports, review articles were also included andthe reference lists from all reviewed articles were assessed tocomplete the literature search. At the end of the reviewingprocess, the two reviewers lists of papers were compared andif any discrepancy occurred, reclassification was performedaccording to the consensus reached.
This strategy identified 112 articles, the abstracts ofwhich were hand searched to identify a subset with thespecific focus of pharmacological treatment of chronic LBPof relevance to the current review. Six studies on pharma-cological management of chronic LBP (irrespective of the
cause) were identified as relevant and were included in thispaper (Figure 1).
3. Results
Table 1 summarizes the included studies examining com-bination pharmacotherapy of chronic LBP. Three studiesevaluated paracetamol in combination with tramadol [35,36] or oxycodone [32].
In the first study (n = 318), three-month treatment withtramadol 37.5 mg/paracetamol 325 mg yielded significantlygreater improvements in pain VAS score (P < 0.015) andPain Relief Rating Scale score (P < 0.001) than placebo.
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Pain Research and Treatment 3
Table1:Table1Clinicaltrialsoncom
binationpharmacologicaltherapyofchro
niclowbackpain.
Reference
Trialdesign
Duration
Maininclusion/exclusion
criteria
Paintype
Intervention(s)anddose
Principal
outcome
L.Roman`oet
al.[31]
Prospective,randomized,
3-waycross-overstudy
4-weekstreatmentwith
eachtherapy
12week
1875years
ChronicLBPfo
r>6
monthsduetodisc
prolapse,lumbar
spondylosis,and/orspinal
stenosis
MinimumVAS
>40mm
(onascaleof0
100mm)
Patientswithneurological
diseaseexcluded
Mixed
Celecoxib36mg/kg/die+
placebo(n=
36)
andPregabalin1mg/kg/dieforthe
firstweek,then24mg/kg/die
+placebo(n=
36)
andCelecoxib36mg/kg/die+
pregabalin1mg/kg/dieforthe
firstweek,then24mg/kg/die
(n=
36)
Combina
tiontherapywas
moreeffe
ctivethaneither
monotherapyformeanpain
reduction
(assessingusing
0100mm
VAS)
Gattietal.,
[32]
Prospective,
observational,and
open-labelstudy
6week
ChronicLBP(4
6months)
Moderatetosev
ere(>3on
a010VAS)
Painnotrespon
siveto
previoussystem
icorlocal
analgesictreatm
ent
Osteoarticular,
nociceptivepain(GroupA)
orneuropathicpain(Group
B)
GroupA
Previoustreatment
discontinued:Oxycodone
5mg+paracetamol325mg/8
hours(n=
78)
GroupB
Previoustreatment(except
gabapentin).Fixed
combinationofoxycodone
5mg+paracetamol325mg/8
hours(n=
72)
GroupA
73.9%an
d78.3%(assessed
using01
0VAS),respectively
GroupB
Allpatien
tsreported
improved
orstable
neuropathicpainsymptoms
exceptpainpreventingsleep
Potaetal.,
[33]
Prospective,
observational,and
open-labelstudy
2month
ChronicLBP(3
3months)
Mixed
(n=
22)
Month1:BuprenorphineTDS
35
g/ml
Month2:BuprenorphineTDS
35
g/ml+pregabalin150mg
orBuprenorphineTDS35
g/ml
+placebo
Significan
treductionsin
pain(assessedusing
0100VA
S)wereobserved
aftermon
th1(P
18years
ChronicLBP
Painintensity>
40
(0100mmVAS)
Patientswithneurologic
deficitsinlower
extremities,
symptomaticdisk
herniation,seve
respinal
stenosis,orspondy
lolisthesisexcluded
Nociceptive
Tramadol37.5300mg+
paracetamol3252600mg
(n=
167)
orPlacebo(n=
169)
Meanfinalpainintensity
scores(as
sessedusing
0100mm
VAS)were
significan
tlylowerwith
combinat
iontherapy(47.4)
thanwith
placebo(62.9;
40,or seeking disability compensation related to back pain wereexcluded.
