Lower pleasantness of palatable foods in nalmefene-treated human volunteers

Appetite, 1991, 16, 249-259

Lower Pleasantness of Palatable Foods in Nalmefene-treated Human Volunteers M. R. YEOMANS

and P. WRIGHT

Department of Psychology, University of Edinburgh

The involvement of endogenous opioids in control of human food intake and appetite was investigated in a double-blind placebo-controlled study using a single, 2.5 mg oral dose of the opioid receptor antagonist, nalmefene. Ratings of the pleasantness of the smell and the taste, but not the appearance, of a number of foods was significantly lower in nalmefene-treated subjects. The magnitude of this effect was greater in food items independently rated as highly palatable. Caloric intake of a buffet-style meal was 20% lower in nalmefene-treated subjects, with the proportional reduction in intake of individual food items also depending on their palatability. These results lend further support to recent suggestions that opioids are involved in reward-related aspects of ingestion.

Opioid receptor antagonists have been found to reduce food intake in many species, including human subjects, in a wide range of experimental situations (see Baile et al., 1986; Cooper et al., 1988; Levine et al., 1985 for reviews). Although it is generally accepted that these opioid drugs exert this effect by blocking the effects of endogenous opioid peptides, the precise nature of opioid involvement in control of feeding remains uncertain. An important development has been suggestions that opioids may normally be involved in reward-related aspects of appetite (Le Magnen et al., 1980; Reid, 1985; Cooper et al., 1988). Evidence to support this comes largely from rats, where opioid antagonists such as naloxone and naltrexone differentially reduce the consumption of sweet solutions such as glucose, saccharin, sucrose and sweetened milk, all of which are normally consumed avidly by rats (Cooper, 1983; Cooper et al., 1985; Lynch & Libby, 1983; Siviy & Reid, 1983). Similarly, opioid blockade is more effective at reducing the intake of a variety of preferred diets, such as chocolate cookies, cafeteria diets and high fat diets, than in reducing intake of less preferred foods such as laboratory chow (Apfelbaum & Mandenoff, 1981; Cooper et al., 1988, Robert et al., 1989). Finally, sham feeding of sucrose is reduced greatly by opioid blockade (Rockwood & Reid, 1982; Kirkham & Cooper, 1988). These various effects could all be explained by opioid involvement in the relative attractiveness of these food items and solutions to the animals. The authors wish to thank Key Pharmaceuticals for supplying the nalmefene used in these studies. M. R. Yeomans is now at the Laboratory of Experimental Psychology at the University of Sussex. Requests for reprints should be addressed to: Dr M. R. Yeomans, Experimental Psychology, University of Sussex, Brighton, BN19QG, U.K. 0125-6663/91/030249 + 11 %03X@/O

0 1991 Academic Press Limited

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M. R. YEOMANS AND P. WRIGHT

Support for opioid involvement in reward-related aspects of feeding has also been found with human subjects. Opioid antagonists reliably reduce the food intake of both normal weight (Trenchard & Silverstone, 1982) and obese humans (Atkinson, 1982; Cohen et al., 1985; Spiegel et al., 1987; Wolkowitz et al., 1988). Moreover, they do so without altering ratings of hunger (O’Brien et al., 1982; Trenchard and Silverstone, 1982; Fantino et al., 1986). Fantino et al., (1986) found both an increase in the preferred concentration of sucrose and a decrease in hedonic ratings of a sweet taste, after naltrexone treatment in human subjects. In addition, we recently reported a 22% reduction in food intake in human volunteers following oral administration of 2.5 mg nalmefene (Yeomans et al., 1990) an opioid antagonist derived from naltrexone, which is both more potent (Michel et al., 1984) and longer acting (Gai & Di Fazzio, 1986) than naloxone. Furthermore, we found that the degree to which intake of individual foods was reduced appeared to be related to the rated palatability of these foods (Yeomans et al., 1990). Thus, there is a body of evidence suggesting a role for opioid peptides in the processes underlying the attractiveness of foods. However, to date no reported study has evaluated the perceived attractiveness of foods following administration of an opioid antagonist. If opioids are truly involved in the perception of attractiveness, then hedonic ratings should be reduced by opioid blockade.

