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Weight Management

Current Use Of Phentermine In A Multi-Modal Weight Loss Program

​Purpose Of Weight Management

One corollary to dealing with patient desires to become more healthy is the treatment of the current epidemic of obesity [5]. I have practiced bariatric medicine [8] since 1995 including wide experience in the use of various weight loss medications.

Regardless of hormone imbalance, and such co-existing issues as fatigue and hair loss, people come to see me primarily for weight loss. They are horrified by their own appearance and their inability to drop weight. About a third of the US population is obese, with associated increased risks of hypertension, dyslipidemia, diabetes, cardiovascular disease, osteoarthritis, and some cancers [5,9,10,11].


An increase in weight is associated with a linear increase in systemic inflammation [12]. Recent data from large-scale studies indicate that only a moderate weight loss is sufficient to provide substantial health benefits [13]. Therefore, regardless of the perceived issue of vanity, weight control has profound health benefits. Helping the patient maintain weight loss, also maintains the health benefit!

My Weight Loss Program Essentials

The goals of my program (as printed in the new patient pamphlet given to each patient) are:● Achieve an optimum level of health, including dropping excess fat stores● To maintain weight loss indefinitely
The following 6 techniques are utilized to achieve these goals:● Weekly monitoring to drop weight efficiently, provide patient safety, and educate. Monthly monitoring indefinitely to maintain weight loss. No charge is made for either of type of these visits.● High-protein, low-carbohydrate nutrition.● Hydration adequate to promote diuresis of fat break-down products.● Cardiovascular exercise daily.● Resistance training twice weekly.● Weight-loss medications, amino acid supplements, and hormone supplementation as indicated and appropriate.

Barriers To Effective Weight Management

Barrier #1. Obesity is a chronic and stigmatized disease [33]. The public, including many medical professionals (MD’s & Pharmacists included!) perceive that obesity is caused by a personality defect.
“Obesity is stigmatized and the obese are perceived as lazy, lacking willpower, and being less motivated than others. In a survey on societal views of obesity, students at Michigan State University indicated that they would prefer marrying a cocaine user, a shoplifter, or a Communist over marrying an obese person. The non-obese majority, having no difficulty controlling their weight, finds evidence for the character weakness of the obese in everyday life.” [14]Accusations of gluttony have not been substantiated in a number of studies. In particular, the Human and Nutritional Evaluation Survey I (HANES I) [15] which surveyed, among other things, the eating habits of 20,749 individuals across the USA, found that the obese actually ate less than their normal-weight counterparts. To lose weight and to maintain a reduced weight by means of caloric restriction, these individuals must reduce their food intake even further in relation to energy expenditure. In order to reach and maintain a normal weight, many are forced to live with chronic hunger. Enduring this level of discomfort on a long-term basis is often more than the patient can bear and the weight is regained.
The regaining of lost weight tends to occur not only after the stopping the weight loss medication but following the cessation of any weight control intervention whether that involves diet alone, protein supplemented fasts, exercise, jaw wiring, surgery, or other means. Thus, return back toward baseline weight is a normal response of the body, and not related just to medication [16].

Barrier #2. Weight loss medication is held to a higher standard in defining the desired outcomes than are other medications. The view that obese people need ‘only to close their mouths’ has caused us to demand a higher standard for medication use in treating obesity than we do for treatments of any other chronic condition. We accept the fact that serum cholesterol values will rise following the cessation of statin therapy. We accept that intraocular pressure rises when pilocarpine treatment is stopped because we understand that glaucoma can be controlled but not cured. Even in the absence of a cure, patients and physicians still view ocular medication, hypotensive agents, a cholesterol-lowering medication, as valuable. All of these failures to cure a problem of dysregulation in human physiology are acceptable. But, obesity is the only analogous clinical situation where the failure of medication to achieve a cure is unacceptable [14].

Barrier #3. Phentermine has a tarnished reputation because of its structural relationship to amphetamines and because of inappropriate prescribing by a few “pill doctors”. Of course, the appropriate use of this medication is as one component within a program of behavior modification, nutritional counseling, and exercise recommendations. Physician contact and monitoring are vital [16].

