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Most Pharmacies have a patient (or more) that is a centenarian. Living to the age of 100 is quite an achievement, considering these patients grew up and lived the prime of their lives in an era that had a healthcare model quite different from today. Knowledge of how diet, exercise, nutrition and medicine interplay to result in a long life wasn’t as advanced as it is today. Some may say the diet 100 years ago was superior to today’s diet. They probably wouldn’t be wrong. Sanitation, pasteurization, and crop control were at a different stage at this point in time than they are today.
I had the pleasure of sitting down with Margaret MacPhee, 103 years old from Baddeck, Nova Scotia recently to ask her what her life experiences that may have helped get her to this age. In an interview that was hopefully not patronizing, she opened up about her life from childhood to today.
Margaret was born at home during the wintertime of 1915 and grew up in a house in Upper Baddeck (Big Baddeck) the fourth oldest child in a family of 11. She wonders how she managed to be living at all growing up back then let alone survive to be 103. Her house had no electricity or phone and was heated from one central stove. Her father was a farmer and her mother “had lots to do with all the children”. This was not uncommon for the families that grew up in the area as every family seemed to be large. She went to school in Upper Baddeck for 11 years then went out working from home to home in the area doing housework. She was married to Charles D MacPhee in 1946 until he passed away in 1992. They had one daughter (Catherine), a large difference from her family size growing up.
Margaret didn’t smoke or drink alcohol during her life. She didn’t recall taking any type of vitamin or herb growing up. As a child she doesn’t directly recall most of the healthcare or medicine of the time. She recalls early in her life coming home from Sydney and then coming down with Scarlet Fever. She doesn’t remember what Dr MacMillan gave her at that point but she survived this. She clearly tells about being quarantined alone in her room where her mother soaked a blanket and hung it in the doorway of the room to keep the germs from spreading to the rest of the house. Given the lack of modern day entertainment sources for children back then, it must have been a lonely time for Margaret during the long hours of the days and nights while she recovered. No one else came down with the disease in the house. She also had measles and as well had whooping cough, which she recalls almost dying from. She lost a brother to the whooping cough (a twin of another brother). Another brother died from croup at a just a few months old. There were no vaccines at this point for them of course and routine visits to the doctor weren’t all that common unless there was a need. Given the lack of antibiotics and vaccines back then, childhood was a journey with pitfalls not seen today that made it more of an accomplishment to get to adulthood than it is now.
When asked of her sleep habits she says, “now I’m sleeping all the time. If I lay down at all I’m asleep!” She says living as a young girl on the farm you were up early to do your chores and then get ready for school. When you came home you started into the chores again. There were three meals a day, breakfast and supper and home and lunch was taken to school. Food eaten back then was grown on the farm. Herring and codfish were also staples as were beef and pork from the farm. Whole food was the norm. Processed and ultra-processed food we see today weren’t the food choice back then living on the farm.
Margaret isn’t one for social media, and as mentioned,growing up they had no phone. They burned kerosene lamps for light at night. Electricity wasn’t something she had in a home until she got married and moved out on her own. One of the biggest differences between then and now was the direct social network everyone had. There wasn’t a night in the winter regardless of how stormy it was, that there weren’t people over at the house. Family or friends and neighbors would visit until 11:00 at night every night. A common activity was playing cards and it wasn’t uncommon for visitors to travel with snowshoes back home. Picturing what it would be like with no power or contact with the anyone (TV, cell phone, social media, email or texting) makes it more understandable how long evenings were passed with groups of visitors every day. She says there isn’t anything like this today. In fact we have seen survival rates from some diseases like cancer have a better survival rate when the patient has a better direct social network available to them. If there was a storm, there were no plows but for two days after the storm everyone would be out with their horse and sleighs making a path on the road.
One of her earliest recollections in the house was a day when her father was out working, perhaps out in the woods, and her mother was out doing chores outside of the house briefly at noon. She was left in the house with her two older brothers, one of them being in charge while she was out. She recalls it being a stormy day, her mother was out feeding the animals and when she came out of the barn she smelled smoke. Looking in the direction of the house her mother saw smoke coming from the house and chimney. Her father smoked and instead of using matches he would use long thin sticks to light his pipe that he lit in the fire. Her babysitting brother found some of these laying around and grabbed one and put it in the fire. There was an open chimney behind the stove with bark, kindling, and papers in it. He threw the stick in the chimney causing everything in it to catch fire. By the time her mother made it back to the house, her brother had taken the younger brother out of the high chair and ran with him into the bedroom off of the kitchen and closed the door, leaving Margaret crawling around on the floor. When her mother got to Margaret she was almost to the blazing chimney. Her mother had her hands full.
Today only two sisters, Agnes (Baddeck) and Marion (Sydney) are still alive. Marion’s daughter was raised for a while by Margaret’s mother when Marion went to Sydney to work, so she thinks of her as a sister. Her siblings lived to be in their 70’s for the most part. Her mother died 4 months shy of her 100th birthday. Margaret remembers her mother as being a hard working woman. She wasn’t a nurse but she feels she could have been and would help deliver babies, was good around animals and people. Her father passed away of a heart attack at 69 years of age.
In looking at what contributes to Margaret’s long life, we can certainly attribute her DNA passed down by her mother as being a major contributing factor. There wasn’t a lot of money to go around the family growing up, but like the other families in the area they got through it. Living on whole unpasteurized milk (not recommended today), curds, butter, cream, butter milk, vegetables and fresh farm raised meat. Today she eats a little differently, margarine and 2% milk, and some processed food she might heat up in the microwave. Aside from being forgetful with names, she is still quite active and comes into the pharmacy regularly. A good sleep habit and regular physical activity are undoubtedly helping her to age in a healthy manner. As a child and an adult, she had no cell phone to keep her up at night disrupting her sleep. Finally, a strong network of other contacts that she regularly saw reflects the results we’ve seen in longevity from other studies.