At baseline, patients were stratified according to con-comitant NSAID and/or APAP use status prior to studyentry and were randomized to duloxetine and placebo withineach stratum. Users were defined as those patients answeredyes to a question soliciting whether or not they weretaking a therapeutic dose of NSAID and/or APAP for 14days per month for 3 months immediately preceding thestudy. Because the use of these analgesics was recorded asa global yes response, this stratum was referred to as theNSAID/APAP user group. Patients who were NSAID/APAPusers were allowed to continue with their stable regimen ofNSAID/APAP throughout the entire study.
For this analysis, efficacy measures included the BriefPain Inventory (BPI) [14] 24-hour average pain severity item
(referred to hereafter as BPI average pain severity) (range,0 = no pain to 10 = pain as bad as you can imagine); theRoland-Morris Disability Questionnaire (RMDQ-24) [15](scale range, 0 =no disability to 24 =severe disability); thePatient Global Impression of Improvement (PGI-I) [16]. ThePGI-I is a scale on which patients provide ratings of their
overall impression of how they are feeling since treatmentbegan with the following range of choices from 1 = verymuch better to 4 = no change to 7 = very much worse.Response to treatment was defined as at least a 50% decreasefrom baseline in BPI average pain severity.
To assess and compare the efficacy of duloxetine overplacebo between NSAID/APAP use subgroups, we utilizedan analysis of covariance (ANCOVA) model to estimateleast-squares mean changes from baseline to endpoint inBPI average pain severity ratings and RMDQ-24 scores. TheANCOVA model included a fixed continuous covariate ofbaseline value, fixed categorical effects of therapy (dulox-etine or placebo), study, NSAID/APAP use (yes/no), and
therapy-by-NSAID/APAP subgroup interaction. Response atendpoint was also analyzed using a logistic regression modelwith terms for therapy, study, NSAID/APAP use (yes/no),and therapy-by-NSAID/APAP subgroup interaction. Statis-tically significant difference in duloxetine efficacy betweensubgroups for reduction in BPI average pain severity, im-provement in RMDQ-24 scores, and BPI pain responsewas determined by a therapy-by-NSAID/APAP subgroupinteraction that was P < .1. The number and proportion ofpatients who reached a PGI-I rating of 1 or 2 at endpointwere summarized by treatment and by NSAID/APAP usesubgroup. Subsequent treatment odds ratios were calculatedfor each subgroup, then compared between subgroups with
the Breslow-Day test, and statistical significance was notedat P < .1. For patients with missing outcomes (due to earlydropout), the last nonmissing observation was treated astheir endpoint value in the analyses.
Safety assessments included discontinuation due toadverse events (AEs), the most common treatment-emergentadverse events (TEAEs), and those possibly related toNSAID/APAP use (bleeding and cardiovascular events).Incidence rates were compared between treatment groupsusing Cochran-Mantel-Haenszel test controlling for study,and statistical significance was noted at P < .05.
3. Results
3.1. Patient Disposition. There was no significant between-treatment difference in rates of study completion in eitherNSAID/APAP use subgroup (Table 1). There was a higherpercentage of duloxetine-treated patients versus placebo,who discontinued due to AEs in the NSAID/APAP nonusersubgroup (P = .002). For any of the other reasons leadingto discontinuation, there were no significant between-treat-ment differences in either NSAID/APAP use subgroup.
3.2. Demographics and Clinical Characteristics. Patients werestratified according to NSAID/APAP use at baseline: dulox-etine NSAID/APAP user (n = 137), placebo NSAID/APAP
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Pain Research and Treatment 3
Table1: Patient disposition.
NSAID/APAP user NSAID/APAP nonuser
DuloxetineN= 137
n(%)
PlaceboN= 82n(%)
PvalueDuloxetine
N= 206n(%)
PlaceboN= 156
n(%)Pvalue
Completed study 90 (65.7) 63 (76.8) .10 136 (66.0) 117 (75.0) .08
Reason fordiscontinuation:
Adverse event 21 (15.3) 5 (6.1) .051 39 (18.9) 12 (7.7) .002
Lack of efficacy 7 (5.1) 4 (4.9) 1.00 5 (2.4) 7 (4.5) .38
Lost to follow up 5 (3.6) 0 .16 7 (3.4) 3 (1.9) .53
Protocol violation 5 (3.6) 4 (4.9) .73 5 (2.4) 2 (1.3) .70
Abbreviation: APAP, acetaminophen; NSAID, nonsteroidal anti-inflammatory drug.
