Long-term Phentermine Pharmacotherapy: An Investigation for Symptoms of Dependence, Cravings, or Withdrawal

Phentermine, an amphetamine congener, is the most widely used anti-obesity drug in the U.S.
Although phentermine is the agent-of-choice among physicians specializing in obesity
treatment, the use of this drug for obesity treatment by other physicians has long been
curtailed because misapprehensions regarding phentermine safety. Concerns of
phentermine-induced adverse cardiovascular reactions and of phentermine-induced addiction
are two fears that have had a profound negative impact on phentermine prescribing. Although
warnings of high incidence rates of adverse cardiovascular and psychiatric effects are
included in FDA labeling and are often repeated in published reviews, the few clinical
reports in the peer-reviewed medical literature of such adverse effects are anecdotal. Fear
of phentermine adverse effects does not inhibit the use of phentermine by obesity treatment
specialists. A 2008 survey of prescribing practices found that 98% of bariatric medicine
specialists used pharmacotherapy in treating obesity and that 97% of those prescribed
phentermine as their first choice.

The fear that phentermine has addiction potential appears to be a factor influencing
curtailment of use. At the time that phentermine was approved in 1959 the expectations were
that it would prove to be addicting, although perhaps less so than amphetamine. These
expectations were based on the chemical structural similarities between phentermine and
amphetamine and on evidence in rats that phentermine stimulated spontaneous activity. No
evidence suggesting the drug had human addiction potential appeared in clinical trials
conducted prior to approval.

After 52 years of use there is no evidence in the peer-reviewed medical literature to
support the hypothesis that phentermine has significant human addiction potential. Research
in addiction medicine has undergone significant development in the last 50 years. Concepts
of addiction have shifted from an early focus on tolerance and withdrawal to a current
emphasis on the psychological components of dependence. Drug addiction has been redefined as
drug dependence and standardized diagnostic criteria have been adopted for drug abuse,
dependence and withdrawal. Psychometric testing methods have been developed, validated, and
applied clinically for measurements of dependence, drug craving, and withdrawal for a wide
variety of substances of abuse including cocaine, heroin, and amphetamine.

Until recently, none of these addiction medicine metrics had been used to study the
addiction potential of phentermine. Presumably, since phentermine is an amphetamine
congener, any clinical characteristics of dependence or withdrawal should mimic those of
amphetamine dependence or withdrawal. One recent retrospective study investigated symptoms
occurring when patients treated with long-term phentermine in a weight management program
abruptly ceased taking phentermine. The study found that patients on long-term phentermine
who ceased phentermine abruptly by their choice did not have an amphetamine-like withdrawal
symptom complex. Significantly there was no evidence of phentermine cravings. Further
investigation is warranted.

The addiction potential of a drug may be investigated by measuring the drug's propensity to
induce dependence, to induce cravings for the drug, and for cessation of the drug to induce
characteristic withdrawal symptoms. In the case of amphetamine withdrawal symptoms appear
very quickly reaching a maximum at 48 hours after drug cessation.

In this prospective study the addiction potential of phentermine will be assessed with
validated psychometric scales to examine patients who have taken phentermine long-term for
two years or more. Patients who have taken phentermine for 7 to 14 days will also be
assessed. Participating patients who have taken phentermine long-term in this study will be
asked to interrupt phentermine therapy for 48 hours to participate in the study. Scale
examinations will be conducted at 24 and at 48 hours after drug cessation.

Hypotheses

1. Long-term phentermine-treated (LPT) patients do not develop phentermine dependence or
cravings.

2. LPT patients who cease taking phentermine abruptly do not experience amphetamine-like
withdrawal symptoms.

Specific Aims

1. To compare the severity of phentermine dependence and craving between LPT patients and
acute phentermine-treated (APT) patients

2. To compare the severity of stimulant withdrawal symptoms before and after phentermine
cessation in LPT patients.

3. To examine the prevalence of phentermine dependence in LPT patients