Margaret has no major regrets looking back. She supposes back growing up there were a lot of regrets of what she had to do but nothing lasting. She recalls a story of two men in their 80’s for how she feels of this stage of life. One says to the other how great he feels and wakes up everyday wanting to take on the world. The other one says he feels just the opposite. He feels like a baby, “I have no hair, no teeth, and I just wet myself”. Margaret also has a good sense of humor.
I’d like to thank Margaret for yet another down to earth talk with her and her willingness to share her experiences with everyone.
Omega 3 supplements have been taking a beating lately with regard to cardiovascular outcomes. One thing that we have seen is the questionable cause and effect of the wide variety of commercially available Omega 3 supplements available on the market and the dose required for any effect at all.
Clinically, one indication I see Omega 3 supplements used for successfully is pain relief. It works along the same pathway as anti-inflammatory medications. But what does the evidence tell us about the effectiveness of such supplementation in an era where vitamins, herbs and supplements are more and more becoming a punching bag for quackery? Is there hard evidence for treating pain without the use of (oral) NSAIDS, opioids, muscle relaxers, antidepressants, counterirritant rubs, and anticonvulsants? Transdermal pain compounding comes to mind, but is there an OTC product you can start today in giving your customers to begin safely reducing their pain?
First of all you need to set expectations. If you are someone in chronic daily pain, you need to be upfront with them as a pharmacist by telling them that 100% pain relief is not a concept that we entertain. Your discussion with goal setting with them should inquire what they want to get out of this. Most patients in chronic pain don’t necessarily need to be pain free, they have learned for years how to live and cope with pain. What they may share with you is the desire to play with their grandkids, to go to church with their spouse, to go for a walk with their dog every day, or to just simply get out of bed and make a meal for themselves.
There have been a number of pain patients I can recall who have claimed that by taking this one supplement, they are able to do some of these activities. As evidence-based healthcare practitioners, we must strike a balance between following anecdotal evidence we’re presented with in the pharmacy and using the invaluable clinical evidence we see as healthcare professionals that really no one else sees. This balancing act inevitably involves stumbles where we fall for an N of 1 to strongly and apply it to everyone we speak to. In other moments of clarity, we look back at the results of our recommendations and accumulate a non-trial-based clinical judgment that we feel strong enough about to make recommendations for in the front store.
Recommendations to use Omega 3 supplementation in relieving pain are based on good quality evidence. When we look at the use of Omega 3 with rheumatoid arthritis (RA) specifically, it is important to reinforce with patients (and to ourselves as pharmacists) that this is not meant to replace what we use conventionally. Disease modifying antirheumatic drugs (DMARDS)should not be dropped in favor of Omega 3 supplementations. In fact DMARDS can help induce the remission of the disease when used early. They can, however, be used in conjunction with them.
Being a disease connected with the immune system, rheumatoid arthritis treatments that work with the body’s immune system are an attractive way to combat the problem. Omega 3 has been shown to affect our immune system. Arachidonic acid, which is an omega 6 product, flows into pathways that create inflammatory molecules which are involved in rheumatoid arthritis, including inside immune cells. The EPA and DHA in marine Omega 3 supplements reduces arachidonic acid. They follow a pathway which results in anti-inflammatory products and affects dentritic cell and T cell function. Additionally, it reduces reactive oxygen species by leukocytes and inflammatory cytokine production by macrophages. But the work on this area and how it pertains directly to RA is less understood. (1)
In a systemic review of 23 studies of Omega 3 use, modest but fairly consistent benefits were seen in relation to joint swelling, pain, the duration of morning stiffness, and the global assessments of pain and disease activity.(1) There was also a benefit in the amount of NSAID therapy used in these patients.
In explaining just how omega 3 has a cause and effect relationship with RA and how studies show that it helps to reduce pain, we look to the similarity in effect between NSAIDS and Omega 3 in the body. Prostaglandin E2 (PGE2) is involved in all processes leading to the classic signs of inflammation (redness, heat, swelling, pain and edema). (2) A typical NSAID blocks the production of Eicosanoids including several prostaglandins as well as thromboxane proinflammatory products involved in pain and inflammation. Omega 3 reduces the production of mainly PGE2. Therefore you get the benefit of reduced pain and inflammation while avoiding the other problems with NSAIDS on the stomach. Unfortunately, the blood thinning still occurs, so those at risk for bleeding or on blood thinners need to be mindful of this. In reducing the dose of Omega 3 to avoid this, patients may put themselves in a dose range that is ineffective for RA. As you may have guessed, Omega 6 supplements increase arachidonic acid which is responsible for the production of these pro-inflammatory products, so combination 3-6 or 3-6-9 products are not recommended.
Based on current data, doses above 2.7g per day of combined Omega 3 ingredients in the fish oil are required for this response, which may be delayed for two to three months before results are fully realized.(3)
A systematic review that looked at the effect of marine fish oil on the pain of arthritic disease determined that it did in fact reduce pain in that population (4). An excellent source for references comes from the Australian NPS MedicineWise from April of this year. Over all it lays out a number of encouraging studies that can put another tool in the pharmacist’s toolbox for helping your RA patient.
Looking back to our “front store experience N of 1 world,” Omega 3 supplementation and joint pain relief always remind me of my 101-year-old customer who reminds me that she wouldn’t be moving at all without this supplement.
Graham MacKenzie is a compounding pharmacist in Baddeck, N.S., and a graduate of Dalhousie College of Pharmacy.