Table2: Baseline characteristics.
NSAID/APAP user NSAID/APAP nonuser
Duloxetine
N= 137
Placebo
N= 82
Duloxetine
N= 206
Placebo
N= 156
Age in years, mean (SD) 53.1 (14.7) 51.4 (13.3) 53.5 (14.9) 53.1 (13.6)
Female,n(%) 89 (65.0) 52 (63.4) 114 (55.3) 85 (54.5)
Ethnicity, n(%)
African American 3 (2.2) 3 (3.7) 19 (9.2) 13 (8.3)
Caucasian 108 (78.8) 61 (74.4) 160 (77.7) 123 (78.9)
East Asian 0 0 2 (1.0) 3 (1.9)
Hispanic 25 (18.3) 17 (20.7) 22 (10.7) 15 (9.6)
Native American 0 0 1 (0.5) 2 (1.3)
West Asian 1 (0.7) 1 (1.2) 2 (1.0) 0
CLBP duration since onset,years, mean (SD)
11.4 (11.5) 9.2 (9.1) 10.8 (11.1) 10.3 (9.0)
QT F class 1,n(%) 94 (72.9) 63 (79.8) 150 (75.4) 99 (68.3)
BPI average pain, mean (SD) 6.1 (1.6) 6.0 (1.6) 5.9 (1.6) 6.1 (1.7)
RMDQ-24, mean (SD) 9.6 (5.0) 8.6 (4.8) 9.1 (4.5) 9.8 (5.3)
There wasa statisticallysignificant difference in RMDQ-24 scoresbetween treatments in thenonuser subgroup, butthis difference was not consideredclinicallysignificant.Abbreviations: APAP, acetaminophen; BPI, Brief Pain Inventory; CLBP, chronic low back pain; NSAID, nonsteroidal anti-inflammatory drugs; QTF, QuebecTask Force; RMDQ-24, Roland-Morris Disability Questionnaire, SD, standard deviation.
user (n = 82), duloxetine NSAID/APAP nonuser (n =206), and placebo NSAID/APAP nonuser (n = 156). Patientdemographics and clinical characteristics are summarizedin Table 2. Most of the patients were female, Caucasian,
and in their early fifties. Most had pain restricted to lowerback (Class 1 per QFT on spinal disorders), with an averageduration of CLBP since onset of at least 9 years. At baseline,the mean BPI average pain severity rating was 6, and themean RMDQ-24 rating for physical function was about 9.5.
4. Efficacy
Mean changes from baseline in efficacy measures are shownin Figures 1 and 2. Treatment-by-NSAID/APAP use sub-group interactions were not significant for reduction n BPIaverage pain severity (P= .31,Figure 1), or for improvementin physical function assessed by the RMDQ-24 ( P = .35,
Figure 2). These results suggest that there was no substantialevidence of differential duloxetine efficacy on pain reductionor improvement in physical function between concomitantNSAID/APAP users and nonusers. The frequency of PGI-
I responses that were much better or very much better(PGI-I endpoint score 2) is presented in Figure 3. Inboth NSAID/APAP use subgroups, a higher percentage ofduloxetine-treated patients achieved PGI-I 2 at endpoint,but the treatment odds ratios were not significantly differentbetween the two subgroups (P= 0.32). Therefore, significantdifferential treatment effects of duloxetine on PGI-I werenot observed between concomitant NSAID/APAP users andnonusers.
The criterion for achieving a pain response was met bya higher percentage of duloxetine-treated patients in bothNSAID/APAP use subgroups (46.2% of users, and 43.6% ofnonusers) than patients treated with placebo (38.0% of users,
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2.5
3
2
1.5
1
0.5
0
LSmeanchan
ge
from
base
line
inBPIaveragepa
inseveri
ty
NSAID/APAP usern = 130 n = 79
NSAID/APAP nonusern =195 n =149
Duloxetine
Placebo
Treatment-by-NSAID/APAP subgroup interaction, P= 0.31
Figure1: Estimated least-squares (LS) mean changes from baselineand standard errors in BPI average pain severity in patients whoconcomitantly used or did not use NSAID or APAP.
2.5
3
2
1.5
1
0.5
0
NSAID/APAP usern = 100 n = 66
NSAID/APAP nonusern =165 n =131
3.