Barrier #4. There is an inappropriate fear of phentermine and its potential abuse by patients. Both short and long term studies have not validated these concerns. It is exceedingly rare for a patient receiving phentermine in a reasonably supervised program to demonstrate even psychological dependence. However, some patients may need the medication in combination with supportive amino acid supplements on an ongoing basis in order to maintain weight loss [16].
Although the majority of the published studies have run for no more than 12 weeks, there are a number of studies that have run for longer periods of time. These studies indicate both the safety and effectiveness of phenylethylamine weight loss medication [17,18]. Goldstein and Potvin [19] cite literature reports of the continuous safe use of phenylethylamine weight loss medication for 14 to 60 weeks. In addition, these review articles summarize the well known adverse effects of the phenylethylamines as adapted from Bray [20].
Side effects generally common to Schedule III and IV phenylethylamines are: nervousness, sleeplessness, headaches, dizziness, nausea, and constipation. With conservative starting doses and cautious modification upward, depending upon a patient’s clinical response, even these listed side-effects can be avoided in most cases.
In 1992, Michael Weintraub, MD [21], of the University of Rochester School of Medicine, published a study using phenylethylamines for up to three and one-half years in the treatment of obesity. In this study, patients utilizing active medication lost more weight than those on placebo. There was no tolerance or drug dependence noted and relatively few side effects.
The Drug Abuse Warning Network (DAWN) in 1998 surveyed 471 hospital emergency departments for drug-related visits and 141 medical examiners in 42 metropolitan areas for drug-related deaths. The emergency department report covered 542,544 drug abuse episodes in hospital emergency rooms and 10,123 drug abuse-related deaths submitted by medical examiner reports. None of the scheduled anorectic agents met the minimum of 200 mentions needed to be included in the emergency department table listings for 1998.No Schedule III or IV weight loss drugs are mentioned in the top 60 drugs cited in the 10,123 deaths reported by medical examiners in the 1998 DAWN reports. Amphetamines and methamphetamines were reported in 884 (8.73%) and phenylpropanolamine in 30 (0.3%) of the fatal episodes.
DAWN data for 2002 shows anorexiants to be mentioned in 1,408 of 102,810,000 (0.0014%) ED visits. This represents 0.23% of all drug abuse mentions in the 2002 report and represents a 48.7% decrease in total mentions of anorexiants since 1995.
Richard & Lasagna [22] cite the Griffiths, et. al., [23] review of the literature on five Schedule III and IV weight-loss drugs and concluded that they were all associated with relatively low or zero abuse: “Clinically, all of the latter five compounds have anorectic properties...there are, however, relatively few cases reports involving abuse of these drugs.”
Considering the large amounts of Schedule III and IV weight-loss drugs that have been used, both in the USA and abroad, the reported incidents of serious side effects noted are low indeed and in some of the case reports, it is impossible to establish for certain that the weight loss drugs are the primary causes of the incidents [16].

Barrier #5. Outdated information and rigid adherence to product insert information discourage appropriate “off label” use of phenylethylamine Schedule III & IV weight loss medication.

Until 1999, phentermine labeling had not changed significantly since 1974. The original labeling with its recommendations dating from 1974, was generally based on short term studies (12 weeks or less) and was the result of negotiations between the drug companies and the FDA [24]. The studies on which this labeling was based include about 200 double blind studies which were analyzed by Scoville of the FDA. These indicated weight loss of about one pound per week with the phenylethylamines vs. ½ pound per week with the placebos. Using the phenylethylamines for only a “few weeks” may indeed make the results “trivial.” However, if there ever was justification for the “few weeks” label, it was based on the studies of 20 years ago that were run for only a “few weeks.” Since that time, a number of long term studies, as noted previously, have been completed and testify to both the efficacy and safety of the anorectics when used on a long term basis. A number of members of the American Society of Bariatric Physicians have had patients on anorectic treatment for time spans measured in multiple years without significant side effects occurring [16].

