1. IN THE NAME OF GOD

2. Rational use of drugs in OSTEOARTHITITIS
Sarah Mousavi, Pharm D,BCPS,
Assistant Professor of Clinical Pharmacy, Pharmacy Faculty, Isfahan University of Medical Sciences

4. In patients with noninflammatory OA, we recommend initiating drug treatment with acetaminophen (paracetamol, APAP), rather than a nonsteroidal antiinflammatory drug (NSAID), especially in patients with only mild to moderate pain (Grade 1A). Patients should be cautioned not to exceed the recommended dose.
Acetaminophen was modestly inferior to NSAIDs for pain and function in four systematic reviews

5. Acetaminophen First choice Inhibits central PGs
Dose: mg q 4-6 hr (max: 4 g/day)

6. Acetaminophen Adverse effects: Drug interactions: Hepatotoxicity
Renal failure (combined with NSAIDs)
Hypertension (regular long-term use)?
Drug interactions:
Isoniazid
Warfarin

7. فرآورده های دارویی Acetaminophen (Tylenol®, Tylophen®)
Tab 80 mg, 325 mg, 500 mg
Tab Acetaminophen Codein (300 mg + 10 mg)
A.C.A
Elixir, Susp., Syrup 120 mg/5 ml
Drop 100 mg/ml
Supp. 125 mg, 325 mg
Amp 1 g (Apotel®)

8. NSAIDs analgesic properties at lower doses
antiinflammatory effects at higher doses
similarly beneficial in OA

9. NSAIDs Acetylsalicylic acid (ASA, Aspirin) Ibuprofen Diclofenac
Tolmetin
Piroxicam
Mefenamic acid
Indomethacin
Naproxen
Meloxicam (partially selective)
celecoxib

10. Nonselective NSAID vs. another nonselective NSAID
Many trials found no clear differences between various nonaspirin, nonselective NSAIDs or partially selective NSAIDs (meloxicam, nabumetone, etodolac) in efficacy for pain relief or improvement in function.
In one short-term trial, salsalate and aspirin did not differ significantly in efficacy for pain relief or symptom improvement.
COX-2 selective (NSAID) vs. nonselective NSAID
COX-2 selective NSAIDs and nonselective NSAIDs did not clearly differ in efficacy for pain relief, based on many good-quality, published trials.

11. COX-2 selective NSAID vs
COX-2 selective NSAID vs. different COX-2 selective NSAID Celecoxib and rofecoxib did not differ significantly in efficacy for pain relief at commonly used and comparable doses, based on consistent evidence from six good-quality trials.
No studies compared efficacy of COX-2s other than celecoxib and rofecoxib.

13. Phramacokinetic Hepatic elimination High bioavailability
High protein-binding
Half-life: ranging from 1 hr for Tolmetin to 50 hr for Piroxicam
Hepatic elimination

14. Efficacy Similar efficacy Adequate trial: 2-3 weeks
Combination: no additional benefit

15. New COX-2 inhibitors
Etoricoxib
Lumiracoxib

16. Etoricoxib was associated with fewer GI adverse events (perforations, symptomatic ulcers, and bleeds) than nonselective NSAIDs in a fair-quality meta-analysis of 10 trials.
In primarily short-term trials, systematic reviews of RCTs suggest that etoricoxib has a similar CV safety profile compared to other NSAIDs, with the possible exception of naproxen. Definitive conclusions are not possible because of small numbers of CV events.

17. Results from one large trial (TARGET) found fewer adverse GI events with lumiracoxib than with naproxen and ibuprofen.
There was no statistically significant difference in rates of serious CV events between lumiracoxib relative to naproxen or ibuprofen in TARGET.
Too few events have been reported in RCTs to accurately assess CV risk associated with lumiracoxib.

18. Adverse effects: gastrointestinal
nausea, dyspepsia, anorexia, abdominal pain, flatulence, and diarrhea:
Affect 10% to 60% of patients
To minimize: should be taken with food or milk, except for enteric-coated products

19. Adverse effects: gastrointestinal
GI Bleeding
GI Ulcer and its complications:
Perforations
gastric outlet obstruction
bleeding
about 16,500 deaths are associated annually with NSAID use in RA or OA patients.