54
LSmeanchange
from
base
line
inRMDQ
Duloxetine
Placebo
Treatment-by-NSAID/APAP subgroup interaction, P= 0.35
Figure2: Estimated least-squares (LS) mean changes from baselineand standard errors in RMDQ rating in patients who concomitantlyused or did not use NSAID or APAP.
and 27.5% of nonusers). The treatment-by-NSAID/APAP
use subgroup interaction was not significant (P = 0.28),which suggests that the duloxetine treatment effects onachieving a pain response were not statistically significantlydifferent between concomitant NSAID/APAP users andnonusers.
5. Safety
The most common AEs that lead to discontinuation in theNSAID/APAP use subgroup in duloxetine- treated patientswere erectile dysfunction and nausea (both events, n = 2,1.5%); events in the nonuser subgroup included nausea,insomnia and somnolence (each event, n = 3, 1.5%).
10
20
30
40
50
60
70 NSAID/APAP user
Duloxetine
Placebo
Odds ratio= 1.78 Odds ratio= 2.58
0
NSAID/APAP nonuser
Pa
tien
ts(%)
Breslow-day test for homogeneity of odds ratios,P= 0.32
Figure 3: Percentage of patients who felt much better or verymuch better at endpoint.
TEAEs within NSAID/APAP use subgroups that occurredat a rate of at least 5% with duloxetine treatment and were
significantly more frequent than with placebo are summa-rized inTable 3. Among NSAID/APAP users, the frequencyof nausea, dry mouth, constipation, somnolence, and fatiguewere significantly greater in patients who received duloxetineversus placebo. In addition to these TEAEs, insomnia, anddizziness were significantly more frequent in patients whoreceived duloxetine versus placebo among the NSAID/APAPnonusers. Cardiovascular and bleeding-related TEAEs aresummarized in Table 4. In either NSAID/APAP use sub-group, between-treatment differences in the frequency ofthese events were not significant.
6. DiscussionThere are few published CLBP studies with nonopioidanalgesics that allowed concomitant NSAID/APAP use. Twostudies investigated the efficacy of TCAs for pain reductionin patients who were allowed to continue taking NSAIDS.One of those two evaluated nortriptyline against placebo[17] and the other compared maprotiline with paroxetine[18], but neither study reported efficacy outcome compar-isons between NSAID/APAP users and nonusers. AnotherCLBP study examined the efficacy of pregabalin combinedwith celecoxib, and the results suggested that combinationtreatment was more efficacious than treatment with eithermedication alone [19].
The post hoc analysis reported here included two clinicaltrials of duloxetine that allowed concomitant NSAID/APAPfor those patients who regularly used them prior to studyentry. The use of additional analgesics in a pain trial isassociated with the r isk of reduced assay sensitivity, andpossibly a high placebo response [17]. This was observedin one of the two duloxetine CLBP trials [12] and in theNSAID/APAP use subgroup in this analysis. However, thetreatment-by-NSAID/APAP use subgroup interaction wasnot significant in the analyses of various efficacy measures,which suggests that the advantages of duloxetine overplacebo in pain reduction and improvement in function werenot significantly different between subgroups.
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Table 3: Treatment-emergent adverse events within either NSAID/APAP use subgroups that occurred at a rate of at least 5% with duloxetinetreatment and were significantly more frequent than with placebo.
NSAID/APAP User NSAID/APAP Nonuser
DuloxetineN= 137
n(%)
PlaceboN= 82n(%)
PvalueDuloxetine
N= 206n(%)
PlaceboN= 156
n(%)Pvalue
At least 1 adverseevent
92 (67.2) 51 (62.2) .850 141 (68.5) 77 (49.4)
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instead of regarding the use of one or the other or both, sothis lack of information limited further analysis. Also, thestudies included in these analyses were not powered to detectdifferential treatment effect between NSAID/APAP use sub-groups. Therefore, the comparisons between NSAID/APAPuse subgroups in this study should be viewed in that light.
In addition, the sample size and the short duration of thestudies also limited the occurrence and detection of rarebleeding events. Finally, these studies excluded individualswith certain comorbidities, so these results may not extendto all individuals in the general population who present withCLBP.
