Clinical trial NCT01402674: Long-term Phentermine Pharmacotherapy: An Investigation for Symptoms of Dependence, Cravings, or Withdrawal
Official title: Long-term Phentermine Pharmacotherapy: An Investigation for Symptoms of Dependence, Cravings, or Withdrawal
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Phentermine Withdrawal
Keywords: Obesity treatment
Phentermine
Withholding treatment
Phentermine dependence
Lead sponsor: Center for Weight Management, California
Sponsor class: OTHER
Collaborators: name: American Society of Bariatric Physicians
First posted: 2011-07-26
Enrollment: 269
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: Inclusion Criteria:

1. Aged 18 years or older.
2. Duration of phentermine treatment

   1. For LPT patients, on phentermine pharmacotherapy consecutively for 2 years or more and willing to take a drug holiday for 48 to 72 hours.
   2. LPT Patients who have taken drug holidays on their own during the most recent 2 years may be included provided there has not been a holiday in the 90 days prior to matriculation in this study.
   3. For APT patients, on phentermine pharmacotherapy for 7 to 14 days at 37.5 mg/day or less.

Exclusion Criteria:

1. Patients with confirmed Axis I psychiatric conditions including depression, ADHD, SAD, bipolar disorder, substance abuse disorders (except caffeine and nicotine) and patients taking drugs for any of these conditions, including anti-depressant drugs, drugs for ADHD and lithium.
2. Patients who were taking phentermine in combination with any other anti-obesity drug.
3. Patients who are taking medications such as beta-blockers, which may modulate the stimulant effect of phentermine.
4. Pregnant patients, nursing mothers, patients with uncontrolled hypertension, hyperthyroidism, severe cardiovascular disease, glaucoma, and known hypersensitivity to phentermine -

Primary outcomes:
measure: Signs or symptoms of phentermine dependence (addiction)
timeFrame: Long-term cohort subjects on phentermine 2 years or more.
measure: Signs or symptoms of phentermine dependence (addiction)
timeFrame: Short-term cohort subjects on phentermine (APT) for 7 to 14 days.
Secondary outcomes:
Other outcomes:
Locations:
city: Roseville
country: United States
facility: Center for Weight Management
state: California
city: Sacramento
country: United States
facility: Center for Weight Management
state: California
Study officials:
affiliation: Center for Weight Management
name: Ed J Hendricks, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hendricks EJ, Greenway FL. A study of abrupt phentermine cessation in patients in a weight management program. Am J Ther. 2011 Jul;18(4):292-9. doi: 10.1097/MJT.0b013e3181d070d7.
citation: Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring). 2011 Dec;19(12):2351-60. doi: 10.1038/oby.2011.94. Epub 2011 Apr 28.
citation: Hendricks EJ, Rothman RB, Greenway FL. How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring). 2009 Sep;17(9):1730-5. doi: 10.1038/oby.2009.69. Epub 2009 Mar 19.
citation: Kampman KM, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, D'Angelo L, Epperson LE. Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav. 1998 Jul-Aug;23(4):449-61. doi: 10.1016/s0306-4603(98)00011-2.
citation: McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM. The nature, time course and severity of methamphetamine withdrawal. Addiction. 2005 Sep;100(9):1320-9. doi: 10.1111/j.1360-0443.2005.01160.x.
citation: McGregor C, Srisurapanont M, Mitchell A, Longo MC, Cahill S, White JM. Psychometric evaluation of the Amphetamine Cessation Symptom Assessment. J Subst Abuse Treat. 2008 Jun;34(4):443-9. doi: 10.1016/j.jsat.2007.05.007. Epub 2007 Jul 13.
citation: Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: I. Reliability, validity and factor structure of a measure. Aust N Z J Psychiatry. 1999 Feb;33(1):89-93. doi: 10.1046/j.1440-1614.1999.00517.x.
citation: Tiffany ST, Singleton E, Haertzen CA, Henningfield JE. The development of a cocaine craving questionnaire. Drug Alcohol Depend. 1993 Dec;34(1):19-28. doi: 10.1016/0376-8716(93)90042-o.