METHOD

Subjects

Twenty-four male volunteers, none of whom were taking any medication, had any history of opiate abuse, or were vegetarian, were allocated randomly either to a nalmefene or placebo condition, according to a double-blind design. The nalmefenetreated group had a mean body weight of 72.8 kg (range 61-89), and a median age of 21.5 years (range 19-23), neither of which differed from those of the placebo group (mean weight 72.1 kg, range 60-93; median age 21 years, range 19-22). Subjects were informed that the study was investigating the effects of nalmefene on aspects of appetite, but the specific experimental hypotheses were not explained until the end of testing. The experimental protocol and details of potential side-effects were explained before testing started, and all subjects were required to sign a standard form giving their informed consent to taking part in the study.

Procedure

On the day of testing, subjects were instructed to eat a normal breakfast but to refrain from eating from 09.00 hrs onwards. They reported to the laboratory at 11.45 hrs, and after a short briefing they completed a series of computerized visual analogue ratings of expressions of appetite (hunger, satiety, thirst and dry-mouth sensations) and of general sensations and moods (alertness, anxiety, drowsiness, elation, light-headedness, nausea and tiredness), presented on a monitor attached to a BBC microcomputer (see Yeomans et al., 1990 for full details). Each rating scale consisted of a horizontal line with the anchors “not at all” and “very” at opposite poles, and the appropriate adjective positioned over the centre of this line. Subjects

251

OPIOIDS AND PALATABILITY

rated themselves by positioning an ‘x’ at the point on the line which best reflected how they felt at that exact moment. Ratings were automatically scored on a scale from 0 (“not at all”) to 100 (,‘very”). Having completed these ratings, subjects were given 150 ml of grapefruit juice to drink, containing either 2.5 mg of nalmefene dissolved in 2.0 ml of tap water (Drug condition), or 2.Oml tap water (placebo condition), after which they were left in a quiet room for 45 min. The experiment was conducted under double-blind conditions, with one experimenter preparing each treatment and assigning subjects to conditions, and a second experimenter administering treatments with no knowledge of the assignment to conditions until all data had been collected. On returning to the laboratory, subjects again completed the ratings of appetite and mood, and exactly 60 min after treatment (at about 13.00 hrs) the food tests started. First, subjects rated various sensory qualities of six standard foods from a buffet, and an additional two spicy foods selected for their distinctive hedonic properties (see Table 1 for details of the foods used). Then subjects were allowed to eat from a buffet consisting of ten food items, including the six previously rated. For the sensory ratings, food items were presented as preweighed 50g portions, in containers with lids. Following instructions given via the computer, subjects removed the lid of the appropriate food only when it was to be examined, and replaced the lid once each set of ratings were completed. All ratings were computerized, as with the mood ratings,

TABLE 1

Nutrient contents (Paul & Southgate, 1978) offood items used in the appetite tests Nutrient content (g/100) Food item

kcal

Carbohydrate

Fat

Protein

Foods used both for sensory ratings and in buffet meal High protein Ham Tuna

120 81

0 0

5

1

18 19

High fat & protein Brie Gouda

315 370

0 0

26 30

20 25

High carbohydrate Potato Ryvita

80 317

20 66

0

2

1 9

NA NA

NA NA

NA NA

Spicy foods, used for sensory ratings only Pakora Tortilla Additional

NA NA

foods provided as part of the buffet meal

Fats Butter Mayonnaise Salad vegetables Lettuce Tomato

740 718

0 2

82 79

0

12 14

1 3

0

1 1

0

0

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M. R. YEOMANS

AND P. WRIGHT

and the ratings were collected for each food item in the order appearance, smell and taste (Table 2). Taste was rated after consumption of a 2.0 g portion of each food. The order of presentation of the eight foods was randomized according to a Latin-square design. Subjects were provided with an unlimited supply of mineral water which they were instructed to use to rinse out their mouth between each food. Once these sensory ratings were completed, subjects repeated the ratings of appetite and mood, after which they were given free access to the buffet-style meal. Each of the ten food items was presented preweighed (to 0.1 g) in a separate container, and in all cases an excess of food was available. Subjects were provided with an empty plate and were instructed to eat as much or as little of any food item as they liked, but only to transfer onto their plate what they would eat. They were also instructed that, should they run short of any food, they were to summon the experimenter who would provide more. Unlimited supplies of mineral water were provided throughout. When subjects had completed eating, they informed the experimenter, who removed the remaining food for reweighing. Subjects finally completed the appetite and mood ratings for the fourth time, and were then asked to report any side-effects they had experienced during the study, and to indicate which of the conditions (drug or placebo) they considered they had been assigned to.