- Miles EA, et al. Influence of marine n-3 polyunsaturated fatty acids on immune function and a systemic review of their effects on clinical outcomes in rheumatoid arthritis. Br J Nutr. 2012 Jun;107 Supp; 2:171-84
- Emanuela Ricciotti Et. al . Prostaglandins and Inflammation. Arterioscler Thromb Vasc Biol .2001 May; 31(5):986-1000
- Rees D, et al Dose-related effects of eicosapentaenoic acid on innate immune function in healthy humans: a comparison of young and older men. Am J Cin Nutr. 2006 Feb;83(2):331-42
- Senftleber NK et al Marine Oil Supplements for Arthritis Pain: A systematic Review and Meta_Analysis of Randomized Trials. Nutrients 2017.
Stone’s Drug Store in Baddeck, Nova Scotia will no longer carry homeopathic products, citing a lack of clinical evidence about their effectiveness.
“Concerns have been raised about the effectiveness of homeopathic products,” said Graham MacKenzie, pharmacist and owner of Stone’s Drug Store. “This led me to review the clinical evidence and I came to the conclusion that these products should no longer be sold at our pharmacy.”
Homeopathy was founded in Germany in the late 1700s and is based on the principle that “like cures like”. The basic concept is that the substances that cause illnesses such as the cold, flu, sleep disturbances, allergies, headaches and baby teething discomfort, will, in diluted form help the body to heal the condition.
“While I can accept the merit behind “like cures like”, as this is the basis for many vaccines, the fact that these substances are so diluted raises concerns,” said MacKenzie. “If homeopathy products can relieve symptoms of so many conditions, how can it do so in such diluted concentration? Where is the evidence?”
Over the past twenty years, the Cochrane Database of Systematic Reviews has conducted reviews of the studies and trials of homeopathic treatments on seven different conditions and found a lack of evidence to support their effectiveness[i]. The Australian National Health and Medical Research Council came to the same conclusion in 2015, stating “[t]here was no reliable evidence from research in humans that homeopathy was effective for treating a range of health conditions.”[ii] Furthermore, the UK National Health Service stated in 2017 that there is “no clear or robust evidence to support the use of homeopathy.”[iii]
Homeopathy products do not require a prescription, are not classified as drugs by Health Canada and can be purchased in most pharmacies as self-selection in the over-the-counter aisles.
“As a pharmacist, my first priority is to provide a wide range of safe and effective health products but if I do not have a professional comfort level with a certain product, I have a duty not to sell it,” said MacKenzie. “I do not see the removal of homeopathic products as restricting the range of choice for patients. Rather, it is an invitation to discuss their health care concerns and to review other options that may be more appropriate, cost-effective and successful for them.”
Stone’s Drug Store had carried five homeopathic products – two for cold and flu, two for sleep and one for teething. These products are no longer available there.
Stone’s Drug Store is located in Baddeck, Nova Scotia. It is a full-service pharmacy that includes a compounding lab to tailor medicines to the needs of patients. Graham MacKenzie has been a pharmacist for 25 years.
June 17, 2017 : looking back hardly a day or two goes by since this year began when a question about medical marijuana or as we call it out here “marijuana” and what is going to happen next July when it becomes real is asked. Last month I was asked by a group of Nurse Practitioners to present on a topic I rarely speak about but fill prescriptions for often – BioIdentical Hormone Replacement Therapy. I like to use the term supplement instead of replacement but it really made me think about the tough upward climb this category has had and continues to have based on a few position statements from such groups as SOGC and NAMS.
Looking at the marijuana issue, never before have we seen a couple of ingredients leap onto the potential healthcare market with the claim to relieve or cure so many, many health issues. Never before have so many N of 1, anecdotal reports driven an entire category of mostly unproven therapies. Granted there are some valuable uses of the drug that have been used for years but many have been very overblown with the main selling point of “no one has died”.
Turning to my upcoming presentation, I started mulling over the studies that have shown for years the benefits and limitations of all types of hormone therapy that I have collected and still continue to collect on the topic. Speaking to the public on a subject is different than talking to medical professionals. I speak to both groups all the time on all topics. To narrow down an hour worth of meaningful, compelling, convincing data that flows easily on a medical treatment that is foreign to a professional group so that you don’t lose them is daunting.
If I present on a topic I have a clear conflict of interest with such as this, I always open with that and some literature from the other side of the argument. There is no problem here with BHRT as lots of naysayers exist. In truth, I have found there are as many cases of overblown promises with BHRT and there are complete opposite downplay of any proven benefits and exaggeration of adverse effects. A segment from Climacteric from just this year was the best I could find that slammed this type of therapy over a dozen sentences. We now see less of an issue with the term BioIdentical, since estrogen and progesterone are both found in the commercial prescription drug industry in Canada more and more in a bioidentical form, especially since the Women’s Health Initiative Study over a decade ago that effectively stopped conjugated equine estrogen and medroxyprogesterone acetate from being dispensed overnight. So at least Big Pharma has caught up with compounding in some ways.
I continue in my talk to disprove the issues just laid out from the climacteric slide: that hormones do pass predictably through human skin and give resultant increases in the body (given the correct fluid is tested), that the stability of the hormone in the right base is predictable, that saliva testing is legitimate and useful in showing levels of active hormones (especially for topically applied hormones), and that all hormone therapies have benefits and risks associated with them, regardless of what hormone therapy that entails.