20. Risk factors for GI toxicity
history of complicated ulcer
History of dyspepsia
use of multiple NSAIDs, including aspirin
use of high-dose NSAID
use of anticoagulant or antiplatelet agents
age older than 65 years
concomitant use of corticosteroids
cardiovascular disease

21. رابطه ضعیف بین زخم گوارشی و علایم وجود دارد؛ بنابراین:
کنترل سالیانه CBC
تست خون مخفی در مدفوع (OB) قابل اعتماد نیست.

22. Prevention of ulcers in high-risk patients
COX-2 selective NSAIDs
PPIs
Misoprostol

23. Adverse effects: cardiovascular
Rofecoxib
Celecoxib: at high doses (> 400 mg/day)?!
Traditional NSAIDs: no significant risk
Diclofenac: some concern?

24. Choice For those with increased GI risk but not on aspirin:
a COX-2 selective inhibitor, or
a traditional NSAID with a PPI
For those taking regular low-dose aspirin for cardiovascular risk (with or without increased GI risk):
a traditional NSAID with a PPI, or
a COX-2 selective inhibitor with a PPI

26. In fair-quality meta-analyses of arthritis trials, most of which evaluated short term
use, celecoxib caused fewer ulcer complications than nonselective NSAIDs and did not increase the risk of myocardial infarction.
Celecoxib 400 mg twice daily was associated with an increased risk of serious
CV events (CV death or myocardial infarction) relative to placebo in a long-term trial of polyp prevention.
Celecoxib was associated with an increased risk of myocardial infarction relative to placebo in the most comprehensive systematic review of RCTs. Most of the 5 CV events with celecoxib were reported in two large polyp-prevention trials evaluating 200 mg or 400 mg twice daily, or 800 mg once daily.
About 3.5 additional myocardial infarctions occurred for every 1,000 patients treated for 1 year with celecoxib compared to placebo.

27. No clear difference in GI safety was found among nonselective NSAIDs at commonly used doses.
The CV safety of naproxen was moderately superior to that of any COX-2 selective NSAID in a large systematic review of RCTs.
There were 3.3 additional myocardial infarctions for every 1,000 patients treated with any COX-2 inhibitor instead of naproxen for 1 year.
The CV safety of nonselective NSAIDs other than naproxen (data primarily on ibuprofen and diclofenac) was similar to that of COX-2 selective NSAIDs in a large systematic review.
In indirect analyses, naproxen was the only nonselective NSAID associated with neutral CV risk relative to placebo.

28. Adverse effects: renal disease
acute renal insufficiency
Tubulointerstitial nephropathy
Hyperkalemia
renal papillary necrosis
Clinical features:
increased serum Cr and BUN
hyperkalemia
elevated blood pressure
peripheral edema
weight gain

29. High-risk patients chronic renal insufficiency
congestive heart failure
severe hepatic disease
nephrotic syndrome
advanced age
taking diuretics, ACEIs, cyclosporine, or aminoglycosides
monitoring of Cr at baseline and within 3 to 7 days of drug initiation

31. Other side effects Hepatotoxicity: hypersensitivity reactions
Diclofenac & sulindac
hypersensitivity reactions
central nervous system complaints:
drowsiness, dizziness, headaches, depression, confusion, and tinnitus
Among currently marketed NSAIDs, only diclofenac was associated with asignificantly higher rate of liver-related discontinuations compared with placebo (1 additional case for every 53 patients treated with diclofenac).

