Obesity is a chronic disease that is affecting masses of individuals. It is often associated with morbidity and early mortality. Like any other chronic disease, it often requires long term treatment. The causes of obesity vary. It could be a genetic disposition, a habit acquired because of surrounding environmental factors, or a habit acquired while compensating for another problem or issue. Obesity is not always caused by the intake of excessive food. Physical exercises and dieting are used as mechanisms to combat obesity.

Obesity has increased drastically in the last four decades, with a third of the population in developed countries being obese. Clinical options for treatment are used. The drugs used for treatment alter or help control weight in individuals. However, drug mono-therapy (using one type of drug to treat an ailment) is having adverse side effects on those affected and slower results. The combination of drugs is a preferred alternative. These drugs will either alter appetite or metabolism, or do both when used together. They also alter the absorption of calories in the body. Obesity medications are rare and the most commonly known are orlistat (xenical), romonabat (acomplia) and sibutramine (meridia) (National Institute of Diabetes, 2007).

Orlistat is the only medication approved by the US Food and Drug Administration (FDA) for long-term treatment of obesity (National Institute of Diabetes and Digestive and Kidney Diseases., 2007). Sibutramine was retracted because of causing side effects associated with the cardiovascular system. No serious effects have been reported from the use of weight loss medications. These medications should be used by those in serious medical risk because of their obesity and not for beauty. Earlier clinical mono-therapy treatments had a higher percentage of failures and weight regain cycles. Drug combination clinical tryouts, have shown 3-5% weight loss from placebo effect, followed by a higher percentage of weight loss and control from the effects of the medications.


History of combined weight-loss drugs

The use of medication to help in weight loss is a very old practice dating back to the second century AD. A Greek physician, Soranus of Ephesus, used elixirs to help his patients stay lean and healthy. In the 1920s and 1930s, new treatments began to emerge. Thyroid hormone became a popular way to treat obese people with euthyroid which caused difficulty while sleeping and palpitations. In 1933, dinitrophenol was used with the side effect of warmth and sweating. DNP fell out of the market in 1938.

In the late 1930s, amphetamines became popular for weight-loss. Phentermine was approved in 1959 and later in 1973, fenfluramine. Fen-phen became the most common prescribed medication for dietary purposes. Dexfenfluramine was developed in the mid 1990s but was later retracted. Fen-phen was among the first combinations to hit the market and it was effective and popular. Later, ephedrine was combined with caffeine and acetylsalicylic acid. After this, many medications were developed to help in weight loss.

Most of the available medications suppress appetite. This gives the patient a feeling of having eaten a lot or decreasing his appetite. They decrease appetite by increasing the levels of serotonin or catecholamine in the brain (these brain chemicals affect appetite and mood). Other prescription weight loss medications are Diethylpropion (Tenuate, Tenuate dospan), Mazindol (Sanorex, Mazanor), Phendimetrazine (Bontril, Plegine, Prelu-2, X-Trozine), Pramlintide, Naltexone, Metreleptin, 5-HTP (5-Hydroxytryptophan)/ Carbidopa, and Phentermine (Adipex-P, Fastin, Ionamin, Oby-trim). Dexfenfluramine (Redux) and Fenfluramine (Pondimin) were withdrawn. Weight loss drugs should be prescribed to people with a Body Mass Index (BMI) above and those with a BMI of above 27 coupled with obesity related illnesses like diabetes (type2), high blood pressure and high levels of fat in the blood or dyslipidemia.

Prescription drugs used to treat other conditions are also used to treat obesity, though mostly short term. These drugs include depression treatment drugs like buropion, seizure drugs like topiramate and Zonisamide, drugs that treat diabetes like metformin. These drugs are often used off label. This means that they can be prescribed by a doctor to treat conditions that may not have been particularly specified by the FDA. Drug combonation is yielding better results than mono-therapy.

Fenfluramine, a serotonergic drug, has been used widely as an appetite suppressant. Some SSRIs (selective serotonin reuptake inhibitors) also have properties similar to this. Some work has demonstrated drugs acting at particular 5-HT (5-hydroxytryptamine) subtypes of receptors having effects on food intake. Fenfluramine, either alone or with phentermine, has been the most widely prescribed appetite suppressant. Phentamine is derived from amphetamines and has an extra methyl group.

Mechanisms of action

The combination of the depression treatment drug bupropion with naltrexone causes inhibition in dopamine and nor-epinephrine reuptake. This is done by bupropion. POMC (proopiomelanocortin) is stimulated by the bupropion and the naltrexone blocks the opioid receptor. This will prevent the automatic inhibition of β-endorphin on the POMC pathway (Halpern et al., 2010).

Bupropion can also be combined with the seizure treatment drug Zonisamide. In this combination, the buoropion also inhibits the reuptake of dopamine and nor-epinephrine which stimulates POMC, at the same time, the Zonisamide raises the levels of dopamine and serotonin which also inhibits AgRP (Agouti-related peptide) and also stimulates POMC. A lot of POMC is stimulated with this combination (Halpern et al., 2010).