Given the criticisms the WHI received, one thing we did find from the CEE/MPA regimen was the decrease in fracture risk. With the older average age of the subjects in that study and the lack of topical hormone or actual BHRT used, there is very little to pull from that study for this talk. There are however many studies that can and do show the benefit of BHRT. Most of these are smaller studies than we are used to in the prescription world. One point to take away though is we have seen a top seller in our prescription market fall away to nothing and the public is looking at us and asking how could we be so wrong all these years about something that was so blatantly clear in a study that it cut the study short? Evidence slowly grows on bioidentical hormones but is showing even to our commercial drug industry that it is a safe benefit.
The International Journal of Pharmaceutical Compounding published a three part study on the topic of BHRT. In this small study, surveys were given to women on HRT. The response rate was 70 on BHRT and 53 on synthetic hormone therapy. Each survey consisted of 15 questions that probed such topics as symptom relief, reasons for starting hormone therapy, side effects, age of starting therapy and type of therapy. In the areas of hot flashes, night sweats, sleep quality, dry skin/hair, vaginal dryness, foggy thinking, mood swings and decreased libido, bioidentical therapy outperformed synthetic therapy in all counts. In side effects from therapy, bioidentical was preferred over synthetic for side effects like difficulty sleeping, weight gain, breast tenderness, bloating, upset stomach, breakthrough bleeding, foggy thinking, mood swings and leg pain. Drowsiness occurred more frequently with bioidentical than with synthetic.
A huge concern with bioidentical and compounded hormones is the threat of cancer in hormone therapy. In 2008 a study that looked at over 80,377 post menopausal women, 2354 of them developed invasive breast cancer. Compared to the women that never used HRT, estrogen alone therapy was associated with a 1.29 fold relative risk, 1.69 with estrogen/progestagen and a relative risk of 1 with the estrogen/progesterone women.
In other studies we have seen the benefits from BHRT in areas of insulin resistance, blood pressure, lipids, endothelial function, arteriosclerosis, thrombotic risk, and neuroprotection. More and more we are seeing studies unfolding showing not only is BHRT a healthy and safe option for women of all ages but is also brings quality of life to these patients that they have lost since the Women’s Health Initiative Study came out. Saliva testing for topicals is also shown to be useful as topically applied hormones aren’t reflected in blood draws like oral is. Oral hormone therapy has shown itself to be an unhealthy route for women and topical application has proven itself to be the preferred choice longterm.
So yes, thank you Marijuana, or more correctly CBD:THC. Your very sudden rush to the market has been touted for virtually every medical issue going right now. There are definite benefits in areas such as pain, perhaps PTSD (and a few others) but completely untested and unproven “benefits” in so many other areas. It has shown us that there are areas like BHRT that we’ve been told we had zero proof for but really do have volumes of proof when we compare it to the complete lack of proof in marijuana for many of the areas it is being used for.
Orozco ,P. et al. Salivary Testosterone is associated with higher lumbar bone mass in premenopausal healthy women with normal levels of serum testosterone. European Journal of Epidemiology 16:907-912,2000
Wright, JV. Bio-Identical Steroid Hormone Replacement. Selected Observations from 23 years of Clinical and Laboratory Practice. Ann.N.Y.Acad.Sci. 1057:506-524 (2005)
Hofling, M, MD et al. Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women. Menopause:The Journal of The North American Menopause Society. Vol 14, No.2, pp 183-190
Holtorf, MD. The Bioidentical Hormone Debate: Are Bioidentical Hormones (Estradiol,Estriol, and Progesterone) Safer or More Efficacious than Commonly Used Synthetic Versions in Hormone Replacement Therapy? Postgraduate Medicine, Volume 121, Issue 1, January 2009
Schwartz, E.T. MD. Hormones in Wellness and Disease Prevention: Common Practices, Current State of the Evidence, and Questions for the Future. Prim Care Clin Office Pract 35(2008) 669-705
Deleruyelle, LJ. Menopausal Symptom and Side Effects Experienced by Women Using Compounded Bioidentical Hormone Replacement Therapy and Synthetic Congugated Equine Estrogen and/or Progestin hormone Replacement Therapy: Part 3 . International Journal of Pharmaceutical Compounding Jan/Feb 2017 pp 6-16
Stephenson, K. MD FAAFP. Salivary Hormone Profile. International Journal of Pharmaceutical Compounding vol 8 no 6 November/December 2004
Wepler, ST. A Review of Bioidentical Hormone Replacement Therapy. International Journal of Pharmaceutical Compounding Vol.6 No.2, March/April 2002
For Information Only, For Those on Frisium/clobazam. Re: SHORTAGE SITUATION. Letter posted online June 4, 2016
Canadian League Against Epilepsy I Ligue canadienne contre l’épilepsie
Clobazam Shortage?Suggestions for Management of Pediatric & Adult Patients with Epilepsy
June 4, 2016
There are shortages of clobazam, generic and brand name (Frisium). The situation has worsened during the past month reaching a crisis level.
Health Canada arranged a teleconference on June 3, 2016 to discuss the clobazam supply situation. Canadian League Against Epilepsy members participated in this meeting to convey the serious implications of a widespread clobazam shortage for patients with epilepsy.
Improvements in the clobazam supply are expected by late June to early July. Apotex Inc., the major supplier of clobazam in Canada, will be returning to regular supply levels. Several batches of Apo-Clobazam are expected to be released to wholesalers during the last two weeks of June.
Also, there should be additional Frisium (brand name clobazam) in the coming weeks from Lundbeck LLC.
There may continue to be some serious supply problems during the next three to four weeks. It is hoped that efforts will be made to identify sources of clobazam in the drug supply chain in order to protect patients.
Clobazam is a Level 1 Critical Drug for patients with epilepsy, according to the Canadian Pharmacists Association classification.