32. Use in aspirin-sensitive asthma
NSAIDs are contraindicated
Celecoxib is tolerated.

33. NSAIDs: Drug interactions
Warfarin
Lithium
ASA (should be taken 8 hrs after or 30 min before NSAID)
Celecoxib (CYP2D6 inhibitor)

36. فرآورده های دارویی ASA (Aspirin) Tab (chewable) 100 mg
Tab EC 80 mg, 81 mg
Tab 325 mg
Tab MC 500 mg
Tab A.C.A

37. Ibuprofen (Motrin®, Advil®)
Tab 200 mg, 400 mg
Cap (softgel) 200 mg, 400 mg (Gelofen®)
Susp. 100 mg/5 ml
Topical Gel 5%

38. Diclofenac sodium (Voltaren®)
Tab EC 25 mg, 50 mg, 75 mg (Voltaren ®)
Tab SR 75 mg (Voltaren® SR)
Tab SR 100 mg (Alfen XL®, Voltaren® Retard)
Cap SR 100 mg (Modafenac® Pain Off®)
Supp. 50 mg, 100 mg
Topical gel 1%
Amp 75 mg/3 ml (IM)
Ophtalmic drop 0.1%
Diclofenac potassium (Cataflam®)
Tab 50 mg (sugar coated)

42. Mefenamic acid (Ponstan®)
Tolmetin
Tab 200 mg
Mefenamic acid (Ponstan®)
Cap 250 mg
Piroxicam (Feldene®)
Cap 10 mg
Topical gel 0.5%
Amp 20 mg (IM)
Supp. 20 mg

43. Indomethacin (Indocid®)
Cap 25 mg
Tab SR 75 mg
Supp. 50 mg, 100 mg
Naproxen
Tab 250 mg
Tab EC 500 mg
Supp. 500 mg

44. Celecoxib (Celebrex®, Cobix®, Celexib®)
Cap 100 mg, 200 mg
Meloxicam (Mobic®)
Tab 7.5 mg, 15 mg
Ketorolac
Tab 10 mg
Amp 30 mg (IV, IM)
Eye drop 0.5% (Acular)

45. Topical Therapies
Capsaicin
NSAIDs
Rubefacients (methylsalicylate)

47. Glucosamine-Chondroitin
Stimulation of proteoglycan production
Exact role is unclear
Safe
A trial is reasonable
At least 1500 mg/1200 mg daily

48. In one large, good-quality trial the combination of pharmaceutical-grade glucosamine hydrochloride plus chondroitin (not currently available in the United States) was not superior to placebo among all patients studied. Neither glucosamine nor chondroitin alone was superior to placebo. In an analysis of a small subgroup of patients with at least moderate baseline pain, there was a modest benefit for pain relief from the combination, but this did not appear to be a preplanned analysis.
Systematic reviews of older trials found glucosamine modestly superior to oral NSAIDs and placebo in most trials, but there was some inconsistency between trials, most trials had some flaws, and results may not be directly applicable to the United
States because the positive trials primarily evaluated pharmaceutical-grade glucosamine available in Europe.

49. 􀂃 Only 2 of 20 placebo-controlled trials assessed effects of glucosamine on radiologic
disease progression. One fair- and one good-quality trial found pharmaceutical-grade
glucosamine superior to placebo for progression of knee joint space narrowing over 3
years.
􀂃 Glucosamine and chondroitin were generally well tolerated and no serious adverse
events were reported in clinical trials.

50. In the United States, glucosamine is not approved by the Food and Drug Administration for medical use in humans.
Since glucosamine is classified as a dietary supplement in the US, safety and formulation are solely the responsibility of the manufacturer; evidence of safety and efficacy is not required as long as it is not advertised as a treatment for a medical condition.
The U.S. National Institutes of Health is currently conducting a study of supplemental glucosamine in obese patients, since this population may be particularly sensitive to any effects of glucosamine on insulin resistance

51. In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate.
In this case, evidence of safety and efficacy is required for the medical use of glucosamine and several guidelines have recommended its use as an effective and safe therapy for osteoarthritis
The Task Force of the European League Against Rheumatism (EULAR) committee has granted glucosamine sulfate a level of toxicity of 5 in a scale, and recent OARSI (OsteoArthritis Research Society International) guidelines for hip and knee osteoarthritis indicate an acceptable safety profile

52. Glucosamine-Chondroitin
Adverse effects: nausea, bloating, cramps, allergic reactions
Do not cause hyperglycemia
Different brands have different efficacy and safety

