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Update in non surgical management of Sodium Hyaluronate
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8/18/2008
UPDATE IN NON-SURGICAL OBJECTIVES
MANAGEMENT OF Describe non-surgical modalities in
OSTEOARTHRITIS management of knee osteoarthritis
OF THE KNEE Discuss evidence for different modalities in
Morteza Khodaee, MD, MPH management of knee osteoarthritis
Department of Family Medicine Discuss the potential complications and side
University of Colorado Denver effects of each modality in management of
August 6, 2008 knee osteoarthritis
Harris: Kelley's Textbook of Rheumatology, 7th ed
(2005) NON-PHARMACOLOGICAL
Conventional Options Unconventional Options
Patient education Laser
Arthritis self-help courses Spa
Exercise Telephone
Insoles /
Vitamins/Minerals
Pulse EMFT (Electromagnetic field
Phone call
therapy)
Temperature modalities Ultrasound
Customized orthotics TENS
Weight loss Acupuncture
Modified activities of daily Yoga
living Nutrients
Herbal remedies
PHARMACOLOGICAL NUTRICEUTICAL
Acetaminophen (Tylenol) Glucosamine
NSAIDs Chondroitin sulfate
Opioid analgesics Ginger extracts
Psychotherapic drugs S mptomatic Slow Dr gs
SYSADOA -Symptomatic Slo Acting Drugs for OA
(includes avocado/soybean unsaponifiables (ASU)
Topicals
Cat's claw
Capsaicin
Shark cartilage
Topical NSAID preparations
S-Adenosyl-L-methionine (SAMe)
Salicylates
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INTRA-ARTICULAR USUAL OUTCOME MEASURES IN OA STUDIES
Corticosteroids 100mm pain Visual Analogue Scale (VAS)
Hyaluronic acids WOMAC (Western Ontario and McMaster
Universities) OA index
24-item
A 24 item questionnaire completed by the patient
and focusing on joint pain, stiffness and loss of
function related to OAK
OARSI Recommendations 2008
EULAR Recommendations
2003
OARSI Recommendations
2008
TOXICITY PROFILE OF THE TREATMENT MODALITIES BASED
ON EXPERT OPINION (23 EXPERTS)
EULAR Recommendations
2003
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8/18/2008
WEIGHT LOSS EXERCISE
Obesity an important risk factor for Muscles are providing stability to the joints
development of OAK Quadriceps weakness has been postulated as a risk
factor for OAK
Higher BMI is associated to an increased risk of
progression of OAK g
Walking can be beneficial
Supervised fitness-walking regimens have been
Increased malalignment (genu varus/valgus) shown to improve function in OAK
Weight loss and exercise are associated with Home-based exercise interventions have also been
improvement in pain and disability in OAK shown to significantly improve symptoms of OAK
EXERCISE GLUCOSAMINE
An RCT (single-blind) of 79 patients Cochrane review (2005)
20 studies with 2570 patients
At 3-month follow-up Results from studies using a non-Rotta preparation or adequate
allocation concealment failed to show benefit in pain and WOMAC
Only land-based exercise showed some function
improvement in pain and muscle strength di l i
studies evaluating the R
h Rotta preparation show that glucosamine was
i h h l i
compared with the control group superior to placebo in the treatment of pain and functional
impairment resulting from symptomatic OA
No clinical benefits were detectable after aquatic Rotta Pharm, an Italian pharmaceutical manufacturer of GS
exercise compared with the control group WOMAC outcomes of pain, stiffness and function did not show a
superiority over placebo for both Rotta and non-Rotta preparations of
Aquatic exercise has significantly less adverse glucosamine
effects compared with a land-based programs Glucosamine was as safe as placebo
Lund et al. A randomized controlled trial of aquatic and land-based exercise in patients with knee Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, Hochberg MC, Wells G. Glucosamine
osteoarthritis. J Rehabil Med. 2008 Feb;40(2):137-44. therapy for treating osteoarthritis.CochraneDatabase of SystematicReviews 2005, Issue 2.Art.No.:CD002946.
GLUCOSAMINE AND CHONDROITIN TRAMADOL
Clegg et al (2006) Cochrane review (2006)
Multicenter, double-blind, placebo- and celecoxib-controlled 11 RCTs with
Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) 1019 participants received tramadol or
1583 patients (1229 with mild and 354 with moderate to severe knee pain) tramadol/paracetamol
Glucosamine and chondroitin sulfate alone or in combination did not reduce p p
920 participants who received p placebo or active-control
pain effectively in the overall group of patients with osteoarthritis of the
knee Tramadol or tramadol/paracetamol decreases pain
Rate of response in the celecoxib control group was 10% points higher than
intensity, produces symptom relief and improves
that in the placebo control group (P=0.008) function, but these benefits are small
Patients with moderate-to-severe pain at baseline, the rate of response was Adverse events, although reversible and not life
significantly higher with combined therapy than with placebo (79.2% vs. threatening, often cause participants to stop taking the
54.3%, P=0.002) medication and could limit tramadol or tramadol plus
paracetamol usefulness.