Prescribers asked to switch a patient from clobazam to an alternate drug, due to the shortage, should first request that the patient’s pharmacist double check all supply avenues to obtain either the same formulation or an interchangeable form (generic or brand) of clobazam. In addition to regular wholesalers, pharmacists can explore if supply is available from other wholesalers, other pharmacies or directly from one of the manufacturers.
All supply avenues should be exhausted before a patient who has been stabilized on clobazam is switched to an alternate drug. A decision must be made more quickly if the patient has minimal supply remaining to prevent interruption in therapy.
Clobazam is a 1,5-benzodiazepine with a long duration of action and has been marketed as an antiseizure drug in Canada for nearly 20 years. This medication is commonly used to treat epilepsy.
Interruption or sudden discontinuation of antiseizure drug therapy can cause a loss of seizure control, or worsening of a patient’s condition, with significant short- and long-term implications for patient safety, independence and quality of life. Breakthrough seizures can have potentially fatal consequences.ii
There are additional concerns related to this particular drug shortage. Sudden discontinuation of clobazam can cause benzodiazepine withdrawal syndrome.iii Abrupt discontinuation of clobazam may exacerbate seizures and cause other benzodiazepine withdrawal symptoms.iv Abrupt withdrawal of clobazam can also put patients at risk of life-threatening status epilepticus.v
Suggestions for Patient Management During the Clobazam Shortage
Patients who require de novo treatment?In patients who require de novo treatment with an antiseizure medication during the clobazam shortage, physicians should consider whether an alternative medication could be used at least initially.
Patients currently taking clobazam?If all supply avenues have been exhausted and there is no clobazam available, an alternate medication should be substituted until clobazam can be resupplied to the patient.
The following rationale for the selection of clonazepam as an alternative medication to clobazam during a drug shortage is from a document written by J.C. Martin del Campo, MD, FRCP and Jorge G. Burneo, MD, MSPH in 2013vi:
From the benzodiazepine group, only two other drugs have been found useful for the chronic management of seizure disorders: nitrazepam and clonazepam.
While there is no published evidence of efficacy under the circumstances, the most reasonable substitute for clobazam is clonazepam.
It is not known if this will be efficacious in all patients or if the recommended equivalent will result in a decompensation of the seizure disorder, but it is reasonable to surmise that it may prevent the development of a withdrawal state resulting in status epilepticus. Any given dosage will need to be carefully monitored by the prescribing physician and adjustments made where necessary.
While making these recommendations, it is hoped that the health authorities and pharmaceutical companies will protect the public by urgently implementing a strategic plan that will prevent such shortages from occurring. It is imperative to be reminded of the potentially fatal consequences of breakthrough seizures.vii
Reproduced with permission from del Campo and Burneo.
Recommendations for Therapeutic Substitution of Clonazepam for Clobazam
Clonazepam (brand name Rivotril) is a 1,4-benzodiazepine. This medication is available as an oral tablet in 0.25 mg, 0.5 mg, 1 mg and 2 mg formulations.
ClonazePAM and cloBAZam have similar lipophilicity and protein binding therefore likely very similar CNS penetration.
Clonazepam is more potent than clobazam. It is at least 10X more potent than clobazam if not ?20X, therefore, 1 mg of clonazePAM may be similar in potency to 10 mg of cloBAZam but could be as potent as 20 mg of cloBAZam.viii
Following conversion to clonazepam, some dose titration may be required to achieve the desired therapeutic effect. Clinical judgement is necessary to determine the optimum dose for each patient.
Patients should be carefully monitored for changes in seizure frequency, as well as the emergence of any adverse effects (excessive sedation, ataxia, increased difficulty handling secretions, worsening liver function) following the switch. ClonazePAM causes more sedation than equipotent doses of cloBAZam and tolerance may be more likely to develop to its antiseizure activity.
The excipients and non-medicinal ingredients between formulations may be different so caution should be exercised in patients with known hypersensitivity to excipient. These, along with any differences in adverse event profiles, can be verified in the appropriate Product Monographs and labels. The Product Monographs are available from the Health Canada Drug Product Database.ix
ADULTS? Initiate at 0.5 mg clonazePAM for every 10 mg clobazam (1:20)x; in 3-5 days, in the absence of adverse effects, increase to 1 mg clonazePAM for every 10 mg clobazam if required, to a maximum of 3 mg clonazepam/day.
Consider initiating clonazepam with a simultaneous gradual tapering of cloBAZam by 5-10 mg/week if supply allows.
PEDIATRICS?Initiate at 0.5 mg clonazePAM for every 10 mg clobazam (1:20); direct substitution can be made, tapering of clobazam is not mandatory. Dose titration, up or down, should be based on patient response.
Dose increases in pediatric patients, if required, are typically 0.25-0.5 mg/day every 5-7 days to a maximum of 0.1 mg/kg/day (or 0.2mg/kg/day for patients on enzyme-inducing drugs)xi
SENIORS, PATIENTS WITH LIVER DISEASE OR PATIENTS ON MEDICATIONS THAT INHIBIT P450-3A4 Initiate clonazepam at lower dosages in the elderly, in patients with liver disease, or in patients who are currently on medications which inhibit cytochrome P450-3A4.
Drug Metabolism and Pharmacokinetics
CloBAZam and clonazePAM are primarily metabolized by CYP 3A4. CloBAZam’s active metabolite, N- desmethylclobazam, is primarily metabolized by CYP 2C19. When substituting clonazePAM for cloBAZam, a thorough drug interaction assessment should be done taking these metabolic paths into consideration.
Information and Support for Practitioners and Patients
Should practitioners have reservations or concerns about the clinical management of their patients with epilepsy during this shortage, they should consult their nearest neurologist with epilepsy expertise or comprehensive epilepsy centre.