53. فرآورده های دارویی Cartigen® (Glu.) PreFlex® (Glu. + Cond.)
Cap 500 mg, 1500 mg
PreFlex® (Glu. + Cond.)
Cap 500 mg, 750 mg
Nutri Flex® (Glu. + Cond.)
Caplet 500/400 mg
Glucogin (Glu. + Cond. + Ginger + Nutrients)
Caplet 600/100 mg
Glucosamine & Condroitin
Ginger concentrate
Se, Zn, Mn, Chromium, Folic acid, Vit D3 (400 IU), Vit E

54. ArthroStop® RAPID (Glu. + Cond. + Bowellin®)
Caplet 530/200 mg
Glucosamine
Condroitin
Bowellia serrata extract
Mn, Vitamin C
Triple Flex® (Glu. + Cond. + MSM)
Caplet 500/400 mg
Move Free® Advanced (Glu. + Cond. + Hyal. + Extr.)
Caplet 750/100 mg
Hyaluronic acid
Uniflex proprietary extract

62. The effect of chondroitin sulfate in patients with osteoarthritis is likely the result of a number of reactions including
its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans and hyaluronic acid, and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes, nitric oxide, and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes.

63. Chondroitin is in dietary supplements used as an alternative medicine to treat osteoarthritis and also approved and regulated as a symptomatic slow-acting drug for this disease (SYSADOA) in Europe and some other countries.
It is commonly sold together with glucosamine. Chondroitin and glucosamine are also used in veterinary medicine

64. Methylsulfonylmethane (MSM) is an organosulfur compound with the formula (CH3)2SO2. It is also known by several other names including DMSO2, methyl sulfone, and dimethyl sulfone.
MSM is sold as a dietary supplement and marketed with a variety of claims, often in combination with glucosamine and/or chondroitin for helping to treat or prevent osteoarthritis.
According to one review, "The benefits claimed [for MSM] far exceed the number of scientific studies. It is hard to build a strong case for its use other than for treating arthritis problems

65. Intraarticular glucocorticoid
can provide excellent pain relief
particularly when a joint effusion is present
After injection, the patient should minimize activity and stress on the joint for several days.

66. Intraarticular glucocorticoid
Initial pain relief: within 24 to 72 hours (peak: 1 week after injection)
Relief lasts up to 4 to 8 weeks.
three or four injections per year

67. Intraarticular glucocorticoid
Adverse events:
Systemic:
hyperglycemia, edema, elevated blood pressure, dyspepsia, and, rarely, adrenal suppression
Local:
infection, osteonecrosis, tendon rupture, and skin atrophy

68. 10 mg for small joints (interphalangeal, metacarpophalangeal, and metatarsophalangeal joints)
●20 mg for medium-sized joints (wrists, elbows, ankles, and acromioclavicular joints)
●40 mg for larger joints (shoulders, knees, hips).

69. Hyaluronic acid reconstitutes synovial fluid reduces symptoms
For unresponsive patients
Weekly injections (3 to 5)

70. فرآورده های دارویی Sodium hyaluronate Hyalgan® FermathronTM Orthovisc®
Synvisc®
Suplasyn®
High Hyalplus
Pre-filled syringe 20 mg

74. Other drugs
Opioids
Tramadol
Piascledine
Teltonal FK 480
Duloxetine

75. Tramadol Tramal®, Biomadol® Tab 50 mg, 100 mg Cap 50 mg, 100 mg
Tab SR 50 mg, 100 mg, 200 mg
Amp 50 mg, 100 mg (IM, IV)

79. Avocado/Soybean oil 1:2 ratio Cap 300 mg
مهار ترشح MMP-3
تحریک ترشح TIMP-1
تحریک سنتز کلاژن توسط کندروسیت ها

80. Avocado/Soybean oil عوارض گزارش شده به FDA:
ایست قلبی تنفسی
افزایش کراتینین سرمی
بی اختیاری مدفوع
احساس ناخوشی (malaise)
افت فشار خون وضعیتی
زردی
پورفیری
عدم قطعیت ارتباط این عوارض با دارو
بیماران داروهای دیگر نیز مصرف می کرده اند.

82. Systematic review of soy isoflavone supplements on osteoporosis in women.
The present meta-analysis reveals that soy isoflavone supplements significantly increase bone mineral density and decrease the bone resorption marker urinary DPD. It shows no significant effect on bone formation markers serum bone alkaline phosphatase. The significant effect of soy isoflavones on BMD and urinary DPD is relative to menopausal status, supplement type, isoflavone dose and intervention duration.
isoflavone dose above 75 mg/d.

