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Managing AI-Induced Musculoskeletal Effects – Part 3

Analgesic Agents


Systemic Analgesics: NSAIDs, Opiates and Acetaminophen,
Although it is true that not all patients suffering the adverse musculoskeletal effects of AI therapy gain any appreciable benefit from NSAIDs, some do, and it is highly individually variable across different NSAIDs.  Cary Presant  and colleagues at Wilshire Oncology reported at ASCO 2006 the results of their comparison study of what works and what doesn't, and it's important to know these comparative stats: so although only 13% of patients benefited from glucosamine, double that number 26% benefited from plain old
acetaminophen (Tylenol), and 45%, almost half, benefited from some NSAID. NSAIDs agents are commonly used with modest success, according to the research of Rowan Chlebowski at UCLA. But as Beth Overmoyer at New Milford observed, NSAIDs can be helpful for some women, but their efficacy is unpredictable; and any relief is likely to come from the stronger and longer acting agents like naproxen (Naprosyn), or possibly also diclofenac (Voltaren), or indomethacin (Indocin) and it's also important to try more than one agent (no less than 48 – 72 hours on each, preferably 7 – 10 days if there is any early sign of benefit however small).  In addition, besides opiates, anecdotal and preliminary data suggests that non-narcotic non-addictive novel agents like tramadol (Ultram, Ultracet) may provide higher levels of pain relief and without opiate side effects (tramadol induces a mild degree of euphoria which may also be contributive).  And although mild opiates  benefited only in 11% of cases and strong opiates in still less, 5%, nonetheless again certain opiates may be more effective, such as variable doses of fentanyl transdermal patch (Duragesic), stepping up dosing as needed each fourth day.


COX-2 Inhibitors – Celecoxib (Celebrex)

The addition of celecoxib (Celebrex) 400 mg bid to exemestane reduced arthralgias and improved response rates in a placebo-controlled trial in women with metastatic disease, as reported by Gilles Freyer's GINECO trial at ASCO 2006. Beth Overmoyer reports good responses with celecoxib, as well as high-dose naproxen, and she notes that the fentanyl transdermal patch also appears to work very well, although this was largely in the metastatic setting.  Although the removal of other COX-2 inhibitors for enhanced cardiovascular (CV) risk has sparked concern over Celebrex, this has been shown to be misplaced – Bill White at the University of Connecticut and coresearchers conducted earlier this year a found failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs in over 7,462 patients over 1,268 patient-years.


It should however  be observed here that, extraordinarily, the natural agent SAMe (S-Adenosylmethionine) was at least as effective in pain relief than celecoxib (Celebrex), and although Celebrex worked faster than SAMe, but both were providing equal benefits after the initial period (approximately 4 weeks), as found recently in the double-blind trial of Wadie Najm at Irvine.  See my fuller discussion of SAMe for pain relief below.


Topical Analgesics: NSAIDs

Given the adverse GI effects of oral NSAIDs, there is now intense interest and development in topical preparations, and some topical NSAID preparations can be as effective as orally administered ones and avoid the GI and other systemic adverse effects. Maggi Banning at Brunel University, Uxbridge reviewed evidence from four randomized controlled trails on the efficacy and safety of topical diclofenac sodium (Voltaren Gel) for pain relief from osteoarthritis, finding it to be both safe and effective for pain control, and non-inferior to oral diclofenac (and Italian researchers found Voltaren Gel as effective for TMJ (temporomandibular joint) dysfunction symptoms as oral diclofenac). 


Topical Analgesics: Natural Agents

In this connection, it's worth noting that Christian Schneider and colleagues compared Voltaren Gel (1%) with a homeopathic ointment, Traumeel S, for the symptomatic treatment of tendinopathy, finding impressively Traumeel S to be at least as effective as Voltaren Gel on all variables, with a trend toward superiority of Traumeel S on motility-related variables (and Traumeel S has been found in the randomized, controlled clinical trial of Israeli researcher Menachem Oberbaum, to significantly reduce the severity and duration of chemotherapy-induced stomatitis).  In a head-to-head comparison Ketoprofen TDS (transdermal) patch was slightly more effective than Voltaren Gel; the patch is just completing final stages of FDA approval and should appear in the very near future.