Statistical Analyses Each of the ten sensory dimensions were compared between nalmefene and placebo groups and across the eight food items using mixed 2-way analyses of variance. Where significant effects of the drug were observed, the data were analyzed further using paired comparisons between drug and placebo conditions, assessing significances by the method of Tukey (Wirier, 1972). A similar method was adopted to compare drug and placebo groups for ratings of mood and appetite, and intakes of

TABLE2

Signz@cant effects in sensory ratings P of effect of factor in analysis of variance Parameter rated How How How How How How How How How How

attractive does the food look? attractive does the food smell? strong is the smell? attractive does the food taste? salty does the food taste? bland does the food taste? pleasant does the food taste? sweet does this food taste? tasty is this food? hot/spicy is this food?

Drug NS < 0.05 NS


Food

Drug x food interaction


NS


NS NS < 0.05 NS

NS NS NS

< 0.05 NS

OPIOIDS AND PALATABILITY

253

individual foods. Total intakes were compared between groups using independent t tests.

RESULTS

Sensory Ratings The nalmefene-treated group gave significantly lower ratings of the attractiveness of the smell and taste of certain foods (Table 2), but not of the appearance of any food (Figure 1). The rated attractiveness, pleasantness and tastiness of foods were all closely inter-correlated (minimum r=0*84, p
100

(a

1“Looks

attractive”

(d 1 “Smel Is strong”

100

100

t

(b)“Smells

attractive”

(e) “Tastes

blond”

loo

1

(c)“Tastes

(f

1“Tastes

attractive”

salty”

FIGURE 1. Mean ratings (SEM bars) for sensory properties of foods for the nalmefenetreated (Cl) and placebo (!ZI) groups. (**p
1

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M. R. YEOMANS AND P. WRIGHT

TABLE3 Intakes of nalmefene and placebo-treated groups

Nalmefene Intake parameter Weight (g) Energy (kcal) Carbohydrate (g) Protein (g) Fat (g)

Placebo

Mean

SEM

Mean

SEM

P of group difference

482.3 679.4

18.4 38.7

591.2 955.8

22.1 42.5

< 0.05
54.8 33.2 33.9

3.3 2.6 3.1

58.7 48.0 54.6

3.9 1.7 4.9

NS <0+01


treated group rated lower the strength of the smells of both gouda and pakora, the two foods whose rated attractiveness differed most, thus it is possible that the effect of nalmefene on attractiveness of smell was due to a reduction in sensitivity of the sense of smell. In takes

The nalmefene-treated group ate significantly less of the buffet-style meal, in terms of both total weight ingested and caloric intake. Intakes of both protein and fat, but not carbohydrate, were significantly lower in the nalmefene-treated group (Table 3). This apparent nutrient specificity reflects significantly lower intakes of certain foods only (Figure 2). The foods whose intakes were lower to the greatest extent were all

FIGURE2. Mean intakes of different foods by the nalmefene-treated percentage of the appropriate placebo intake. (*p < 0.05, **p < 0.01).

group expressed as a

OPIOIDS AND PALATABILITY

255

foods which were rated as highly attractive by the placebo group. To test this further, the intake of individual food items by the nalmefene group, expressed as a percentage of placebo-group intake, were correlated with general ratings of palatability for these foods, using data from previous work in this laboratory (Yeomans et al., 1990). This correlation was significant (r = 0+8, p c 0.01). Mood and Appetite Ratings Ratings of hunger, satiety, thirst and dry-mouth sensation did not differ between the nalmefene-treated and placebo groups at any stage of the experiment (Figure 3). Ratings of hunger rose only slightly in the 60 min before and after treatment, and then fell slightly, but significantly, in both groups after completion of the sensory ratings. As expected, hunger ratings fell markedly after consumption of the meal, and ratings of satiation mirrored those of hunger throughout the study. Of the mood ratings, the only significant differences between nahnefene and placebo-treated groups were in alertness, where the nalmefene group was significantly more alert after treatment, and in elation which was attenuated in the nalmefene group (Figure 4). No subjects rated appreciable nausea or light-headedness at any time. The only reported side-effects were slight headaches reported by three subjects, two in the nalmefene condition and one in the placebo condition. Thus, there is no evidence to suggest that effects of nalmefene on feeding would be a consequence of an effect on mood or general well-being. Of the 12 subjects receiving nalmefene, nine felt