The North American Association for the Study of Obesity has stated in their Guidelines for the Approval and Use of Drugs to Treat Obesity [25], “Tolerance is a misnomer if a drug continues to have a sustained effect in maintaining a lower body weight. As long as a drug helps to maintain a reduced weight level it should be considered efficacious, even if no further additional weight loss occurs. Continuation of the drug should depend on maintaining a beneficial balance between the health benefits of the maintenance of weight loss and the side effects of the drug.” (Emphasis mine)

Albert Stunkard [26], Professor of Psychiatry at the University of Pennsylvania Medical School, argued as early as 1982 that “appetite suppressants” act primarily by lowering the body weight set point and only secondarily by suppressing appetite. The evidence, he contends, does not support the development of tolerance to the anorectics. He concludes, regarding appetite suppressant medication, “use it on a chronic basis or not at all.” He later stated in his excellent, The Salmon Lecture-Some Perspectives on Human Obesity [27], the following:

“For many years it has been established practice to prescribe appetite suppressant medication for only limited periods of time. The evidence for this belief is obscure, and a set point interpretation of tolerance makes clear its limitation. In terms of body weight, tolerance to appetite suppressants does not develop, which means that the old argument against their use (a loss of efficacy) is no longer valid. These agents retain their efficacy. Paradoxically, it is precisely this maintenance of efficacy that argues against their short term use.”

“If any benefits of appetite suppressants are lost when the medication is discontinued, then such medication should not be used on a short term basis. Current policy appears to be diametrically opposed to rational use of appetite suppressant medication, and current practice appears wholly unwarranted. Furthermore, the myth of tolerance seems to have prevented use of appetite suppressants in precisely those situations in which they are indicated, that is over the long term.” (Again, emphasis mine)

“There are strong positive indications for the long term use of appetite suppressants. Many obese hypertensive and diabetic patients can control their conditions by weight loss. Unfortunately, however, many of them cannot lose weight by diet alone. As a result, they are forced to rely on long term use of medication to control their hypertension, diabetes, and other conditions. If these patients must receive long-term medication, they may well be better off on appetite suppressants than on the usual remedies. At the very least, weight loss will control their complications in a more physiologic manner. Over the long term, the risks of treatment with appetite suppressant medication may be less than those of the medications they are now taking. Long term studies of the safety of appetite suppressant medication are needed. If they can be shown to be safe, major changes in the treatment of obesity-related disorders could result.”

A number of studies (10-16 months duration) have suggested that phenylethylamine weight loss medication can be given for periods of up to several years with reasonable safety and without weight regain occurring [17].

Patients in this category will go to the pharmacy to pick up weight loss medication and will be seen not to be obese. Pharmacy staff should not be presumptuous and assume inappropriate use!

Even though use of long term and combination anti-obesity medications does not appear in FDA approved labeling of the drugs involved, it is consistent with the AMA’s policy of off-label use [28]. It is the consensus of the American Society of Bariatric Physicians that “short term” labeling for anti-obesity pharmacological agents should be updated. However, since there are insufficient monetary incentives for long term pharmaceutical studies of generic anorectics this is unlikely to occur [16]. (Again, emphasis mine)

Although not described in approved labeling, it may be appropriate to use anti-obesity agents in combination with one another or with other medications (e.g. anti-depressants), which has been described in various articles, books and shared clinical experiences. Such use is consistent with the FDA policy as elucidated in the FDA Drug Bulletin, April 1982:

“Use of Approved Drugs for Unlabeled Indications.Food and Drug Administration Drug Bulletin, 1982, no. 12, pages 4-5.

"The appropriateness or legality of prescribing approved drugs for uses not included in their official labeling is sometimes a cause of concern and confusion among practitioners.

"Under the Federal Food, Drug, and Cosmetic (FD&C) Act, a drug approved for marketing may be labeled, promoted, and advertised by the manufacturer only for those uses for which the drug's safety and effectiveness have been established and which FDA has approved. These are commonly referred to as 'approved uses.' This means that adequate and well-controlled clinical trials have documented these uses, and the results of the trials have been reviewed and approved by FDA.