In addition, the comfrey-based German analgesic product Kytta-Salbe, applied at 2g 3X daily for 3 weeks, was investigated for relief of osteoarthritis in a randomized, double-blind, placebo-controlled clinical trial conducted by Merck researchers, being found effective, reducing pain and increasing mobility and quality of life.


Furthermore, Swiss researcher Reto Widrig at the Institute of Complementary Medicine conducted a randomized, double-blind, reference-controlled study was to compare the efficacy of a specific commercial arnica gel, A Vogel Arnica Gel marketed as Atrogel (from BioForce) with Optifen Gel, a NSAID (5% ibuprofen) gel, Atrogel was applied by rubbing in a 4 cm (1.6") strip of the gel to any affected joints 3 times daily for 3 weeks, but subjects are instructed to not to wash their hands for 1 hour after application.  The study found that Atrogel was as effective as the NSAID gel, in reducing pain intensity, number of painful joints, and duration and severity of morning stiffness.


Finally, given that radiological  findings from Dutch researchers using MRI revealed small amounts of synovial fluid in the hand joints of many patients, with characteristic enhancement and thickening of the synovial sheath seen typically with osteoarthritis and ostemalacia, other natural CAM interventions may be of benefit. CFAs or cetylated fatty acids (under the Celadrin brand, also as InflameAway Celadrin) are special are cetylated, esterifed fatty acids (cetyl myristoleate, cetyl myristate, cetyl palmitoleate, cetyl laureate, cetyl palmitate, and cetyl oleate), that halt the production of inflammatory prostaglandins compounds, also reducing the production of the negative immune factors like IL-6 that play a central and critical role in the inflammatory process. Four clinical studies in the past six years have been shown Celadrin cream to be of benefit in osteoarthritis, applied to affected areas on an as needed basis (the dosage with the alternative oral preparation is three capsules daily. It has exhibited no side effects whatsoever and no drug interactions.


Glucosamine Revisited – Quality Control
One issue with declaring no benefit on glucosamine (1500mg/daily) + chondroitin (1200mg/daily), is the unfortunately not widely known abysmal lack of quality and purity control in the health food industry: the evidence-based laboratories of Consumerlab for example found that several brands contained only a fraction of the claimed amounts of the active ingredients, and / or failed other critical quality control testing.  All rated NOT approved were Symtec, Weil / Andrew Weil (failed to disintegrate at all in 1 hours and 10 minutes), Swanson (less than one twelfth (8%) of the claimed amount of chondroitin), Nature's Plus (which was found to contain no chondroitin whatsoever, despite claiming 600mg per tablet, and trumpeting on the label to be "
"...the highest quality chondroitin sulfate supplement ever developed in a single tablet"), etc.  On the other hand Schiff, Twinlab, GNC, Rite Aid, Country Life, Puritan's Pride, and Vitamin World were some of the brands that passed and were fully approved (not all brands are tested).


Calcium and Vitamin D
Calcium and Vitamin D are critical to bone health. Calcium should not exceed 2000mg daily, and 1500mg is typically all that is required for bone health if the formulation is highly available – so favor calcium citrate or calcium phosphate, and avoid calcium carbonate formulations which are problematic for many individuals, and dose with no more than 500mg calcium per dose (three times daily). As I indicated in my previous coverage, Vitamin D needs to be the D3 (cholecalciferol), and NOT the D2 (ergocalciferol) form, and dosing for bone health needs to be at least 2000 IU (international units) daily, and 3000 IUs / daily for bone and breast cancer health.


All anti-osteoporotic bisphosphonates have some modest propensity for benefiting bone pain. Of the convenient oral agents, risedronate (Actonel) and alendronate (Fosamax) are the two most optimal oral anti-osteoporotic bisphosphonates in the US, while the bisphosphonate clodronate (Bonefos) is the most optimal outside of the US, and again outside of the US the non-bisphosponate strontium ranelate (Protelos) is at least as effective as these. The aggressively marketed ibandronate (Boniva) is however suboptimal, as it is limited to vertebral (spinal) fractures alone, making it a poor choice for the broad anti-osteoporotic protection any rationale individual would want of complete bone benefit, namely against vertebral, non-vertebral, and hip fractures. There is another anti-osteoporosis agent, calcitonin-salmon (Maicalcin), used as an intranasal spray, and although it is not as effective or as consistent in action as Actonel, Fosamax, Bonefos or Protelos, one virtue it has is that it provides a significant degree of analgesic (pain-relieving) effect (as shown in 13 different double-blind, placebo-controlled trials), and an underground trick is to supplement an existing anti-osteoporotic agent with Miacalcin for its pain benefit.   


