Low Back Pain: Treatment and New Evidence Clinical Trial Dolor

Professor Marco Antonio Naslausky Mibielli Serra dos rgos University-Teresopolis Head of Service from Clinical Hospital University Master in Medicine - Orthopaedic and Traumatology

Clinical Trial DOLOR

Diclofenac Combined with B Vitamins in Acute Lumbago: Rapidness of Pain Relief Compared to Diclofenac Monotherapy (DOLOR)

Low Back Pain

Clinical Significance
Fifth most common symptom-related reason for all physician visits in the U.S. The lifetime prevalence in Europe is 60-80% Estimated 84% (Waddel) of adults will experience at least one episode of LBP at some point of the life Just 25% of Adults do sufer from this disorder and about one third of this patients report substantial limitation in their activity

Low Back Pain

Low Back Pain (LBP) = Symptom of musculoskeletal disorders involving the lumbar vertebrae

Progression of LBP:
Acute - subchronic - chronic - recurrent (severe acute episodes)

Mechanical Causes

Triggers
Contributing conditions

Spinal disc herniation

Spinal stenosis

Fractures

Improper lifting

Sports injury

Carrying heavy briefcase or backpack

Poor standing posture

Poor sitting posture

Excess weight & Lack of muscle tonus

Pregnancy

Sleep position

Stress and muscle tension

TYPES OF PAIN
Nociceptive Pain: caused by activity in neural pathways in response to potentially tissuedamaging stimuli. Mixed Type: caused by a combination of both primary injury or secondary effects. Neuropathic Pain: iniciated or caused by primary lesion or dysfunction in the nervous system.

Nociceptive Pain

Neuropathic Pain component in Low Back Pain

Presence of a lesion or disruption to primary sensory neurons (peripheral, dorsal) due to:
Trauma Compression Tumor Ischemia Inflammation: metabolic disturbances, degenerative disorders or cytotoxic substances

Nervous system dysfunction Hyperalgesia and allodynia due to cytokine release (NGF, TNF, NFkappaB)

Patients with Low Back Pain: Targets of Drug Therapy

Rapid and efficient amelioration of pain Restoration of mobility Improvement of sleep Improvement of reduced daily activities Fitness for work Avoidance of chronification

Diclofenac - Mechanisms of Actions:

Anti-inflammatory - Analgesic - Antipyretic Inhibition of Prostaglandin Synthesis by Inhibition of Cyclooxygenases (COX) - Moderate Preference to block COX-2 ! Inhibition of Lipoxygenase Pathways - Reducing Formation of Leukotriens Inhibition of Phospholipase A2 Blockade of Voltage-dependent Sodium Channels Blockade of Acid-sensing Ion Channels Modulation of Potassium Channels (ASICs)

Mechanisms of NSAIDs Action

Brune 2007

Diclofenac - Kinetics
Increased concentrations of Diclofenac in target areas Lower protein binding of Diclofenac Enhanced drug-diffusion into intracellular Space in therapeutic areas Fast decline of concentrations in compartments causing side effects (CV, GI, Kidney)

Concentration of Diclofenac in Plasma and Synovial Fluid over Time

Diclofenac versus Placebo in LBP patients: Assessment of 50% pain reduction McQuay 1997

Characteristics of B-Vitamins B1 and B6

B-Vitamins counterract nerve damage by various mechanisms Vitamin B1 formation of Acetylcholine transmission of impulses from nerves to muscles regeneration of the nervous system after strain reduction of hyperexcitability lessening of Na currents alterations in injured neurons suppressing thermal hyperalgesia Vitamin B6 modulates GABA release from pre-synaptic cells influences biosynthesis of neurotransmitters serotonin, epinephrine, GABA Vitamins B1 and B6 activate cGMP involved in the inhibition of thermal hyperalgesia

Characteristics of B-Vitamin B12

Vitamin B12 biosynthesis of neurotransmitters (EGF) methionine (myelin) synthesis) Vitamin B12 deficiency increased production of TNF-alpha, IL-1, IL-6, NFB, NGF a noxious role in the progression of neuropathy a deficiency can be normalised by Vitamin B12 treatment

Improvement of Cold and Warm Sensation in Janka 1991 Patients with Diabetic Polyneuropathy
Cold sensation
dotted: Placebo continuous : Vitamins B1, 6, 12