Clegg et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database of
osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808. Systematic Reviews 2006, Issue 3. Art. No.: CD005522.
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ACETAMINOPHEN OPIOIDS
Cochrane review (2006) Is recommended in 9/9 current guidelines
15 RCTs Weak opioids narcotics can be considered for
5986 participants the Rx of refractory pain in patients with OAK
gg p
The evidence suggests that NSAIDs are superior to
acetaminophen for improving knee and hip pain in people St g opioids should only be used in
Stronger i id h ld l b di
with OA patients with severe pain
The size of the treatment effect was modest, and the
median trial duration was only six weeks
In OA subjects with moderate-to-severe levels of pain,
NSAIDs appear to be more effective than acetaminophen
Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for Zhang et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II:
osteoarthritis. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004257. OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008 Feb;16(2):137-62.
INTRAARTICULAR CORTICOSTRROID INJECTION IA CORTICOSTEROIDS
Prednisone Potency Duration
Cochrane review (2006) Corticosteroids
Dose
mg/ml
Equivalent
(mg)
28 trials (1973 participants) Betamethasone sodium phosphate (Celestone
6 50
High Long
Soluspan)
Comparing IA corticosteroid against, placebo, HA Dexamethasone sodium (Decadron) 4 40 High Long
products, j
p g ,
, joint lavage, and other IA corticosteroids Dexamethasone acetate (Dexasone LA) 8 80 High Long
Few side effects have been reported Triamcinolone hexacetonide (Aristospan) 20 25
Inter- Inter-
mediate mediate
Inter- Inter-
Methylprednisolone acetate (Depo-Medrol) 40 50 mediate mediate
Inter- Inter-
Triamcinolone acetonide (Kenalog) 40 50
mediate mediate
Hydrocortisone acetate (Hydrocortone) 24 5 Low Short
Bellamy et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane
Database Syst Rev. 2006 Apr 19;(2):CD005328.
INTRAARTICULAR CORTICOSTRROID INJECTION INTRAARTICULAR CORTICOSTRROID INJECTION
Cochrane review (2006) Cochrane review (2006)
One week post injection IA CS compare to IA HA
1-4 weeks post injection
IA CS more effective than IA placebo for pain reduction
No statistically significant differences
Sparse data on function, neither statistically significant 5-13 weeks post injection
nor clinically important difference HA products more effective than IA CS for one or more of the
2-3 weeks post injection following variables
WOMAC OA Index
Evidence of pain reduction
Lequesne Index
No evidence for efficacy in functional improvement Pain
4-24 weeks post injection Range of motion (flexion)
Number of responders
Lack of evidence of effect on pain and function
Bellamy et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Bellamy et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane
Database Syst Rev. 2006 Apr 19;(2):CD005328. Database Syst Rev. 2006 Apr 19;(2):CD005328.
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INTRAARTICULAR CORTICOSTRROID INJECTION INTRAARTICULAR CORTICOSTRROID INJECTION
Cochrane review (2006) Cochrane review (2006)
Comparisons of IA corticosteroids The response is generally rapid, but may not be sustained in
Triamcinolone hexacetonide superior to Betamethasone for the longer term
number of patients reporting pain reduction up to 4wks post Longer term benefits have not been confirmed
injection Hyaluronic acid (HA) products, while slower in onset of action,
Comparisons between IA CS and joint lavage may have a more sustained duration of benefit
No differences in any of the efficacy or safety outcome
measures
Bellamy et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Bellamy et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane
Database Syst Rev. 2006 Apr 19;(2):CD005328. Database Syst Rev. 2006 Apr 19;(2):CD005328.
CURRENTLY FDA APPROVED VISCOSUPPLEMENTS
INTRAARTICULAR HA INJECTION
Often mentioned as potential "structure- Euflexxa (1% sodium hyaluronate)
3-injection series (one week apart), $310
modifying" agents
Hyalgan (1%sodium hyaluronate)
Currently considered symptom-modifying drugs 5-injection series (one week apart), $310
HA is a large molecular weight Synvisc (Hylan G-F 20)
glycosaminoglycan 3-injection series (one week apart), $340
Supartz (1% sodium hyaluronate)
5-injection series (one week apart), $425
Orthovisc (1% sodium hyaluronate)
3-injection series (one week apart), $295
INTRAARTICULAR HA INJECTION INTRAARTICULAR HA INJECTION
Cochrane review (2006) Cochrane review (2006)
76 trials HA class of products is superior to placebo
Follow-up periods varied between day of last injection and 18 ms
The clinical effect for some products against placebo on some
40 trials compared hyaluronan/hylan and placebo (saline or arthrocentesis)
variables at some time points is in the moderate to large effect
10 trials compared IA CS
size range
6 trials compared NSAIDs
3 trials compared with physical therapy Comparable efficacy against NSAIDs
2 trials compared with exercise More prolonged effects than IA corticosteroids.
