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Long-term Phentermine Pharmacotherapy: An Investigation for Amphetamine-like Abuse

PotentialEJ Hendricks, FL Greenway, M Srisurapanont, EJ Hendricks, FL Greenway, M Srisurapanont,

SL Schmidt, D De Marco, MJ Hendricks, Y IstratiySL Schmidt, D De Marco, MJ Hendricks, Y Istratiy

Introduction: A commonly held presumption is that phentermine therapy can induce abuse or dependence, at a lower incidence rate, with similar symptoms, but of lesser severity than amphetamine and methamphetamine-induced dependence. No human data supporting these presumptions has ever been published. Intense cravings for amphetamine are a hallmark symptom of amphetamine abuse and dependence. If phentermine-induced abuse occurs, phentermine cravings could be expected to occur during long-term use. Methods: 117 patients phentermine-treated for 8.4 (±5.2) years with 53.4 (±19.5) mg/day (Long-Term Patients, LTP) and 152 patients phentermine-treated for 9.3 (±3.4) days with 34.5 (±9.5) mg/day (Acute-Term Patients, ATP) were examined. LTP were interviewed using Module K (Non-alcohol psychoactive substance use disorders) of the Mini International Neuropsychiatric Interview (MINI) modified for phentermine, then examined using the Severity of Dependence Scale (SDS) modified for phentermine, and Tiffany’s 45-question cocaine craving questionnaire modified for phentermine (PCQ). ATP were examined with SDS and PCQ. SDS and PCQ scores were analysed using Mann-Whitney U tests.Results: Based on the MINI, no LTP had phentermine abuse or dependence. SDS mean total scores were not significantly different: LTP 0.42 (±0.75); ATP 0.50 (±0.91), P = 0.528. (Typically SDS scores for amphetamine-dependent subjects are >4.) PCQ total mean scores: LTP 1.93 (±0.64); ATP 2.25 (±0.71), P <0.001, but ATP>LTP, reverse the ratio expected if phentermine induced cravings.Conclusions: Patients treated with phentermine for averages of 8.4 years and 53.4 mg/day had no sign of amphetamine-like abuse or dependence. Long-term phentermine treatment did not induce phentermine cravings.

In 1959 when the US FDA approved phentermine for treating obesity the only evidence that phentermine could induce abuse or addiction came from studies in rats. The facts that rats “liked” phentermine, that phentermine is a stimulant, and that phentermine is a substituted phenethylamine with a structure similar to amphetamine led to the presumption that phentermine abuse and addiction might occur. Although there was no evidence of human addiction potential, the US DEA decided phentermine should be classed as a category IV controlled substance. After 53 years of widespread use, phentermine addiction has never been reported. Nor have there been reports of investigations of the human addiction potential for phentermine. Phentermine is a mild stimulant. A few laboratories have reported finding phentermine in samples from long-haul truck drivers and in subjects in drug treatment programs, but absence of clinical reports suggests phentermine abuse, if it indeed occurs, is rare. We used validated modern addiction medicine metrics to examine phentermine-treated patients for signs or symptoms of amphetamine-like abuse, addiction (psychological dependence), or phentermine cravings. Cravings for the drug or substance in question are now considered a hallmark sign of abuse or addiction.

To examine patients treated with phentermine long-term for signs of phentermine abuse, addiction (psychological dependence), or phentermine cravings

ABSTRACT

BACKGROUND

OBJECTIVE

METHODS

These data strongly suggest that long-term phentermine pharmacotherapy for obesity for up to 21.5 years and at doses up to 112.5 milligrams per day does not induce abuse, or addiction (psychological dependence), and that long-term phentermine pharmacotherapy does not induce phentermine drug cravings. These data suggest fears of causing addiction with long-term phentermine are exaggerated and present a needless barrier to better care for overweight and obese patients worldwide. 

CONCLUSIONS

DEMOGRAPHICS

RESULTS

RECRUITMENTRECRUITMENT

Mini International Neuropsychiatric Interview (MINI): a structured interview guide for making a DSM-IV-TR diagnosis of mental disorders, including substance dependence and abuse. Module K, for diagnosing non-alcohol psychoactive substance use disorder (MINI-SUD), was used and modified by restricting questioning to phentermine. Severity of Dependence Scale (SDS): a Likert-type (score 0-3), five-question psychometric scale used for assessing the severity of substance dependence was modified by replacing the word “drug” with “phentermine.” Cocaine Craving Questionnaire NOW (CCQ-NOW): a seven-point Likert-type (score 1-7) forty-five-question psychometric scale originally developed for assessment of cocaine drug cravings, but also used for methamphetamine cravings in methamphetamine dependent subjects, was modified for phentermine by replacing the words “cocaine” and “coke” with “phentermine,” to create a PCQ-NOW.

REFERENCES

Patients were recruited in two cohorts from a private fee-for-service obesity medicine specialty practice. Overweight, obese, and weight loss maintenance patients in this practice are typically treated with anti-obesity drugs long-term. Patients were recruited for the Long-Term Phentermine-treated (LTP) cohort if they had been treated with phentermine for a minimum of one year while patients for the Acute-Term Phentermine (ATP) cohort were recruited after they had been on phentermine for 7 to 14 days.

All patients were 18 years of age or older; there were no other age restrictions. Patients who had taken cumulative phentermine drug holidays exceeding 60 days in the previous 12 months or who had taken any drug holiday in the previous 30 days were excluded from the LTP cohort. Patients with current Axis I psychiatric diagnoses were included provided these were stable and under treatment. Patients with dependence on drugs other than nicotine were excluded since phentermine was not prescribed for such patients.

Beginning in August 2011, patients newly started on phentermine were recruited for the ATP cohort as they appeared for follow-up examinations after 7 to 14 days of treatment. At the same time eligibility of returning patients for inclusion in the LTP cohort was determined as the patients appeared at the clinic. Those eligible were invited to participate. Few ATP and LTP eligible candidates declined participation.

This clinical trial is registered at clinicaltrials.gov as NCT01402674.

  APT (N=152) LPT (N=117)

  Mean (SD) Mean (SD)

Age, Years 44.18 ±12.39) 51.18 ±11.40)

BMI 34.88 (±7.31) 33.79 (±7.59)

Treatment Duration 9.30 (±3.35) D 8.35 (±5.16)Y

Rx Range (Days/Yrs) 4 – 22 Days 1.1 – 21.5 Yrs

Phentermine (mg/d) 34.46 (±9.23) 53.43(±19.46)

Dosage range (mg/d) 15 - 93.75 18.75 – 112.5

Office examinations   72.1 (±51.7)

Rx hiatus < 1 month   117 (100%)

Rx hiatus > 1 month   70 (60%)

Avg. Rx hiatus (mo)   19.5 (19.9)

Mini International Neuropsychiatric Interview (MINI-SUD)

MINI-SUD interviews for each of the 117 LTP patients examined were negative for phentermine dependence or abuse.  

Severity of Dependence Scale (SDS)LTP patients’ mean SDS scores were slightly higher, 0.50 (0.91) than the ATP patients’ mean scores, 0.42 (0.75) but the difference was not significant (p = 0.528).  

Phentermine Craving Questionnaire – NOW (PCQ-NOW)

Total scores for the LTP patients were significantly lower than the corresponding scores for the ATP patients. (p<0.001) Domain scores were also significantly lower: desire (p=0.002), lack of self-efficacy (p<0.001), compulsivity (p<0.001), and relief (p=0.017)

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