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Drug Evaluation

Naltrexoneforthetreatmentof obesity:reviewandupdate

Michael William Lee & Ken Fujioka

1. 2. 3. 4. 5. 6. 7. Background Role of opiates in feeding behavior: animal studies Role of opiates in feeding behavior: human studies Naltrexone as a potential obesity treatment Potential efficacy of naltrexone in combination with buproprion Summary Expert opinion

Scripps Clinic Center for Weight Management, 12395 El Camino Real, Suite 317, San Diego, CA 92130, USA

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of North Carolina For personal use only.

Since their discovery in the brain and gastrointestinal tract nearly 40 years ago, endogenous opioid peptides have been progressively shown to play a role in the regulation of food intake. Animal and human studies regarding opioid peptides and ingestive behavior are reviewed. While the opioid receptor antagonist naltrexone is associated with minimal weight loss as monotherapy, it does have potential utility in the treatment of obesity when combined with the pro-opiomelanocortin activator bupropion.

Keywords: bupropion, naltrexone, pharmacotherapy, weight loss Expert Opin. Pharmacother. (2009) 10(11):1841-1845

1. Background

Endogenous opioid peptides have long been known to influence eating behavior. The following review of animal and human studies will establish the relationship between opioid peptides and food intake. In addition, this article summarizes the current clinical data on the opioid receptor antagonist naltrexone as a potential obesity treatment.

2. Roleofopiatesinfeedingbehavior:animalstudies

The first evidence that opioid peptides had a role in eating behavior was discovered in 1979, when the opioid receptor antagonist naloxone was found to cause a significant reduction in short-term food intake in rats [1]. Subsequent animal studies have shown that , and receptors are involved in the short-term control of feeding [2,3]. It was, therefore, not surprising that the administration of opioid agonists generally enhanced eating behavior in animals [4,5]. Conversely, other rat studies have shown that the ingestion of palatable food activated -endorphin in the hypothalamus [6]. Increased -endorphin levels in cerebrospinal fluid were also documented in rats that drank sweetened solutions and water, but not quinine and salt [7]. Such findings have led to the opioid-palatability hypothesis, which posits that opioid release plays a role in the expression of food palatability, and vice versa [9]. Numerous experiments have demonstrated that the intravenous administration of naloxone will reduce short-term food intake in a variety of animal species, including birds and tigers [8]. Rat studies in particular have supported the aforementioned theory that opioids are involved in the enhancement of feeding through food palatability [9]. For example, naloxone reduced food intake with palatable diets and had a greater effect on the consumption of a sucrose-rich diet compared to a cornstarch-rich diet. Naloxone also selectively decreased the intake of sweet solutions in sham-fed rats.

10.1517/14656560903048959 © 2009 Informa UK Ltd ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted

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Naltrexone

Weeks 0 -2 Weight loss (%) -4 -6 -8 -10 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of North Carolina For personal use only. -12 0 2 4 8 12 16 20 24 26 30 36 42 48

Figure 1. Percentage weight loss with bupropion over 48weeks. Values are mean ± s.e.m. for the percentage weight loss from baseline. Subjects treated with bupropion SR 300 mg/day had significantly greater weight loss than subjects treated with placebo at 20 weeks (p < 0.05). Subjects treated with bupropion SR 400 mg/ day had significantly greater weight loss than those treated with bupropion SR 300 mg/day at 24, 26, 30, 36 and 42 weeks (p < 0.05) and with placebo at 12, 16, 20 and 24 weeks (p < 0.0001).

: Placebo; : Bupropion SR 300 mg/day; : Bupropion SR 400 mg/day. Adapted from [26].

3. Roleofopiatesinfeedingbehavior:

humanstudies

Compared to animal studies, there are limited data on the effects of opioid agonists on short-term eating in humans that would support the opioid-palatability hypothesis. While one study showed that the mixed opioid agonist-antagonist analgesic butorphanol doubled caloric intake after injection [10], another study found no such effect on feeding [11]. Although some studies have found that the opioid peptide -endorphin was elevated in obese subjects [12,13], there is yet no clear-cut evidence that the consumption of palatable food is responsible for the elevation of opioid levels in obesity [9].