2 trials compared with arthroscopy
2 trials compared with conventional treatment
15 trials compared with other hyaluronans/hylan
Bellamy et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Bellamy et al. Viscosupplementation for the treatment of osteoarthritis of the knee.
Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD005321. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD005321.
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INTRAARTICULAR HA INJECTION INTRAARTICULAR HA INJECTION
Knee Pain VAS
A prospective RCT (2008)
199 patients in Hylan G-F-20 group
193 patients in Sodium Hyaluronate group
No placebo
Evaluations at pre-injection, 6 weeks, 3, 6, 12 months
Outcome measures
Knee pain on 0-10 visual analogue scale (VAS)
WOMAC
Oxford knee score
EuroQol EQ-5D scores
Raman et al. Efficacy of Hylan G-F 20 and Sodium Hyaluronate in the treatment of osteoarthritis of the knee: a
prospective randomized clinical trial. Knee. 2008 Aug;15(4):318-24.
Raman et al. Efficacy of Hylan G-F 20 and Sodium Hyaluronate in the treatment of osteoarthritis of the knee: a
prospective randomized clinical trial. Knee. 2008 Aug;15(4):318-24.
ELECTROMAGNETIC FIELDS THERAPY ELECTROMAGNETIC FIELDS THERAPY
Cochrane review (2002) Thamsborg et al(2005)
Only 3 studies with a total of 259 OA patients were Pulsed electromagnetic fields (PEMF) for knee OA
included Randomized, double-blind, placebo-controlled trial
2h daily Rx 5 days/wk X 6 wks in 83 patients
py
Electrical stimulation therapy had a small to moderate follow-up evaluation 6 wks after R
A f ll l ti k ft Rx
effect on outcomes for knee OA Outcome measure; ADL, pain and stiffness (WOMAC)
No beneficial symptomatic effect of PEMF in the treatment of knee
OA in all patients
However, in patients <65 yrs there is significant and beneficial effect
of treatment related to stiffness
Hulme J, Robinson V, DeBie R, Wells G, Judd M, Tugwell P. Electromagnetic fields for the
treatment of osteoarthritis. Cochrane Database of Systematic Reviews 2002, Issue 1. Art.
No.: CD003523 Thamsborg et al. Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized,
double-blind, placebo-controlled study. Osteoarthritis Cartilage. 2005 Jul;13(7):575-81.
TRANSCUTANEOUS ELECTRICAL NERVE
BALNEOTHERAPY STIMULATION (TENS)
spa therapy, mineral baths Cochrane review (2000)
Cochrane review (2002) 7 trials
Seven trials (498 patients) were included in this review
148 patients in TENS treatment group
Some beneficial effects of mineral baths compared to no
treatment 146 patients in placebo group
Of all other balneological treatments no clear effects were TENS and ’acupuncture like’ TENS (AL-TENS) over at
found least 4 Wks are effective for pain control and relief of
The scientific evidence is weak knee stiffness in OA
Verhagen AP, Bierma-Zeinstra SMA, Boers M, Cardoso JR, Lambeck J, de Bie RA, de Vet HCW. Balneotherapy for
osteoarthritis. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006864.
Osiri M, Welch V, Brosseau L, Shea B, McGowan J, Tugwell P, Wells G. Transcutaneous electrical nerve
stimulation for knee osteoarthritis. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.:
CD002823.
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TENS TENS
Small study done in Turkey with 100 pts B OA Pain VAS after 50 m walk at baseline and at the end of
Randomized in 5 treatment groups the study period (8 wks), and the group differences
Shortwave diathermy+hot packs+isokinetic exercise
TENS+hot packs+isokinetic exercise
Ultrasound+hot packs+isokinetic exercise
Hot packs+isokinetic exercise
Isokinetic exercise (controls)
Cetin et al. Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and Cetin et al. Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and
functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial. Am J Phys Med functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial. Am J Phys Med
Rehabil. 2008 Jun;87(6):443-51. Rehabil. 2008 Jun;87(6):443-51.
A SYSTEMATIC REVIEW OF PHYSICAL
LOW LEVEL LASER THERAPY INTERVENTIONS IN KNEE OA
A randomised, placebo-controlled, single blinded (Turkey) Meta-analysis by Biordal et al (Norway 2007)
60 patients with knee OA randomized in 3 groups 36 RCTs
Active laser with dosage of 3 J/per painful point
2434 patients (1391 received active Rx)
Active laser with a dosage of 1.5/J per painful point
Placebo laser treatment groups
Compared to baseline, at week 3 and at month 6, no significant
improvement was observed within the groups
No significant differences among the treatment groups at any time
Tascioglu F, Armagan O, Tabak Y, Corapci I, Oner C. Low power laser treatment in patients with knee
osteoarthritis. Swiss Med Wkly. 2004 May 1;134(17-18):254-8.