Warm sensation

treatment 18 weeks

less means better

Percentage of Axons of N. saphenus 10 Days after Cold Damage

70

60 50 40 30 20 10 0 Regenerating Degenerating not assigned B Vitamins Control

Axons covered with myelin sheaths

Writhing-test in Rats: Number of Pain Related

Symptoms

Vehicle Diclofenac Diclofenac +B-Vit

Rocha e cols. 2004

Clinical Trial DOLOR

Participating Professors from:
UNIFESO Universidade Federal do Rio de Janeiro (UFRJ) Universidade Estadual do Rio de Janeiro (UERJ) Instituto Nacional de Traumatologia e Ortopedia (INTO) Centro Ortopdico Traumatolgico Sociedade Brasileira de Ortopedia e Traumatologia Instituto de Ps-Graduao Mdica Carlos Chagas (ICC)

DOLOR - Primary Study Objective

Percentage of patients with pain reduction: VAS < 20 mm Patients satisfaction after 3 days of treatment allowing them to terminate the study
Comparison of treatment groups: DB: Fixed combination of diclofenac + vitamins B1, B6, B12 versus D: Diclofenac monotherapy

DOLOR: Secondary Study Endpoints

Number of patients with pain reduction: VAS < 20mm Patients satisfaction after 5 and 7 days of treatment allowing them to terminate the study
Severity of pain (VAS) Finger-floor-distance (FFD) as parameter of motility Patients functionality questionaire (PFQ)

Visual-Analog Pain Scale (VAS)

No Pain

Most Severe Pain

PATIENT FUNCTIONALITY QUESTIONNAIRE (PFQ)

Due to my back pain I do not sleep well

I have to lie down more often It is difficult for me to get up from my bed or a chair I can stand only for a short while I can walk up stairs only slowly It is difficult for me to wash or dry off my whole body It is difficult for me to put on my clothes I can only walk short distances I try to avoid picking things up from the floor I have to changemy posture more often I cannot carry heavy things I have to ask other people for assistance 1 point was given for each yes answer

DOLOR Subject Characteristics

Inclusion criteria
acute episode of low back pain < 3 days non-hospitalized, 18 years of age VAS between 20 and 80 mm

Exclusion criteria
Hypersensitivity to test products Pregnancy or lactation Acute disc damage Need of surgical treatment Intake of other analgesics Physical treatment Blood coagulation diseases Gastric or intestinal ulcers Asthma or acute rhinitis Pathologic laboratory values

DOLOR: Study Course

Visit 1: Pre-treatment - screening, randomization - baseline evaluations - study medication distribution Visit 2*: after 3 days of treatment Visit 3*: after 5 days of treatment Visit 4: after 7 days of treatment *Patients with sufficient pain reduction at Visits 2 and 3 may terminate the study

DOLOR: Efficacy and Tolerability Evaluations

Findings on admission Findings during the study
Medical history Complete physical evaluation Visual-analog pain scale VAS (0-100 mm) Patient functionality questionnaire (PFQ) Motility evaluations (FFD) Laboratory tests. Complete physical evaluation Motility evaluations VAS and PFQ evaluations Laboratory tests Adverse event monitoring

Correlation VAS (cm) vs. PFQ Sum at study begin

DOLOR - Primary study objective Results after 3 days of treatment - Visit 2

Study completed Due to clinical success Due to insufficient efficacy

Group DB n = 187 n %
87 10 46.5 5.3

Group D n = 185 n %
55 10 29.7 5.4

Due to side effects Study continued (n)

3 87

1.6

0 120

success rate: 16.8%; OR: 2.1 Chi2 = 12.06; p = 0.0005

DOLOR - Primary study objective after 3 days of treatment (V2)

140 120 100 80 60 40 20 0 Clinical success Insufficient efficacy Side effects Study continued

Group DB Group D

Study completed

p> 0.0005 NNT 5.95

DOLOR: Clinical Results After 5 Days (Visit 3)

Group DB n= 87 n / % Patients Study completed due to success Study continued Chi2: 29,07 n 71 16 p > 0.0001 % 82 18 OR: 5.6 Group D n= 120 n 52 68 % 43 57

NNT = 2.6

DOLOR Result after 5 days of treatment - Visit 3

70 60 50 40 30 20 10

0
Clinical success Study continued

Group DB Group D

Study completed

p> 0.0001

NNT 2.6

DOLOR - Visual Analog Scale Visit 1 vs Visit 2

DOLOR - Patients with Changes in VAS between Visit 1 and Visit 2

Group DB Group D

n
Impaired <0 11 58 87 30 1

%
5.9 31.0 46.5 16.1 0.5

n
10 94 55 23 3

%
5.4 50.8 29.8 12.4 1.6

No change = 0 - 20 Improved > 20 - 40 Improved > 40 - 60 Improved > 60

Improved: 63.1% vs. 43,8% p = 0,001

OR = 2,5

DOLOR: Patients Functionality Questionaire

DB D DB D

DOLOR - Patient Functionality Questionnaire Patients (%) with Improvement at Visit 2