Patients and caregivers can contact their local Canadian Epilepsy Alliance agency for information and support by calling 1-866-EPILEPSY (1-866-374-5377).
i “Level 1 Critical Drug: Drug therapy for disease is essential and cannot be interrupted for even one dose or one day.” From: Canadian Pharmacists Association (2010), Drug Shortages: A Guide for Assessment and Patient Management www.pharmacists.ca/cpha-ca/assets/File/cpha-on-the-issues/DrugShortagesGuide.pdf?ii Steinhoff, B.J., et al. (2009) Substitution of anticonvulsant drugs. Ther Clin Risk Manag., 5, 449–457. www.ncbi.nlm.nih.gov/pmc/articles/PMC2701486/pdf/tcrm-5-449.pdf
iii Frisium Product Monograph (2015) iv ibid
vii Steinhoff, B.J., et al. (2009) Substitution of anticonvulsant drugs. Ther Clin Risk Manag., 5, 449–457.?viii Sankar, R. et al. (2014) Clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series. J. Med. Case Rep., 8: 429. www.ncbi.nlm.nih.gov/pmc/articles/PMC4302143/pdf/13256_2014_Article_3028.pdf?ix Product monographs are available for download from the Health Canada Drug Product Database: www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php?x Benzodiazepine equivalence table http://www.benzo.org.uk/bzequiv.htm (accessed May 16, 2016)?xi Farrell, K. and Michoulas, A. (2008) Benzodiazepines. In J.M. Pellock et al. (Ed), Pediatric Epilepsy: Diagnosis and therapy, 3rd Edition. Demos Medical Publishing, New York, page 559.?xii Brodie, M.J., et al. (2016) Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study. Epilepsy Research 123, 68-74.?xiii ibid?xiv Comparison of benzodiazepines http://www.vhpharmsci.com/vhformulary/tools/benzodiazepines- comparison.htm (accessed May 18, 2016)
|Drug||Benzodiazepine Group||Active Metabolite||Half-life of parent (hrs)||Half life of active metabolite (hrs)|
v Engel, J. (2013). Seizures and Epilepsy, 2nd Edition. Oxford University Press, New York, page 557.?vi Del Campo, M. and Burneo, J. (2013). Therapeutic alternative to clobazam: Medical recommendation for adults with epilepsy. Retrieved from Epilepsy Ontario website: epilepsyontario.org/wp- content/uploads/2014/01/Clobazam_Therapeutic-alternative-for-adults_Jan2013.pdf
Who is it that really makes the final call on what your treatment is for any of your medical conditions? Most would say their doctor. As a pharmacist however I see something different. It is common to see a patient come to the dispensary counter after their physician has already phoned to see if a first choice drug is covered. Maybe I call the Doctor after I see the prescription and tell them the patient’s plan doesn’t pay for that choice. I see people go without therapy that used to be covered but isn’t anymore. OTC meds are often considered for the most part as “off the radar” for these plans, as if OTC means something useless or not Doctor or Pharmacist recommended. It is often frustrating for medical professionals to feel like their hands are tied and that they are being told what to write for. Newer and more expensive medications that may have obvious benefit over older drugs may be left out in the cold for lengthy waits until a plan decides to cover them. As well, unrealistic hoops may be required to be jumped through before an effective one is covered. It is not uncommon for refills to be made for an unused and ineffective drug that is not taken for weeks or months to show a plan that a drug is being “tried” in order to get the next one approved. Meanwhile the patient suffers needlessly until the more effective one is paid for by the plan. Slow prior approval processes can become mired down in a way that has patients waiting needlessly for letters from physicians, OT’s, and other specialists.
Unbeknownst to the rest of the world is the strangle hold these plans have on pharmacies. While it is true that pharmacies fill more prescriptions when patients have third party plans, it becomes a profit based on volume that puts big chain pharmacies that avoid smaller communities at an advantage and smaller more community minded independents out. Gone are the days when pharmacies had some say in their dispensing fee, now a four letter word to the public but the main way dispensaries make money. Pharmacies used to be and should be able to run based on their pharmacy sales but not so much any more. dispensing fees don’t cover the cost of filling a prescription for most pharmacies. For the first time we are now seeing a decrease in dispensing fees. It has become a take it or leave it contract.
Small communities that have relied on the donations of these strong businesses have seen this drop off or eliminate altogether, reducing spinoff benefits. Keep in mind that small independent pharmacies have a more timely and positive response to the types of charity requests seen daily. Preferred provider contracts give lower prescription prices at specific chains, something that used to be illegal. The drop in pharmacy revenue causes front store prices to climb and customers find themselves paying for services that they assumed should be for free, like tax receipts, refill extensions, med reviews, calling the doctor and consultations – things that we are accustomed to getting gratis.
So, physicians are somewhat dictated to, pharmacies are told their price for what they are selling and who is it that controls your health? Of course there are benefits. Most wouldn’t afford the healthcare they have without their plan and that plan is a business that deserves to have some control over its own costs. It should not be a dictatorship that slowly undermines our entire healthcare model.
The Value of a local Independent Pharmacy
It’s difficult to find anything for free these days. I see bills for such things as faxing to a local number, photocopying, corking fee to open wine bottles at a function, cutting up a cake, supplying year end receipts, filling out health insurance forms, consultations, supplying information, It is also difficult to have a donation request responded to without a waiting period for most people.