"The FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such 'unapproved' or, more precisely, 'unlabeled' uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.

"The term 'unapproved uses' is, to some extent, misleading. It includes a variety of situations ranging from unstudied to thoroughly investigated drug uses. Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations. Before such advances can be added to the approved labeling, however, data substantiating the effectiveness of a new use regimen must be submitted by the manufacturer to FDA evaluation. This may take time and, without the initiative of the drug manufacturer whose product is involved, may never occur. For that reason, accepted medical practice often includes drug use that is not reflected in approved drug labeling.

"With respect to its role in medical practice, the package insert is informational only. FDA tries to assure that prescription drug information in the package insert accurately and fully reflects the data on safety and effectiveness on which that drug approval is based."

To repeat: The package insert “is not meant to establish or reflect the applicable standard of care, does not contain or set forth a standard of care, and is not a practice guideline.” [30]

“FDA approved indications were not intended to limit or interfere with the practice of medicine.” [43] “Off-label use does not imply an improper use and certainly does not imply an illegal use or a contraindication based on evidence.” [44] “It is undisputed that the prescription of drugs for unapproved uses is commonplace in modern medical practice and ubiquitous in certain specialties.” [45] In fact, prescriptions of off-label uses of drug “may account for more than 25% of the approximately 1.6 billion prescriptions written each year, with some recent estimates running as high as 60% [46].

Keep in mind that a medication's manufacturer composes information such as the package insert as part of the FDA's regulatory scheme. This information is not created to establish a medical standard of care but rather is required for a manufacturer to market, advertise, and promote a medication [31]. The purpose is to theoretically limit the manufacturer's exposure to tort liability for a medication [31]. Understanding this background is the first step to effectively dealing with this information. “The approved indications for a drug can be driven as much by politics and business as by medicine.”[42]

Barrier #6. Many physicians, because of a lack of guidelines, fear regulatory retaliation. Comment by ASBP: “Unfortunately, fear of confrontation with regulatory agencies is often a barrier to the appropriate use of controlled drugs. However, since the introduction of the original Anorectic Usage Guidelines in 1990 and in light of recent medical and scientific research and opinion, several state medical regulatory agencies have changed previously outdated and antiquated policies overly restricting or banning anorexiants. As a patient advocate, the American Society of Bariatric Physicians is proud to have been the first major organization to lift the torch of enlightenment to the medical community and state agencies regarding modern day pharmacological treatment of obesity.” [16]