60 50 40 30 20 10 0 sleeping getting up climbing stairs washing walking

Group DB > Group D (p < 0.05)

Group DB n = 187 Group D n = 185

DOLOR - Patients with Changes in PFQ Sum between Visit 1 and Visit 2
PFQ Sum Group DB n Impaired > 0 No change = 0 Improved > 0 - 3 Improved > 3 - 6 Improved > 6 - 9 11 29 33 51 44 % 5.9 15.5 17.6 27.3 23.5 Group D n 14 39 49 45 26 % 7.6 21.1 26.5 24.3 14.0

Improved > 9 - 12

19

6.5

12

6.5

p = 0.0034

OR = 1.5

DOLOR: Finger-to-Floor Distance

mm: mean SD Before treatment Day 2

Group DB n = 187 19.6 6 13.7 7 n = 87

Group D n = 185 21.2 6 16.6 7 n = 120 12.9 5 p = 0.001 p = 0.05 p = 0.001

Day 3

9.9 6

DOLOR - Finger-to-Floor-Distance Difference between Visit 1 & Visit 2

50 40 30 20 10 0 worsened no improved change : >0 >5 > 10 > 15 mm

Group DB > Group D: p < 0,05

DB (n = 187) D (n=185)

Correlation of Finger-Floor-Distance and VAS-Values after 3 Days of Treatment

DOLOR - Number of Patients with AEs

Visit 2
Patients with AEs in Group n= AEs (n) GI-symptoms CNS-symptoms Glossitis GOT/GPT elevation Glucose elevation Decreased PPT Palate alteration Hypertension Urticaria, skin eruption Increased BSR Tinitus Insomnia 6 2 1 1 1 4 1 1 1 1 1 3 8 7 9 1 1 3 1 3 1 7 2 5 10 5 2 1 8 2 DB 19 D 20 DB 14

Visit 3
D 12 DB 3

Visit 4
D 12

Fatigue
Dry mouth Depression

1
1 1

GI-symptoms: Dyspesia, Flatulence, Pyrosis nocturna, Diarrhea, Constipation CNS-symptoms: Nauseaa, Vertigo, Headache

DOLOR: Number of Patients with Adverse Events

Group DB Group D

AE = 1
n Visit 2 Visit 3 12 11

AE > 2
n 7 3

AE = 1
n 15 9

AE > 2
n 5 3

Visit 4
Total

1
24

1
11

10
34

2
10

Low Back Pain - Conclusions

The symptoms most patients are suffering appear to be related to functional pathology, psycho-social factors and environmental components Pain may be of nociceptive and neuropathic origin Drug treatment should be multi-modal Short term administration of Diclofenac is a potent choice for treatment of LBP relief Vitamins B1, B6, B12 provide various effects counteracting nerve damage and extent nociceptive pain treatment by Diclofenac with potent activity against neuropathic pain

Study Publication
DOLOR study paper published in Current Medical Research & Opinion (November 2009) A MEDLINE-indexed, peer-reviewed, international journal publishing original research on new and existing drugs and therapies 5-Year ISI Impact Factor (2008): 2.866 Ranked 27/107 in the Medicine, General & Internal category in the 2008 ISI Journal Citation Reports and 32/82 in the Medicine, Research & Experimental category.

Evolution of Back Pain

Monocentric Clinical Trial: Patients with Acute Lumbago Lettko 1987

Clinical results after 7 days
Diclofenac 150mg/day + B-Vit n = 99 n / % of patients Study terminated due to success Study continued n 19 80 % 19.2 80.8 Group D 150 mg/day n = 96 n 7 89 % 7.3 92.7

p = 0.01

Monocentric Clinical Trial Patients with Acute Lumbago

Clinical results after 3 days
Diclofenac 75mg/day + B-Vit n = 52
n Patients - study successfully terminated Study discontinued due to failure 4 p = 0.01 8 %

Kuhlwein & Koch 1991

Diclofenac 75mg/day n = 52 n %

18

35

6
10

11
19

Multicenter Clinical Trial Patients with Acute Lumbago Brueggeman et al 1990

Clinical results after 3 days
Diclofenac 150 mg/day + Vit. B1, B6, B12 n = 184 n Pain Improved from heavy to mild /none 53 % 28.8 Group D 150 mg/day n = 192 n 48 % 25

p > 0.049

THANK YOU