In our 22nd episode we continue our low dose discussion. We talk about the concept of n-of-1 trials and allowing patients to determine their dose. We review some of the benefits of low-dose prescribing, such as low side-effect risk and reduced costs, but emphasize the medical conditions in which low doses are inappropriate. We end by offering some practical suggestions to assist patients with very low doses (in which James forces Mike to acknowledge the superior power of pharmacists).

Show Notes

1) Placebo what it is and should you use it – go with low dose instead?

BMJ 2008;336;1020

BMJ 1995; 311:551-3

2) Cost has an effect on adherence

Med Care 2001 39: 296–301

J Manag Care Pharm 2006 12: 377–382

In our 21st episode we jump into our ongoing debate about low and very low dose of medication. We present the reason why initial doses of new drugs are often too high and the logic for trialing lower doses in patients. We also review over 10 examples of medications proven in randomized control trials to be equally effective (or more) at lower doses. Although promoting low dose, the size of the podcast is moderate dose (while the quality is high dose with minimal side-effects).

Show Notes

1) Examples of evidence for effective lower doses – these examples typically show lower doses were as effective as higher doses, but in some of the examples higher doses were somewhat more effective but lower doses nonetheless produced clinically important results

6.25 mg of hydrochlorothiazide is effective at lowering blood pressure, and comes in a number of combination products – initially 50 to 200 mg was the recommended starting dose

Arch Int Med 1994;154:1461-8

6.25 mg of captopril has been shown to be effective for blood pressure yet captopril 25 mg PO TID is still a commonly recommended initial starting dose for hypertension.

Circulation 1983;67:1340-6

25 mg of sildenafil (Viagra) has been shown to be an effective dose for erectile dysfunction

Bandolier

25 mg of sumatriptan (Imitrex) works almost as well as100 mg and in fact for most drugs in this class there is a flat dose-response curve seen at the doses studied.

Cephalalgia 2002;22:633-58.

5 mg daily of fluoxetine (Prozac) has been shown to have an effect similar to 20 mg daily.

N Engl J Med 1994;331:1354-61

0.25 mg (1/40th of the recommended initial starting dose of 10 mg) of ezetimibe (Ezetrol) provides 50% of the LDL lowering effect seen with 10 mg

Clin Ther 2001;23:1209-30

15 mg of elemental iron daily has been shown to be as effective for anemia as 50 mg and 150 mg, with a lower incidence of side effects.

Am J Med 2005;118:1142-7

150 mg daily of bupropion (Zyban) produces the same rate of smoking cessation at one year as 300 mg daily.

N Engl J Med 1997;337:1195-202

200 mg of ibuprofen (Motrin) is as effective as 400 mg for migraine headache.

Headache 2001;41:665-79

25 mg of ranitidine (Zantac) has been shown to be as effective as 125 mg for heartburn relief.

Aliment Pharmacol Ther 1999;13:475-81

Compared to standard-dose treatment, low-doses of depot antipsychotics improve psychosocial function and reduce the frequency of side effects.

Schizophrenia bulletin 1993;19:155-64

Tricyclic antidepressant doses of 75-100mg are as effective for depression as doses greater than100mg.

BMJ 2002;325:991-5

500 and 1000 µg of oral B12 was more effective than 2.5, 100 or 250 µg at improving the surrogate marker of B12 deficiency (methylmalonic acid).

Arch Intern Med. 2005;165:1167-1172

Meta-analysis showing higher doses of statins produced greater reductions in cardiovascular events – as an aside, a number of these trials compared different drugs in addition to different doses and the difference in outcome was approximately 1.5% in cardiovascular outcomes

CMAJ 2008;178:576-84

2) Doubling the dose of inhaled corticosteroids for asthma exacerbations is not effective

Lancet 2004;363:271-5

Thorax 2004;59:550–6

In our 20th episode we try to answer our accumulating listener mail. We review questions around cardiovascular disease risk-benefits and try to demystify the calculators. Listeners question antidepressants: when they should start to work, when to change dose/type and their use for chronic pain. Other issues include stopping bisphosphonates, addressing the placebo effect and uncertainties with industry funded trials. In the end, Mike talks about Giraffes and James becomes spastic.

Show Notes

1) Meta-analysis data for mortality benefit with statins in primary prevention

TI meta-analysis on statins in women for primary prevention.

“For women without cardiovascular disease, lipid lowering does not affect total or CHD mortality. Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively.”

JAMA 2004;291:2243-52

2) Don’t change the doses of antidepressants too quickly

Br J Psyc 2006;189:309–16

3) How quickly do antidepressants work?

Arch Gen Psyc 2006; 63: 1217-23. (for how fast anti-depressants work)

4) How long do we use bisphosphonates?

N Engl J Med 2004;350:1189–1199

JAMA 2006;296:2927-38

Options in treatment, which ones have evidence of non-vertebral fracture and the absolute benefits of those treatments. We discuss reliability of monitoring bone density of patients on therapy and the duration of therapy.

Show Notes

1) Evidence for fracture reduction

There is good evidence from randomized controlled trials (RCTs) that alendronate, etidronate, ibandronate, risedronate, calcitonin, 1-34 PTH, and raloxifene prevent vertebral fractures compared with placebo.

There is good evidence from RCTs that risedronate and alendronate prevent both nonvertebral and hip fractures compared with placebo.

There is good evidence that zoledronic acid prevents vertebral and nonvertebral fractures, and fair evidence that it prevents hip fractures.

Agency for healthcare research and quality – report

2) Calcitonin appears to be effective in the management of acute pain associated with acute osteoporotic vertebral compression fractures by shortening time to mobilization

Osteoporosis Int 2005;16:1281-90

3) Relative and absolute benefits from using alendronate for 2-3 years

Approximately

45% reduction in vertebral fractures – 2% absolute reduction for primary and 6% for secondary

20% reduction in non-vertebral – just secondary prevention – 2% absolute reduction

50% reduction in hip fractures – just secondary prevention – 1% absolute reduction

Cochrane Library