Bjordal et al. Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-
analysis of randomised placebo-controlled trials. BMC Musculoskelet Disord. 2007 Jun 22;8:51
A SYSTEMATIC REVIEW OF PHYSICAL A SYSTEMATIC REVIEW OF PHYSICAL
INTERVENTIONS IN KNEE OA INTERVENTIONS IN KNEE OA
Efficacy for each intervention
measured at the end of Rx CONCLUSION:
Mean difference over placebo for pain
measured on a 100 mm VAS
TENS, EA and LLLT administered with optimal
LLLT (Low Level Laser Therapy)
mean thresholds “important improvement”
doses in an intensive 2-4 week treatment
TENS/IF (Transcutaneous Electrical g y
regimen, seem to offer clinically relevant short-
Nerve Stimulation and Interferential
Currents)
mean thresholds “slight improvement”
term pain relief for OAK
mean thresholds “minimal perceptible improvement”
EA (Electro-acupuncture)
PEMF (Pulsed Electro Magnetic
Fields)
MA (Manual Acupuncture)
US (Ultrasound)
Bjordal et al. Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and
meta-analysis of randomised placebo-controlled trials. BMC Musculoskelet Disord. 2007 Jun 22;8:51 Bjordal et al. Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and
meta-analysis of randomised placebo-controlled trials. BMC Musculoskelet Disord. 2007 Jun 22;8:51
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CAPSAICIN
TOPICAL AGENTS
Spicy ingredient found in red peppers
Capsaicin
Mechanism of action is thought to be through
Topical NSAID preparations selective stimulation of unmyelinated type C
Salicylates afferent neurons, causing the release of substance P
0.025%
One RCT with 70 patients 0 025% cream qid X 4 wks
ith ks
Transient burning is the most common side effect
Good safety record
Decreased pain compare to placebo (P = 0.033)
$23.37 on
Deal et al. Treatment of arthritis with topical capsaicin: a double-blind trial.
Clin Ther. 1991 May-Jun;13(3):383-95.
TOPICAL NSAIDS DICLOFENAC
Multiple preparation in Europe Voltaren 1% gel (20g, 50g, 100 g)
>15 topical NSAIDs available worldwide $12-$44
Diclofenac has been studied the most 1st FDA approved topical prescription treatment
Piroxicam (Feldene) 0.5% gel for OA pain (Oct 2007)
Not available in the US
Pennsaid lotion approved in UK
Ibuprofen 10%
$65 for 1.5% 60ml
Is available by prescription to be made
Ketoprofen (Oruvail) Gel 30-60g, $20-30
Is available by prescription to be made (10% & 20% gel)
OTC TOPICAL NSAIDS TOPICAL NSAIDS
Usually not available in the US Metaanalysis done by Lin et al (2004)
Can be ordered on line Topical NSAIDs were superior to placebo in relieving
OA pain only in the 1st two weeks of treatment
$22 on
Nurofen (Ibuprofen 5%)
Lin et al. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-
analysis of randomised controlled trials. BMJ. 2004 Aug 7;329(7461):324. Epub 2004 Jul 30.
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TOPICAL NSAIDS TOPICAL NSAIDS
Effect sizes (95% confidence intervals) in pain relief between
Meta-analysis done by topical therapies or NSAID and placebo or vehicle
Biswal et al (2006)
Topical NSAID are effective
for pain relief in knee OA
for a longer duration
Biswal et al. Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis: Biswal et al. Longterm efficacy of topical nonsteroidal antiinflammatory drugs in knee osteoarthritis:
metaanalysis of randomized placebo controlled clinical trials. J Rheumatol. 2006 Sep;33(9):1841-4. metaanalysis of randomized placebo controlled clinical trials. J Rheumatol. 2006 Sep;33(9):1841-4.
TOPICAL SALICYLATES TOPICAL SALICYLATES
They have been used for years May be beneficial for pain
Menthol (10%) may enhance their penetration reduction
Methyl salicylate, particularly if combined with a penetration- Literature is extremely limited
enhancing substance such as menthol 10% (BenGay) and
(Flexall)
camphor (Flexall), are probably more effective than trolamine
salicylate (Aspercreme & Sportscreme)
REFERENCES
Cochrane Database Systematic Review
Jordan et al. EULAR Recommendations 2003: an evidence based approach to the
management of knee osteoarthritis: Report of a Task Force of the Standing Committee for
International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003
Dec;62(12):1145-55.
Zhang et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part
II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008
Feb;16(2):137-62.
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