So what does a pharmacy do differently? (especially a small town or independent pharmacy). Well we give volumes of donations to local causes after weekly and sometimes daily requests. Quite often we give you your year end tax receipts free, call your doctor for free, fax your form to your drug plan (after we have filled it out for you), talk to you on the phone for 10-15 minutes at a time or sit down for even longer about your health concerns for free. In my area I am the only pharmacy and often a temporary charge medications if a patient doesn’t have the money, I do public speaking for free for anyone who asks. I do glucose and cholesterol tests for free, make deliveries daily to our nursing home and supply free INR tests to their residents as needed, and OTC counselling off and on all day long. Most people assume many of these things are done readily for free by their local pharmacy. Other services eek their way out as well, like a 45 minute grocery store tour to help people eat better http://www.stonespharmasave.com
While it is true that pharmacies charge a dispensing fee for filling a prescription, it is that one fee that fuels most of these other daily contributions and tasks. Keep in mind that some pharmacies charge for some of these services and some do not. As well, lots of businesses do stuff for free. Should I be charging for all of these services? Some would say yes. The local independent pharmacy that sticks out its neck and serves the small community that bigger name pharmacies don’t go is invaluable to the community in more ways than just a place to fill prescriptions.
When I am asked to “prove” something by showing a study, it reminds me of how backwards we can be when it comes to stacking studies against each other to make a point. We come up with rebuttals like, “the patient size was too small”, “the study is too old” and “the study wasn’t double blinded”. In fact, virtually every study that has ever been done can be debated for some reason or other. As well, it is safe to say that not much has ever been proven of any value or consequence by just one study alone.
Let’s say that a colleague and myself have a disagreement on whether or not chromium has the ability to prevent hypoglycemia. This can start out with a quick exchange of some handpicked positive and negative outcome studies that may be well designed or not or maybe had the power to determine the outcome or not. Maybe a study hid some of the data or the statistical analysis was done improperly. Maybe my colleague had 10 times as many studies compared to mine. Is that what decides the outcome of all of these scientific studies? That one person can scrounge up more studies than someone else? How does that person explain a well-designed study that doesn’t back up his or her argument? Do they quietly pass off the study as a fluke or placebo effect or do they start to see what scientific study is for us – many studies that create a whole picture much like individual pieces of a puzzle make a picture.
Let’s say we have a puzzle. It is a puzzle of a field of green grass on a sunny day with blue sky and some white clouds. It turns out that this picture is a picture of a rabbit sitting in the field, only a very small part of the picture, less than one percent is taken up with the rabbit. This translates into just 2 pieces of the 500 piece puzzle. Let’s say my colleague and I divide the puzzle in two and each take half of the puzzle home with us. We separately lay out the pieces and get a vague idea about what the picture shows. It turns out I have both pieces that make up the rabbit, statistically not what we would expect but it happened. I call my colleague and tell him about the picture we are looking at and how it appears to be one with a rabbit in the field. He says, “that’s crazy, there’s no rabbit in this picture”. He said he’s looked at all of his pieces and no evidence of any rabbit.
So who is correct? Well based on what is in front of each of us, we are both correct. When we both meet to put the puzzle together on one table, the entire picture becomes clear. The puzzle changes from a field on a sunny day to a rabbit on a sunny day. Each piece of the puzzle is a scientific study.
This exercise shows us what the power of a study means, or an analysis of many studies can show. For an infrequent result, the amount of pieces that are required to find the rabbit are large. My colleague arrived at what would be called a negative result and mine was a positive result. In a book called Statistics Done Wrong, (Alex Reinhart) it is described that in a review of studies between 1975 and 1990 in prestigious medical journals, almost a third of these studies yielded negative results. A full 64% of these studies didn’t have the power to determine a 50% difference in the primary outcome they were looking for between treatment groups. When a 25% difference was present, a full 84% of studies didn’t have the power to find this.
As always, I believe that scientific studies are the best thing we have to unlock what we do not know. One study however, can be deceiving when taken as a single data point on a graph. Scientific studies are a group effort.
Lately we have heard stories of Pharmacists not doing their job correctly. To be exact, in a survey of a sample of pharmacies, it was discovered that medications that are kept in the pharmacy but did not need a prescription, there was insufficient or completely absent counselling on behalf of the pharmacist. These medications are in a special class in that they can only be sold in a pharmacy, behind the counter of the dispensary, and the customer must ask for the medication in order to be screened for interactions with existing medications and medical conditions, as well as proper use of the medication so that it is safely used and gives the best results.
Although there were arguments that the sample size used in this observation was too small to make an overall conclusion, just 50 pharmacies, and that the study was not scientific, showing even one pharmacy not counselling this type of medication is not good. As pharmacists we don’t shoot for a certain percentage of jobs done correctly across the country in the run of a day. We more importantly look at any incidence of improper counselling and try to better ourselves by looking at why we didn’t do our job correctly. Undoubtedly spurred on by a few recent reports of dispensing errors across the country, this survey began in BC and spread across the country based on the results in that one province. Trust me, when a pharmacist makes a mistake, it hits them like a ton of bricks, regardless of the outcome.
This nationally broadcast report was fuelled by a week long buildup that caught the eyes of pharmacists and general public alike. Word began to spread in the New Year about the story and certainly when it finally came to air, there was a huge reaction from those who watched it. Many pharmacists chimed in. Initially claiming unfair reporting in that it made pharmacists look completely inept. Others claimed that the story completely avoided the good that pharmacists do that is totally ignored for the most part. This was followed by examples of what we do as pharmacists every day. The reporter afterwards quickly claimed that the show was more about quotas imposed on pharmacists to increase script count than exposing pharmacists not doing their job correctly. It was certainly a perception of mine leading up to the program and certainly after watching the program that the latter was the case.