7. Conclusions
In this post hoc analysis of data pooled from two studiesin patients with CLBP, there were no statistically significantdifferences in the treatment advantage of duloxetine overplacebo on measures of pain reduction, improved physical
function, or patient global impression of improvementobserved between concomitant NSAID/APAP users andnonusers. In other words, concomitant use of an NSAIDor APAP did not significantly enhance or interfere with theefficacy of duloxetine. The safety of duloxetine with con-comitant NSAID/APAP use was consistent with the knownduloxetine safety and tolerability profile.
Conflict of Interests
All authors are employees of Eli Lilly and Company.
Acknowledgments
The studies included in this analysis were sponsored by EliLilly and Company, Indianapolis, Indiana, USA.
References
[1] G. B. J. Andersson, Epidemiological features of chronic low-back pain,The Lancet, vol. 354, no. 9178, pp. 581585, 1999.
[2] L. Manchikanti, Epidemiology of low back pain, PainPhysician, vol. 3, no. 2, pp. 167192, 2000.
[3] V. Chang, P. Gonzalez, and V. Akuthota, Evidence-informedmanagement of chronic low back pain with adjunctive anal-
gesics,Spine Journal, vol. 8, no. 1, pp. 2127, 2008.[4] R. Chou and L. H. Huffman, Medications for acute and
chronic low back pain: a review of the evidence for an Ameri-can Pain Society/American College of Physicians clinical prac-tice guideline,Annals of Internal Medicine, vol. 147, no. 7, pp.505514, 2007.
[5] T. Kuijpers, M. Van Middelkoop, S. M. Rubinstein et al., Asystematic review on the effectiveness of pharmacologicalinterventions for chronic non-specific low-back pain, Euro-
pean Spine Journal, vol. 20, no. 1, pp. 4050, 2011.
[6] M. E. Farkouh and B. P. Greenberg, An evidence-based reviewof the cardiovascular risks of nonsteroidal anti-inflammatorydrugs, American Journal of Cardiology, vol. 103, no. 9, pp.12271237, 2009.
[7] S. O. Dalton, C. Johansen, L. Mellemkjr, B. Nrgard, H. T.Srensen, and J. H. Olsen, Use of selective serotonin reuptakeinhibitors and risk of upper gastrointestinal tract bleeding apopulation-based cohort study,Archives of Internal Medicine,vol. 163, no. 1, pp. 5964, 2003.
[8] Y. K. Loke, A. N. Trivedi, and S. Singh, Meta-analysis: gas-trointestinal bleeding due to interaction between selective ser-otonin uptake inhibitors and non-steroidal anti-inflammatorydrugs,Alimentary Pharmacology and Therapeutics, vol. 27, no.1, pp. 3140, 2008.
[9] C. Andrade, S. Sandarsh, K. B. Chethan, and K. S. Nagesh,Serotonin reuptake inhibitor antidepressants and abnormalbleeding: a review for clinicians and a reconsideration ofmechanisms,Journal of Clinical Psychiatry, vol. 71, no. 12, pp.15651575, 2010.
[10] Cymbalta, Prescribing Information, Eli Lilly and Company,Indianapolis, IN, USA, 2011.
[11] V. Skljarevski, D. Desaiah, H. Liu-Seifert et al., Efficacy andsafety of duloxetine in patients with chronic low back pain,Spine, vol. 35, no. 13, pp. E578E585, 2010.
[12] V. Skljarevski, M. Ossanna, H. Liu-Seifert et al., A double-blind, randomized trial of duloxetine versus placebo in themanagement of chronic low back pain, European Journal of
Neurology, vol. 16, no. 9, pp. 10411048, 2009.
[13] W. Spitzer, F. LeBlanc, and M. Dupuis, Scientific approachto the assessment and management of activity-related spinaldisorders (the Quebec Task Force), Spine, vol. 12, pp. S16S21, 1987.
[14] C. S. Cleeland and K. M. Ryan, Pain assessment: global useof the Brief Pain Inventory,Annals of the Academy of MedicineSingapore, vol. 23, no. 2, pp. 129138, 1994.
[15] M. Roland and R. Morris, A study of the natural history ofback pain. Part I: development of a reliable and sensitive mea-sure of disability in low-back pain, Spine, vol. 8, no. 2, pp.