The Role Of Phentermine

Phentermine acts to release the neurotransmitter, norepinephrine, from neuronal stores [37]. Norepinephrine is synthesized from tyrosine at nerve terminations, stored in granules and released in the synaptic cleft to act on post-ganglionic receptors. After they act on those receptors, the monoamines may be deactivated through catechol-O-methyltransferase or to undergo reuptake by the same granules [34]. One major effect of saturation of norepinephrine nerves by norepinephrine is appetite suppression [35]. As well, phentermine causes an outpouring of epinephrine from the adrenal glands resulting in an increase of peripheral energy expenditure [35]. Included in this effect is a breakdown of fat stores [36].
To repeat: Two phentermine effects resulting in weight loss are appetite suppression and breakdown of fat stores.
Because of the above-described effects, a long-term result of the daily use of Phentermine is the relative depletion of norepinephrine stores. L-Tyrosine is taken daily to replete norepinephrine stores and L-Cysteine is utilized to create a more efficient conversion of L-Tyrosine into norepinephrine [38]. Norepinephrine and serotonin are in dynamic balance. Thus, 5-HTP is utilized to create serotonin, since giving L-Tyrosine alone can cause a depletion of serotonin [39].
Typically, L-Tyrosine and L-Cysteine are each administered in 500 mg capsules 3 x per day. However, Tyrosine can be delivered in larger doses, up to 1500 mg 3 x per day to produce norepinephrine stores. Cysteine on the other hand acts as a catalyst and doses need not be increased. In fact, smaller doses of Cysteine work just as well, but are not commercially available [38]. The use of these amino acids allows the weight loss benefits of Phentermine to become extended over time.
Another technique to be used in tandem to extend the weight loss benefits of phentermine is to cycle its use, taking a 4-week break periodically. The weight maintenance use of phentermine does not require cycling.
How is phentermine used and in what doses? Patients are initially given mild to moderate doses on a BID schedule and adjusted according to patient response. Again, patients are to monitor weekly but are encouraged to immediately report side effects or any concern whatsoever. Doses typically range from 15 mg once or twice daily to 30 mg twice daily, as tolerated and benefit noted. However, I have patients who do not take phentermine at all due to either preference or intolerance. Since the 8 mg tablet has been unavailable for almost 10 years, I have several patients who will subdivide a 15 mg capsule to create a tolerable dose. On the other hand, I have two patients (out of hundreds) who take 37.5 mg tablets 3 x per day. The dose varies according to patient benefit and tolerance. One dose does not fit all regardless of what you read in the product insert.
Regarding doses of phentermine prescribed, the American Society of Bariatric Physicians conducted a survey of its members in the Fall of 2007 and the Spring of 2008. The results were published in the Journal, Obesity in March of 2009 with a detailed report also published in the Jan-Feb, 2009 issue of the ASBP News [40,41].
97% of respondents used phentermine in their practice. Only 16% limited phentermine to 12 weeks or less. 52% of respondents used phentermine with patients for an unlimited period of time. The average low dose used was 15 mg, and the average high dose was 56.25 mg. About 20% of respondents stated that their highest dose is 75 mg daily. (Emphasis mine)
The issue of “Short-term; Adjunct” and “short-term monotherapy” have been dealt with earlier in this document. (top of page 5) Also: “Advances in medication discovery suggest that novel molecular entities that target 2 different neurochemical mechanisms, that is, “combination pharmacotherapy,” will yield efficacious antiobesity medications with reduced adverse side effects.” [50,52]
An example of a combination therapy that does not cause heart valve injury nor PPH is the use of Phentermine along with Fluoxetine [51]. As well, the amino acid 5-HTP is a precursor of serotonin, and the use of it does not cause valvulopathy. The new 5-HT2C receptor agonist, Lorcaserin (trade name Belviq), has not caused valve injury.
Back in the 1990s, Fenfluramine caused valvular injury via activation of the numerous valvular “serotonin 2B (5-HT2B) receptors by norfenfluramine, the major metabolite of fenfluramine.” [50]
So, Fenfluramine was removed from the market. Phentermine was not associated with valve injury, and it remains today the most popular weight loss medicine, as well as the safest.
“The use of sympathomimetic appetite suppressants and serotonin-selective reuptake inhibitors (SSRIs) has been questioned due to anecdotal reports of serotonin syndrome. A survey of bariatric physicians using these medications in clinical practice did not find any cases of serotonin syndrome among 1174 patients. The monitored use of the combination of these medicines by trained practitioners is justifiable.” [53]
In fact, there are no studies that directly link phentermine only usage to Primary Pulmonary Hypertension or valvular heart disease [48]. “There is no evidence that phentermine causes valvulopathy. Phentermine is the most widely used anti-obesity drug. In view of the serious cardiovascular risks associated with obesity, it is important to clarify that phentermine is a safe and effective anti-obesity medication.” [49]
Phentermine does not release serotonin in therapeutic doses. Phentermine acts to release the neurotransmitter, norepinephrine, from neuronal stores [37].
Inappropriate condemnation of Phentermine has occurred saying that “tolerance” to its effects occurs after a relatively short period of time, at which point, naysayers state that use of the medicine should be abandoned in such patients.
Response: Tolerance to weight loss maintenance effect of phentermine does not occur (See “Barrier 5", pages 3-4; middle of page 7). When tolerance to weight loss production occurs, and further weight loss is sought, I agree, discontinue phentermine while simultaneously continuing the restoration of norepinephrine neuronal stores via supplementation of L-Tyrosine.54 The motivated patient may re-start phentermine with the production of weight loss in 4 to 8 weeks. Effective dose varies from patient to patient as described on page 7, the last 2 paragraphs.

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