83. Teltonal 480 FT® Arthroherb® Tab 480 mg
Devil’s claw root extract (Harpagophytum procumbens)
Harpagoside
anti-inflammatory

84. Teltonal 480 FT® منع مصرف: موارد احتیاط مصرف: روش مصرف؟ زخم گوارشی
کودکان زیر 12 سال
بارداری و شیردهی
موارد احتیاط مصرف:
سنگ صفراوی
عدم تحمل لاکتوز
دیابت
روش مصرف؟

86. Teltonal 480 FT® عوارض: اسهال تهوع و استفراغ گیجی سردرد
واکنش های حساسیتی

87. Rheumatidin® (Celadrin®)
Softgel cap 350 mg

88. Celadrin® is made from a patented complex blend of special esterified fatty acids, derived from bovine tallow oil.
Celadrin® works similar to, but much more dramatically than the essential fatty acids EPA and DHA from fish oils.
Celadrin® decreases inflammation and lubricates cell membranes throughout the body, restoring fluids that cushion bones and joints to promote flexibility and mobility. Over time, because of the reduction of inflammation delivered by using Celadrin®, the joints and surrounding tissue have an opportunity to promote healthy joints.

89. For oral application, Celadrin® was studied using a double-blind, multi-center, placebo-controlled trial (the most scientifically validated type). Sixty-four participants between the ages of 37 to 77 were given Celadrin® capsules and were evaluated at the beginning of the trial, at 30 days and at the end of the 68 day study.
Compared to those given a placebo, those who were given Celadrin® had more flexibility, fewer aches, less pain and were able to walk further distances than the placebo group.
The study therefore concluded that Celadrin®, when taken orally improved joint and mobility problems.

90. Celadrin ® empowers glucosamine to perform faster and more efficiently in building joint cartilage as well as accelerating and promoting joint health.
The dual action of Celadrin® and glucosamine provide rapid joint cushioning, quickly alleviate inflammation, build cartilage and restore the entire joint area.

93. Bromelain extract is a mixture of protein- digesting (proteolytic) enzymes or proteases, and several other substances in smaller quantities. The proteolytic enzymes are sulfhydryl proteases, since a free sulfhydryl group of a cysteine side chain is required for function

94. As a potential anti-inflammatory agent, it may be useful for treating arthritis, but has neither been confirmed in human studies for this use, nor is it approved with a health claim for such an effect by the Food and Drug Administration or European Food Safety Authority

95. While there have been studies which positively correlated the use of bromelain with reduction of symptom severity in osteoarthritis,“
the majority of the studies have methodological issues that make it difficult to draw definite conclusions", as none definitively established efficacy, recommended dosage, long term safety, or adverse interaction with other medications.

96. Walker AF, Bundy R, Hicks SM, Middleton RW (2002)
Walker AF, Bundy R, Hicks SM, Middleton RW (2002). "Bromelain reduces mild acute knee pain and improves well-being in a dose- dependent fashion in an open study of otherwise healthy adults". Phytomedicine 9 (8): 681–6.
Hale LP, Greer PK, Trinh CT, James CL (2005). "Proteinase activity and stability of natural bromelain preparations". Int Immunopharmacol 5 (4): 783–93.

97. Mixodin

98. یکسودین از عصاره های طبیعی زردچوبه، زنجبیل و فلفل سیاه که مواد موثره کورکومین، جینجرول و پایپرین موجود در این ادویه ها در آن خالص و تغلیظ شده، تهیه گردیده است. ترکیبات میکسودین شامل عصاره زردچوبه " کورکومین" 300 میلی گرم، عصاره زنجبیل " جینجرول " 7.5 میلی گرم و عصاره فلفل سیاه " پایپرین " 3.75 میلی گرم می باشد.

99. Mixodin دوز: روزی 2-3 کپسول
منع مصرف: بارداری-شیردهی، سنگ کلیه و کیسه صفرا
هشدار