141144, 1983.[16] W. Guy,ECDEU Assessment Manual for Psychopharmacology,
National Government Publication, 1976.
[17] J. Hampton Atkinson, M. A. Slater, R. A. Williams et al., Aplacebo-controlled randomized clinical trial of nortriptylinefor chronic low back pain, Pain, vol. 76, no. 3, pp. 287296,1998.
[18] J. H. Atkinson, M. A. Slater, D. R. Wahlgren et al., Effectsof noradrenergic and serotonergic antidepressants on chroniclow back pain intensity, Pain, vol. 83, no. 2, pp. 137145,1999.
[19] C. L. Romano, D. Romano, C. Bonora, and G. Mineo, Pre-gabalin, celecoxib, and their combination for treatment ofchronic low-back pain,Journal of Orthopaedics and Trauma-
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Hindawi Publishing CorporationPain Research and TreatmentVolume 2012, Article ID 104782,5pagesdoi:10.1155/2012/104782
Clinical StudyEffect of Diclofenac with B Vitamins on the Treatment of
Acute Pain Originated by Lower-Limb Fracture and Surgery
Hector A. Ponce-Monter,1 Mario I. Ortiz,1, 2Alexis F. Garza-Hernandez,2
Raul Monroy-Maya,3 Marisela Soto-Ros,3 Lourdes Carrillo-Alarcon,1, 4
Gerardo Reyes-Garca,5 and Eduardo Fernandez-Martnez1
1Area Academica de Medicina del Instituto de Ciencias de la Salud, Universidad Autonoma del Estado de Hidalgo,
42090 Pachuca, HGO, Mexico2 Research and Traumatology Departments, Hospital del Ni no DIF, 42090 Pachuca, HGO, Mexico3 Hospital General de los Servicios de Salud del Estado de Hidalgo, 42090 Pachuca, HGO, Mexico4 SubDireccion de Investigacion de los Servicio de Salud de Hidalgo, 42030 Pachuca, HGO, Mexico5 Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, IPN, 11340, DF, Mexico
Correspondence should be addressed to Hector A. Ponce-Monter,[email protected]
Received 11 August 2011; Revised 22 September 2011; Accepted 27 September 2011
Academic Editor: Mara Asuncion Romero Molina
Copyright 2012 Hector A. Ponce-Monter et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.
The aim of this study was to compare the efficacy of diclofenac, for the treatment of acute pain originated by lower-limb fractureand surgery, with that of diclofenac plus B vitamins. This was a single-center, prospective, randomized, and double-blinded clin-ical trial. Patients with lower-limb closed fractures rated their pain on a 10 cm visual analog scale (VAS). Patients were then ran-domized to receive diclofenac or diclofenac plus B vitamins (thiamine, pyridoxine, and cyanocobalamin) intramuscularly twicedaily. Patient evaluations of pain intensity were recorded throughout two periods: twenty-four hours presurgery and twenty-four hours postsurgical. One hundred twenty-two patients completed the study. The subjects assessments of limb pain on the VASshowed a significant reduction from baseline values regardless of the treatment group. Diclofenac plus B vitamins combination wasmore effective to reduce the pain than diclofenac alone. The results showed that the addition of B vitamins to diclofenac increasedits analgesic effect. The novelty of this paper consists in that diclofenac and diclofenac plus B vitamins were useful for treatment ofacute pain originated by lower-limb fracture and surgery.
1. Introduction
A number of situations are prone to develop pain symptoma-tology, such as tissue degeneration, infection, inflammation,cancer, trauma, surgery, and limb fractures. Each of thesephysiological abnormalities requires a therapeutic approachdifferent from the last. In acute pain, caused by fracture and/or surgery, several classes of analgesics have been utilized.These basic remedies for analgesia, however, are still confinedto a small number of medications, including nonsteroidalanti-inflammatory drugs (NSAIDs), local anesthetics, andopioids. In addition, most of these drugs have side effects,limiting their use in clinical practice [1,2].
The clinical use of combinations of analgesic agents hasincreased significantly in the last few years. The purpose is
to associate two or more drugs with different mechanisms ofaction, in hopes of achieving a synergistic interaction thatyields a sufficient analgesic effect with low doses of eachagent, therefore, reducing the intensity and incidence of un-toward effects [3].