4. Naltrexoneasapotential

high doses, naltrexone is contraindicated in acute hepatitis or liver failure. In patients who are not opioid-free, naltrexone can precipitate an acute withdrawal syndrome. Naltrexone will also antagonize the effects of opioid-containing medicines, such as cough and cold remedies and antidiarrheal preparations [15]. In the early 1980s, anecdotal reports commented on the decreased food intake and weight loss in former narcotic addicts treated with naltrexone [16]. Small double-blinded, placebo-controlled studies have demonstrated that naltrexone results in an 20% reduction in short-term food intake in normal-weight humans [17-19]. While hunger at the onset of a meal did not seem to be affected, the rated pleasantness of foods was decreased. This alteration in the hedonic response to food was not accompanied by changes in the sensory evaluation of food (i.e., smell and taste). The effects of naltrexone on the eating behavior of obese subjects have been less consistent. In one study, increasing doses of naltrexone (25 ­ 200 mg) given over four consecutive days reduced intake of laboratory luncheon meals by 30% in 17 obese men [20]. In an 8-week, randomized, placebo-controlled, double-blinded study of 60 obese subjects, 50 ­ 100 mg of naltrexone resulted in a statistically significant weight loss of 1.7 kg in only the female subjects [21]. In a 28-day in-patient study of eight moderately obese male subjects, 3-day periods of naltrexone therapy (100 ­ 300 mg/day administered in two divided doses) did not decrease food intake or body weight [22]. In a 10-week, randomized, placebo-controlled, double-blinded study of 27 obese females and 14 obese males, naltrexone at a daily dose of 200 mg did not produce statistically significant weight loss compared to placebo [23]. Based on the above data, naltrexone monotherapy is associated with minimal or no weight loss. Because the physiological mechanisms regulating caloric intake and body weight are highly integrated, complex and redundant [24], the limited efficacy of single obesity agents such as naltrexone is not unexpected.

5. Potentialefficacyofnaltrexonein

combinationwithbuproprion

obesitytreatment

Primarily used for the treatment of opioid and alcohol dependence, naltrexone is metabolized by the hepatic enzyme dihydrodiol dehydrogenase to its active metabolite 6-naltrexol. Both naltrexone and 6-naltrexol are competitive antagonists at the - and -opioid receptors. The plasma half-lifes of naltrexone and 6-naltrexol are 4 and 13 h, respectively. Naltrexone has a bioavailability of 5 ­ 40%, and a tmax of 1 h. Naltrexone and its metabolites are primarily eliminated by the kidneys [14]. Naltrexone is commercially available in a 50-mg oral formulation and 380-mg extended-release injectable suspension. Side effects include nausea, headache, dizziness, anxiety and fatigue. Due to the risk of hepatocellular injury at

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Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus play a key role in the regulation of energy balance. Activation of POMC neurons by peripheral signals such as leptin results in an increase in metabolic rate and a decrease in food intake. Such activation leads to autoinhibitory opioid feedback; POMC cleavage produces the endogenous opioid -endorphin, which inhibits POMC neurons [25]. As a dopamine and norepinephrine re-uptake inhibitor, bupropion is thought to produce weight loss through POMC stimulation. As shown in Figure 1, such weight loss is modest (5 ­ 10%) and non-progressive, reaching a plateau after 6 months of therapy [26].

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B. 0.0

Weight loss (%)

Weight loss (%)

-2.5

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-7.5 Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of North Carolina For personal use only. BL

BUP + NAL 4 8 12 Week 16 20 24

-7.5 BL

BUP + NAL 4 8 12 Week 16 20 24

Figure 2. Weight loss with bupropion, naltrexone and bupropion/naltrexone. A. Intent-to-treat population. B. Completer population. Mean (-s.e.m.) percentage change in total body weight from baseline through study weeks 16 (P + P and NAL + P) and 24 (BUP + P and BUP + NAL).

BL: Baseline; BUP: Bupropion; NAL: Naltrexone; P: Placebo. Adapted from [27].