As someone that works for an independent in a small community, the concept of pressure imposed by quotas for increased prescription count is definitely foreign to me and one I must admit I had never heard of before. Pharmacists interviewed for the program claimed that this pressure to increase script count was responsible for other parts of their job slipping, including counselling these behind the counter medications and focussing properly on the filling and checking process. Let’s suppose this were true, and maybe it is. Then obviously it is something eroding pharmacy that needs to be addressed. These pharmacists interviewed pointed to the problem of non pharmacists now able to own pharmacies – something new over the last couple of decades. The profession of pharmacy is certainly not against change, but the change we have seen over the last 20 years has absolutely lead to great things, but in some cases has also lead to the erosion of the profession.
Before I graduated from the College of Pharmacy in 1993, things were strict. You kept things professional by not being able to advertise “free prescription delivery”, you couldn’t connect any incentive to a prescription like “points” for your prescription purchase or bonuses for transferring your prescription file to a pharmacy, you couldn’t say “accurate prescription filling” because it was unprofessional and implied someone else had inaccurate prescription filling, among other strict rules. Gradually, we saw big box stores start to include incentives to their employees when they had their prescription filled at their banner, then drug plans that are affiliated with the pharmacy with restrictions that you are covered when you get your prescription filled only at that pharmacy chain and no other. While on the subject of third party plans, in my opinion the most dramatic effect overall in the pharmacy business today, we have seen a very gradual undermining of the pharmacy business because dispensing fees and reimbursement to pharmacy from the third party plan has not grown with what is reality in dispensing. Dispensing has become a volume business in order to show a real profit. In fact we are starting to see decreases in dispensing fees from third party plans. In a lot of ways I feel these plans are a part owner in my business.
A sweeping move initiated by provincial governments across the country was a huge hit to the bottom line of pharmacies, like Nova Scotia’s Fair Drug Price Act. A move that seemingly made sense to the general population in that it aimed at lowering prescription prices by coming up with an imaginary dollar value for various popular generic medications, regardless of what the pharmacy paid for it. This move came about from the practice of generic companies giving rebates for purchases, a common practice in many types of business. The government saw this as their money. These were the main dollars we used to run the programs of our pharmacy and the dollars we used for donations and community programs that came to us for help. Very quickly this money was gone. In effect, this attempt by the government to lower prescription drug prices was accomplished on the backs of the pharmacies in the provinces. Our communities are now realizing the effect of lack of income in their community pharmacies. Before too long, we saw other third party plans jump on this bandwagon, and gone were more dollars we used to run health programs we conceived on our own for the health our community.
Enter the expanded scope of practice. We as pharmacists were allowed now to write prescriptions in certain cases of minor ailments, extend existing prescriptions, do med reviews, injections, adaptation of prescription, and order and interpret lab tests. The reason was we can charge for these services to make up for what we were losing on the other end with rebates. Definitely this is an honourable theory: make money for actually doing something that helps with the health of our patients. The problem being that there was now no money to run these new services anymore and most plans weren’t on board with paying for them .
One might argue, “then why not just drop your affiliation with third party plans?” Then we could set our own prices bases on our own pharmacy needs and staff levels . Small town low volume stores could have better control over their income and not allow third party plans to control what they earn on a prescription. Instead of getting paid 12 dollars for a prescription that costs 15 dollars to fill, you could charge what you paid for the drug and a fee that allows the dispensary to make money on its own regardless of the front shop. Well we do this because it allows our patients to afford their medications and they probably fill more prescriptions for their health when they have coverage, not to mention that all pharmacies not dropping plans means patients shop for pharmacies that take these plans.
This brings us back to the original issue of why are we dropping essential counselling and why are we too busy to catch interactions? Well perhaps the pressure we should be looking at isn’t the pressure to fill more prescriptions, it’s the pressure imposed by third party plans on the pharmacy whereby they don’t make enough on each prescription to pay for itself in the first place. Maybe this is the reason for the “quota” being imposed on pharmacies to fill more. The lack of reimbursement forces any pharmacy to scratch for more prescriptions since they cannot afford to hire the staff to run these extra programs and give time to the pharmacist to do their work of not only bettering health, but preventing harm from meds.
To top off the issue of missed interactions because of lack of time, consider the thought process involved with each and every prescription when the possibility of the patient dying from the medication exists each time a prescription is filled. The side effect of any medication is death and there are so many side effects and potential warnings on any given medication it would take an hour to explain them all to each patient. On top of that, the sheer volume of prescription interactions with other meds or disease states makes the evaluation of these interactions an art that is not just based on book smarts, but also on clinical experience. If there is a 0.00001 chance of a dangerous interaction occurring do you call the doctor, alert the patient and change the drug? Is the evaluation of these interactions a black and white science or is it based on followup with the patient on their overall health and history. Recently I wrote a blog on a type of interaction called prolonged QT interval ( https://stonespharmasave.com/blog/?p=694 ) that describes the complex evaluation involved with just one interaction. There are thousands of such interactions to evaluate for each fill and you reset your brain when you fill the next prescription. If I give you a prescription there is a very slight chance you might leave the pharmacy, take the medication, have an adverse reaction or interaction with another medication and die. Perhaps I will be on the evening news for not telling the patient this. Do I tell you this? Not necessarily. But if I evaluate the probability of this reaction occurring then I am in a better position to act on it. When we take off in an airplane do we sign off on the fact that it might crash? There is inherent risk in taking any medication. It’s our job to make sure you have the best possible medication and outcome from that medication.
Getting back to the lack of counselling in these behind the counter medications – guilty. We accept that. The more pharmacy and pharmacies are left to be run by corporations (big box stores and third party plans) and not pharmacists, the more and more this profession will erode and show up on more undercover specials.