B vitamins are a water-soluble group of vitamins includ-ing thiamine, riboflavin, niacin and niacinamide, pyridoxine,cobalamin, folic acid, pantothenic acid, biotin, choline,inositol, and para-aminobenzoic acid (PABA). In particular,some of these B vitamins (thiamine, pyridoxine and cyan-ocobalamin) have been used, not only in the treatment ofpain and inflammation resulting from vitamin deficiencybut also alone or in combination with diclofenac orother NSAIDs for various painful diseases such as poly-neuropathies, degenerative diseases of the spinal column,
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rheumatic diseases lumbago and pain originated from tonsil-lectomy [48]. However, most clinical studies have evaluatedthis combination in neuropathic pain [46,8]. Recently, astudy demonstrated the utility of the diclofenac-B vitaminscombination in the pain originating from tonsillectomysurgery [7]. Nevertheless, the sample size of this last study
was too small to be representative and the administrationroute was the intravenous via. On the other hand, this di-clofenac-B vitamins combination has never been tested inthe acute pain produced by fracture or other kind of surgicalprocedures. Therefore, the main objective of the presentclinical study was to compare the efficacy and tolerability ofdiclofenac for treatment of acute pain following lower-limbfracture and surgery, with that of diclofenac in combina-tion with B vitamins (thiamine, pyridoxine, and cyanocobal-amin). Indeed, we previously conducted a pilot study with14 patients, with the aim of establishing the adequate exper-imental conditions as well as to calculate the appropriatesample size, wherein both treatments were equally effective
in reducing pain [9].
2. Materials and Methods
This was a single-center, prospective, randomized and dou-ble-blinded clinical trial. The study was carried out at theHospital General SSH Pachuca, Hidalgo, Mexico from Jan-uary 2008 to February 2010. The study protocol was ap-proved by the Ethic and Investigation Committees from theHospital General SSH Pachuca, Hidalgo, Mexico as well asthis was conducted according to the Declaration of Helsinki.
The participants of the study were patients with lower-limb closed fractures, ranging in age from 18 to 55 years, with
acute pain 5 cm according to a 10 cm visual analog scale(VAS; 0 = no pain and 10 = the worst pain), good healthdetermined by clinical history and laboratory studies, with-out sanguineous dyscrasias or hypersensitivity to drugs to beemployed, and who consented to participate voluntarily.
After giving their consent, patients rated their pain ona VAS, and they were then randomized into one of twogroups receiving 75 mg diclofenac or 75 mg diclofenac plus Bvitamins (thiamine: 100 mg, pyridoxine: 100 mg, and cyano-cobalamin: 1 mg) twice daily (all intramuscularly). Patientevaluations of pain intensity were recorded throughout twoperiods: twenty-four hours presurgical and twenty-fourhours postsurgical. Twenty-four hours after the first drug ad-ministration, patients underwent elective lower-limb sur-gery. Standardized general anesthetic techniques were usedfor all patients. Patients received 50 mg ranitidine intra-venously twice a day throughout the study. If the pain was notcontrolled after two hours, patients received rescue treatmentwith morphine. At the end of the study, the improvement inpain levels was evaluated by a Likert scale. The categoricalLikert response alternatives consisted of four descriptions.Responses were rated 03: 0 =complete relief, 1 =moderaterelief, 2 = slight relief, 3 = without relief. Gastrointestinalside effects, rash, or spontaneous complaints of other adverseeffects such as postsurgical bleeding problems during thepostoperative phase were registered.
Data are shown as the mean SEM. Data were evaluatedusing tstudent and a nonparametric statistical analysis, theMann-Whitney U test. P < 0.05 was required for signifi-cance.
3. Results
One hundred twenty-two patients completed the study,sixty-two in the diclofenac group (forty-two male and twentyfemale) and sixty in the diclofenac with B vitamins group(twenty-seven male and thirty-three female). The mean standard deviation age in the diclofenac group was 37.9 10.5 years and 35.0 8.8 years in the diclofenac plus B vita-mins group, which does not represent a significant differencebetween the groups (P >0.05).