Phentermine can be combined with 5-HTP (5-Hydroxytryptophan)/ Carbidopa. The phentermine increases the release of nor-epinephrine while the 5-HTP inhibits the conversion of 5-HTP to serotonin. This conversion is peripheral. The inhibition will reduce the chances of nausea. The 5-HTP gets to reach the CNS (Central Nervous System) and is transformed to serotonin while there (Halpern et al., 2010).

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Topiramate which is a drug for seizure treatment can be combined with phentermine. Nor-epinephrine release is increased by the phentermine while the topiramate increases the rate and levels of thermo-genesis and fat oxidation. It also reduces appetite. Pramlintide and Metreleptin can be combined too. The pramlintide, through a mechanism called amylin analog will increase the feeling of satiety subsequently reducing food intake. The Metreleptin will reverse weight loss effects in expenditure of energy. This is through a synergistic action done with pramlintide in anorexic related CNS signaling (Halpern et al., 2010).

Before the retracting of sibutramine, it could be combined with pramlintide. Through amylin analog, pramlintide gives the feeling of satiety and reduces the intake of food while the subutramine would inhibit the uptake of nor-epinephrine and serotonin. The synergistic action with pramlintide will also signal the CNS anorexigenically. Pramlintide can also be combined with phentamine which increases nor-epinephrine release. Pramlintide in turn increases satiety through amylin analog and makes food intake levels lesser.

Combinations that are off label have been done too. Orlistat and sibutramine were combined which gave the result of using sibutramine alone. The uptakes of serotonin and nor-epinephrine were inhibited. Orlistat and metformin were combined with no benefits especially in women who were non-insulin resistant. Some combinations have not been studied yet like the combination of orlistat and nor-adrenergic drugs and phentermine and 5-HTP/ Carbidopa. Clinical tries have suggested good results with the latter combination (Halpern et al., 2010).

Combined therapy for treatment of obesity has its advantages. There is a higher chance that this treatment will be efficient because of synergic action. The effects of the drugs on their own are not as great as when they are used in combination. The internal reactions yielding effective results (endogenous synergism) are enhanced and promoted. The combination of medication helps beat the coping mechanisms that the body has when one drug's effects are felt. For instance, the carvings that may come up as a result of reduced appetite from a drug like pramlintide are rebuffed be a drug like metreleptin.

Combinations help deal with the side effects. Prescribing drugs with opposite effects will work well for the patient.  For instance, the combination of Phentermine with 5-HTP/Carbidopa helps reduce the chances of nausea. This will increase the tolerability if the medication and treatment. Combining low doses will reduce the chances of occurrence of adverse side effects. A drug with adverse side effects could be reduced in dosage and supplemented with another in w low dose (Halpern et al., 2010).

Drug combination has its disadvantages too. The chances of increased side effect incidences are higher due to medication interaction. These side effects include sleeplessness, pulmonary hypertension, dizziness, headaches, high blood pressure, stuffy nose, trouble sleeping, nervousness, valvular disease, euphoria, gas with discharge, anxiety, increased bowel movements, constipation, oily discharge, dry mouth, oily stools, and temporary loss of bowel control (Healthtree.,2010). The cost of treatment is high and some who really need it may not be able to afford it.

Before an individual chooses medication for treatment of obesity, he should familiarize himself with the risks involved so that he can be prepared to cope with any problems. This knowledge will help the patient pinpoint any problems with the treatment and its effects on him. It will also increase the chances of the treatment being successful. One of the risks is that the patient runs the risk of potential dependence or abuse of the drugs. Other than orlistat, all the other medications for obesity treatment are controlled substances. Doctors should be careful when writing prescriptions and especially to patients with a history of substance abuse like alcohol or drugs.

Patients should also be careful of the fact that they may develop tolerance to the drugs. When the patient continues to gain weight during ongoing treatment, it is a sigh of having developed tolerance. The medication may have reached its limit on effectiveness. The patient may also develop an attitude of viewing obesity as a choice rather than a chronic disease. This may make him stop medication while it is required that he continue with the treatment just like when treating other chronic diseases like diabetes.


Obesity is a multi-factorial and chronic condition. It should not be treated as a disease that affects those who are careless with their eating and living habits, but rather a condition that affects the population as a whole. An ideal obesity pharmacotherapy would be one where appetite is suppressed, thermogenesis is increased, metabolism is increased and absorption of fat is decreased. Chances are low that a single drug can have all these properties; combination is the best way out. It is a hard condition to beat and the advent of combined therapy treatment is one step up in the fight.

Medication for weight-loss treatment should be combined with nutritional and behavioral therapy to achieve the best results. Long-term results can only be achieved through consistency, discipline and hard work. These qualities should be imbued in the patient during behavioral therapy. The spread of obesity throughout the world especially in developed countries is alarming. This makes the development of new combined medical therapy treatments crucial to the comfortable existence of mankind.

There are limitations to the effectiveness of combined drug therapy. This implies that more medication is needed that will do more good to those in treatment. Although these drugs have mild side effects that may increase when the drugs are used in combination, the synergic acting of these drugs in different pathways while combating obesity is an added advantage that outweighs the side effects. These drug combinations can be altered to fit the patient's medical profile. It is quite an encouragement that weight loss drugs are yielding better results when combined.

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