In an effort to sustain POMC activation and weight loss by bupropion, Greenway et al. have recently explored the use of naltrexone to antagonize -endorphin mediated POMC autoinhibition [27]. Electrophysiological studies in mice demonstrated that bupropion, naltrexone and combined bupropion/naltrexone reversibly increased the frequency of action potentials in POMC neurons. Combined bupropion/naltrexone treatment was subsequently shown to produce at least a fully additive reduction in food intake in lean and obese mice. A randomized, placebo-controlled, double-blinded trial in obese adult subjects was then conducted [27]. Approximately 60 subjects were assigned to each of the following four treatment groups: placebo and placebo (P + P), sustained release bupropion (300 mg) plus placebo (BUP + P), immediate release naltrexone (50 mg) plus placebo (NAL + P) and sustained release bupropion (300 mg) plus immediate release naltrexone (50 mg) (BUP + NAL). As shown in Figure 2, combined BUP + NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. Weight loss for the BUP + NAL completers statistically diverged from NAL + P and P + P at week 16, and from BUP + P by week 24. BUP + NAL therapy was also well tolerated, with the most common adverse event being nausea.

6. Summary

7. Expertopinion

While naltrexone is associated with minimal weight loss as monotherapy, this opioid antagonist has potential utility in the treatment of obesity when combined with the POMC activator bupropion. Larger studies of longer duration are underway to determine if such combination therapy is consistently effective and well tolerated.

When combined with bupropion in a 6-month study, the opioid receptor antagonist naltrexone was shown to produce a placebo-subtracted weight loss of up to 4.7% [28]. Because naltrexone is thought to potentiate the anorectic effects of bupropion, this combination therapy does hold promise. However, for combination bupropion/naltrexone therapy to be utilized as a widely accepted obesity treatment, it will need to possess an efficacy and safety profile comparable to, or better than, currently available weight loss medications. The two medications that are currently approved for weight loss and weight maintenance both produce a 5 ­ 10% decrease in weight after 1 year of treatment. As a lipase inhibitor, orlistat decreases the absorption of fat by 25 ­ 30%. Minimal amounts of the drug are systemically absorbed, and side effects are mainly gastrointestinal, affecting up to 25% of patients during the first year of use. Such adverse events include loose stools, oily discharge and fecal incontinence. A combined norepinephrine and serotonin reuptake inhibitor, sibutramine induces satiety and prevents decline in metabolic rate associated with hypocaloric diets. Sibutramine can increase systolic and diastolic blood pressures by 1 ­ 3 mmHg; heart rate can also increase by an average of 4 ­ 5 beats per minute. Sibutramine is contraindicated in patients with heart disease, uncontrolled hypertension and cerebral vascular disease [28]. Combination bupropion/naltrexone therapy should thus consistently result in weight loss of at least 5%. In addition, based on updated FDA guidance to industry regarding the development of products for weight management, such weight loss should be greater than 5% compared to placebo. Alternatively, the proportion of subjects who lose greater than or equal to 5% of baseline body weight should be at

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least 35%, and approximately double the proportion in the placebo-treated group [29]. While combination bupropion/naltrexone treatment seems to be well tolerated compared to orlistat and sibutramine (the most common adverse event being nausea), the development of psychiatric effects remains a possibility when utilizing these two centrally-acting medications simultaneously. It is also unknown if such therapy will be suitable for use in patients with pre-existing psychiatric illness, especially those already on psychoactive medications. Because naltrexone is contraindicated in acute hepatitis or liver failure, documentation of hepatic safety will be necessary. Finally, the potential for adverse interactions with alcohol, opioids and opioid-containing medications (including cough and cold

remedies and antidiarrheal preparations) will need to be clearly described and categorized. Four Phase III clinical trials utilizing a fixed dose combination of naltrexone sustained-release and bupropion sustainedrelease have now completed enrollment. These studies are of at least 1 year duration, and a total of > 4000 subjects have been randomized [30]. Should efficacy and safety be achieved as outlined above, it would be reasonable to see this obesity therapy in widespread clinical use in the next 5 years.

Declarationofinterest

K Fujioka has served as a consultant and received grants for clinical research from Orexigen Therapeutics, Inc.

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Affiliation

Michael William Lee MD & Ken Fujioka MD Author for correspondence Scripps Clinic Center for Weight Management, 12395 El Camino Real, Suite 317, San Diego, CA 92130, USA Tel: +1 858 794 1250; Fax: +1 858 794 1244; E-mail: [email protected]

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Naltrexone for the treatment of obesity: review and update