For anyone on any bisphosphonate, it is imperative to take precautionary steps to minimize the rare, but serious, risk of
osteonecrosis of the jaw (ONJ): I have developed evidence-based guidelines for the prevention and management of ONJ in my detailed Consumer Alert: Osteoporosis Drugs - A Pain in the Jaw?
And I would strongly advise all bisphosphonate users to follow the recommendations set forth there (with technical details on my Breast Cancer Watch site).

Omega-3 Fatty Acids (OFA)

3 grams of omega-3 fatty acids from fish oil have been found  in numerous controlled trials to reduce pain intensity of joint symptoms in arthritic and related disorders, with patients who also added olive oil to the daily regimen experiencing even greater symptom improvements.  And the recent meta-analysis of Robert Goldberg and Joel Katz at York University found that supplementation with omega-3 PUFAs for 3 to 4 months reduced joint pain intensity, morning stiffness, number of painful and/or tender joints, and the need for NSAID consumption.


S-Adenosylmethionine (SAMe)

A substantial body of scientific evidence indicates that S-adenosylmethionine (SAMe) can relieve symptoms of arthritis and other bone related inflammatory disorders, with numerous double-blind studies involving more than a thousand participants in total demonstrating that it is approximately as effective for this purpose as standard anti-inflammatory drugs (NSAIDs).  So the double-blind trial of Innocenzo Caruso and colleagues found that SAMe at 1,200 mg of SAMe per day was as effective as 750 mg daily of naproxen. It's important to note the velocity of benefit: although naproxen worked more quickly, producing readily apparent benefits at the 2-week follow-up, the full effect of SAMe was not apparent until 4 weeks, yet by the end of the study, both treatments were producing the same level of benefit; therefore it is important to give SAMe an adequate trial, requiring at least 4 weeks duration.  And as I noted above, SAMe (at 1200mg/daily) was at least as effective in pain relief than 200mg of the powerful COX-2 inhibitor celecoxib (Celebrex), with Celebrex starting to work faster than SAMe, but both providing equal benefits after the initial period (approximately 4 weeks), as found recently in the double-blind trial of Wadie Najm at Irvine, and interestingly with the benefits of SAMe continuing to increase with time compared to Celebrex whose effects remain constant.. 


Thus SAMe to date matches the pain-relieving benefit of celecoxib (Celeberex), naproxen (Naprosyn) and other powerful NSAIDS without the adverse GI and other events associated with NSAIDs and the COX-2 inhibitors (and the weight of the evidence also suggets that SAMe has some plausible benefit as a natural antidepressant).


Exercise and Acupuncture

Harold Burstein at Dana-Farber has found that a regular exercise program seems to mitigate some of the symptoms. Beth Overmoyer at New Milford recommends stretching exercises, such as yoga or body sculpting.  In addition, Katherine  Crew at Columbia University found in a trial that acupuncture (twice weekly for 6 weeks) is a safe and effective treatment for AI-induced arthralgias, with improvements in body pain and osteoarthritis index measures; patients reported improvement in the mean worst pain, pain severity, and pain-related functional interference.


Desvenlafaxine (Pristiq)
A new antidepressant, Desvenlafaxine (Pristiq), developed by Wyeth, derived from venlafaxine (Effexor), is nearing final FDA approval, an dhas been found in a study by Claudio Soares at the Women's Clinic of McMaster University to improve measures of pain, well-being, and functioning, while also improving hot flashes, managing sleep disturbance and cognitive impairment with minimal sexual side effects. 

The final peice of this series, to appear shortly, will be a brief summary of findings across the three already posted parts of my coverage (including this one).

Constantine Kaniklidis
Medical Researcher 

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