International Journal of Obesity (1999) 23, 723±732 ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00 http://www.stockton-press.co.uk/ijo Synergistic interactions between Fen¯uramine and Phentermine PJ Wellman1* and TJ Maher2 1Behavioral Neuroscience Program, Texas A&M University, College Station, Texas 77843-4235, USA and 2Division of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115, USA `Fen-phen' refers to the off-label combination of the appetite suppressants fen¯uramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fen¯uramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may re¯ect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fen¯uramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity. Keywords: monoamine oxidase inhibitors; serotonin; drug-drug interactions; isobologram Introduction lost during treatment with an appetite suppressant is quickly regained when the drug is terminated. Weintraub et al 6 reported on a novel approach to Obesity remains a chronic disorder of increasing the pharmacological treatment of obesity using com- prevalence1 that contributes to early death and binations of appetite suppressants rather than tradi- health disorders.2 Moreover, obesity is known to tional monotherapy. This clinical trial employed a have considerable psychological costs in the form of combination of fen¯uramine (30 mg prior to dinner) ostracism and discrimination.3 These physical and with phentermine (15 mg in the morning) and com- psychological costs provide ample motivation for pared the weight reducing effects of this combination obese and near-obese persons to lose body weight. with that induced by fen¯uramine alone (20 mg ± 3 Among the obesity treatments developed and times per day) or phentermine alone (30 mg in the implemented over the last 50 y are behavioral mod- morning). Over a 24 week period, the combination of i®cation, exercise, dietary restriction, surgical low doses of these anorexic medications produced a approaches such as gastric stapling and=or banding, weight loss (8 kg) greater than that of placebo (4 kg), and pharmacotherapy.4 The latter approach involves but that was equivalent to the monotherapies (fen- the use of centrally acting drugs to suppress appetite ¯uramine alone or phentermine alone). Moreover, and reduce body weight5 and, more recently, agents fewer adverse effects were reported for the combina- that act peripherally to diminish absorption of dietary tion of fen-phen than for either drug alone. In 1992, fat from the gastrointestinal tract (for example, Orli- Weintraub et al 7 reported on a 4-y study that exam- stat). Many factors have contributed to resistance to ined the impact on body weight of a combination of pharmacotherapy including the beliefs that: obesity is phentermine with fen¯uramine. This study similarly not a disease but a psychological issue, that the noted that the fen-phen combination produced sub- effects of appetite suppressants are modest at best, stantial weight loss in some subjects and that this and that all appetite suppressants share common combination therapy could be used for as long as actions with the dangerous stimulant amphetamine.5 4y.7 Moreover, a major concern remains that any weight The fen-phen approach to pharmacotherapy was widely adopted following the Weintraub et al 7 pub- lication. Sales of each appetite suppressant soared and it is estimated that some 18 million prescriptions were *Correspondence: Paul J Wellman, Behavioral Neuroscience written for the fen-phen combination between 1992 Program, Texas A&M University, College Station, Texas 77843- and 1997.8 However, fen¯uramine and the active 4235, USA. E-mail: [email protected] enantiomer dexfen¯uramine (dexfen) were withdrawn Received 5 November 1998; revised 16 February 1999; accepted 3 March 1999 from the market in September 1997 following Fen¯uramine ± Phentermine synergism PJ Wellman and TJ Maher 724 mounting concerns that use of the fen¯uramines was will be less effective. Of greater interest is the associated with valvular disease9 and that appetite possibility that the two drugs will mutually amplify suppressant use has been associated with the devel- their respective clinical effects resulting in drug-drug opment of primary pulmonary hypertension (PPH: synergism. A synergistic combination produces a 10 ± 15). greater effect than that associated with the simple The use of fen¯uramine or dexfen¯uramine in sum of effects of both drugs alone. It is interesting to combination with phentermine was `off-label' in the note that synergism between phentermine and fen- sense that although each of these drugs had been ¯uramine was an issue raised by Weintraub et al 6 in approved for use in the treatment of obesity, the their original fen-phen study: FDA had not explicitly approved this combination `Our data also suggest a synergistic effect of the of drugs. The FDA had subjected each of these drugs two medications used together. The combination individually to varying degrees of scrutiny for safety treatment group showed a marked, sustained and ef®cacy. There was a presumption on the part of increase in total fullness whereas mean results some that one could rationally predict the safety and from participants receiving the other active treat- ef®cacy pro®le of the combination therapy from ear- ments remained near baseline and similar to the lier research studies using each monotherapy alone. placebo response. It appears that the combination As a consequence, there appear to have been no of half doses of two treatments that by themselves preclinical studies conducted to determine the safety have no effect, even in full doses, results in of the combination of a fen¯uramine with phenter- increased effects ± in this case total fullness.' mine. Unfortunately at the time of development of the (6: pages 1147 ± 1148.) fen-phen pharmacotherapy, our understanding of the pharmacology of fen¯uramine and of phentermine Synergism may apply not only to the clinical out- was incomplete while our understanding of the fen- comes of the fen-phen combination, but also to the phen combination was essentially nonexistent. adverse reactions associated with the combination. Thus, the primary emphasis of the present review is to consider the known synergism between the fen¯ur- amines and phentermine with regard to eating and Rationale for the fen-phen combination body weight, cardiovascular activity (valve disease There exist two different rationales for the fen-phen and PPH), and central nervous system activity. combination therapy. The ®rst is that a combination of low doses of two drugs that share a common clinical effect (for example, suppression of appetite) will summate to produce a desired clinical effect. Neuropharmacology of Fen¯uramine and Phentermine Because adverse side effects are usually a function of The FDA approved Phentermine in 1959 while fen- dose, combining low doses of different drugs should ¯uramine was approved in 1973. The assumption of ideally maintain the desired clinical effect (that is, most investigators was that fen¯uramine acted to those effects will add together) while reducing the reduce feeding by indirectly enhancing serotonin incidence of unwanted side effects. A secondary activity in brain.17 ± 19 Fen and=or its desethylated notion behind combining these two drugs is that metabolite (norfen) blocks the reuptake of serotonin fen¯uramine acts as a depressant while phentermine into axon terminals, and at higher doses releases 5-HT acts as a stimulant.16 Fen¯uramine is a racemic from presynaptic terminals.20,21 Thus, the net effect of mixture of two enantiomers, levofen¯uramine (levo- these actions is to increase 5-HT activity within the fen) and dexfen. Whereas, levofen has been shown to synapse, leading to suppression of appetite, and even- exert antidopaminergic (for example, sedative) activ- tually to weight loss. Additionally, Curzon and co- ity, phentermine has dopaminergic properties. workers22 have also suggested that fen¯uramine anor- Mixing phentermine with racemic fen¯uramine exia may partly re¯ect direct actions of fen at brain 5- would theoretically cancel out these dopaminergic HT receptors (for example 5 HT2c receptors). effects, so as to minimize patient complaints and Unlike fen¯uramine, phentermine has been viewed improve compliance. as a dopaminergic agonist similar in action and Fen-phen combination therapy, however, rests on mechanism to amphetamine.23,24 An emerging theme the assumption that the two drugs to be combined of the recent research literature is the realization that produce their