In the study presented here, all patients received medi-cation for forty-eight hours and the acute pain induced bylower-limb fracture and surgery was monitored and record-ed. The lower-limb fractures that the patients presented
with were 8 fractures of the patella, 47 ankle fractures, 24tibia shaft fractures, 14 tibial plateau fractures, 20 diaphysealfractures of the femur, 6 subtrochanteric femoral fractures, 2fractures of the calcaneus, and 1 fracture of the talus. Therewas no statistically significant difference in the type offracture and gender between the two treatment groups(P >0.05).
The subjects assessment of limb pain on the VAS in bothtreatments showed a significant reduction from baseline at4, 8, 12, 24, 36, and 48 hours after treatment. Diclofenacplus B vitamins was more effective to reduce the pain thandiclofenac alone at 8, 12, 24, 36, and 48 hours after treatment(P < 0.05) (Figure 1). However, diclofenac was more suc-
cessful to decrease the pain than diclofenac plus B vitaminsat 4 hours after treatment (P < 0.05) (Figure 1). The valuein the Likert scale of the diclofenac plus B vitamins groupwas 1.37 0.5 with this value being statistically different atthe value of 1.56 0.5 for the diclofenac group. No statisticaldifference was found when comparing the groups accordingto gender and type of fracture (P >0.05).
Rescue treatments were not applied. All the patients re-ported pain in the administration site, but generally speak-ing, all the regimens were well tolerated. None of the patientshad any bleeding complication or gastrointestinal complainbefore or after surgery.
4. DiscussionFractures of the lower limb are common, especially in theelderly, and are often associated with considerable morbidityand lengthy hospitalization. The immediate goal of treatingacute lower-limb fractures is to decrease pain and swelling aswell as to protect adjacent structures from further injury. Forthis reason, after immobilization of the lower limb, NSAIDsare invaluable in treating these musculoskeletal conditions,primarily due to their analgesic and anti-inflammatory ef-fects. Unfortunately, NSAIDs propensity to cause gastroin-testinal damage and patient discomfort limits their use. It isknown that as many as two to four percent of patients whotake NSAIDs during long-term therapy may have serious
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30
40
50
60
70
80
90
100
0 5 10 15 20 25 30 35 40 45 50
VAS(mm)
Time (hours)
Diclofenac alone
#
Diclofenac + B vitamins
Figure 1: Time course of the effect of diclofenac alone or diclofenacplus B vitamins for the treatment of pain produced by lower-limbfracture and surgery. The points represent the average standarderror of the media values of the visual analogous scale (VAS)evaluated at different hours. Significantly different from diclofenacgroup (P
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it was confirmed that the analgesic effects induced by B vit-amins were partially blocked by naloxone, suggesting that Bvitamins could release endogenous opioids that could acti-vate opioid receptors [25]. Besides, there is experimentalevidence suggesting that the effects induced by the combi-nation of B vitamins involve the nitric oxide-cGMP system
[30,31]. However, other mechanisms have been proposed,for example, it has been shown that pyridoxine is capable ofblocking the synthesis of prostaglandin E2 in humans [32].In light of this evidence, it is possible to suggest that severalmechanisms could be implicated in the diclofenac-B vita-mins combination to obtain a major analgesia in comparisonwith the analgesia by diclofenac alone. The real mechanismsinvolved in the potentiation for the combination await futureelucidation.
Patients often experience unpredictable therapeutic anddiagnostic procedural-related pain in emergency rooms thatcan be associated with considerable stress and anxiety [33].Although procedural pain may be reduced by a variety of
psychological and pharmacological interventions [33], mostof these are not given in all the nonelective settings. For exa-mple, in our study, after the intramuscular injection all thepatients reported pain at the administration site; however,the characteristics of this pain were not evaluated or re-corded.
One weakness of our study was that participants had dif-ferent types of lower-limb fractures and surgeries, and thisdiversity could have affected the results in favor of providinga better analgesic effect with the combination of diclofenacwith B vitamins. However, it was noted that although thepatients had different types of fractures, there was no sta-tistically significant difference in the level of pain that both
groups of patients presented with on their admission. There-fore, it is necessary to evaluate the effectiveness of this combi-nation in a particular type of fracture or surgery, either mem-ber.
In conclusion, the present study gives evidence that thecombination of diclofenac plus B vitamins could be a safeand inexpensive postsurgical analgesic strategy. Likewise, it isnecessary to undertake controlled studies using this combi-nation in different states of acute postsurgical pain to demon-strate its security and efficacy.
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