100

IOO(a)

p

;I-

Hunger

( b)

Satiety

@S*

P 5

40-

3 =

zo-

0

\e

I:,/

20-

I

’

Predrug

Postdrug

I Premeal

I

o-

Postmeal

I

’

Predrug

Postdrug

I Premeal

I Postmeal

1

100

100 (c)

(d)

Thirst

01Predrug ’

I

I

I

Postdrug

Premeal

Postmeal

I

01

Dry-mouth

’

Predrug

I

Postdrug

I

Premeoi

I

Postmeal

FIGURE 3. Mean ratings by nahnefene-treated (0 --- 0) and placebo (0 --- 0) groups, made before @drug) and after treatment (postdrug), at the end of the sensory food ratings (premeal), and at the end of eating (postmeal).

256

M. R. YEOMANS

_

AND P. WRIGHT 80

Alertness

k(b)

Elation

70 60 50 40

20’

Predrug

30 i

Postdruq

Premeal

Postmeal

20’

Predrug

Postdrug

Premeal

Postmeal

FIGURE 4. Mean ratings by nalmefene-treated (O---O) and placebo (O---O) groups, for changes in equivalent nalmefene and placebo conditions, relative to baseline values (**p
they were in the placebo condition, which did not differ from placebo where eight of the 12 felt they were in the placebo group. This confirms both the lack of side-effects, and the effectiveness of the double-blind procedure.

DISCUSSION

The nalmefene-treated group had significantly lower ratings of attractiveness of the taste and small, and lower intakes, of some foods only. These results have important implications for our understanding of opioid function during feeding, since they support the hypothesis that endogenous opioids are involved in processes underlying the perception specifically of the attractiveness of foods. This conclusion follows from the observation that the key dimension in determiningthe effects of nalmefene on eating is palatability: both here and in a previous study (Yeomans et al., 1990), the degree to which intake of individual food items was reduced in the nalmefene condition was correlated with the rated palatability of that food. Similarly, Drewnowski et al., (1989) found that naloxone caused greater reductions in intake of highly palatable fat/sugar mixtures (e.g. sweetened cream) than in intake of similiar, but less palatable stimuli (e.g. unsweetened milk). With rats, Cooper & Turkish (1989) reported that natrexone reduced intake of chocolate cookies but enhanced intake of laboratory chow, and Apfelbaum & Mandenoff (1981) reported that naltrexone treatment caused a large reduction in food intake for rats eating cafeteria diets, but a small reduction only for rats eating chow. Palatability is also the most commonly used explanation for the hyperphagia seen in rats with cafeteria diets (e.g., Louis-Sylvestre et al., 1984; Rogers & Blundell, 1984) although this interpretation has been questioned, since these diets often confound nutritional composition and hedonic qualities (Ramirez et al., 1989). However, when considered with other studies investigating effects of opioid antagonists in rats, which have found reduced intake of, or preference for, normally preferred solutions such as sucrose (Le Magnen et al., 1980), saccharin (Cooper, 1983; Lynch, 1986; Siviy & Reid, 1983) or dilute saline (Cooper & Gilbert, 1984; Gosnell & Majchrzak, 1990) The case for opioid involvement in the determination of palatability appears convincing.

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There was an apparent nutrient-specific effect of nalmefene, with significant reductions in fat and protein but not carbohydrate intake. However, this appears to be an indirect consequence of the attenuated intake of palatable foods with high fat and protein contents (i.e. Gouda, ham etc), since intakes of palatable foods with low nutrient contents (e.g. tomato) were also attenuated. Controlled studies in human subjects have reported quantitative relationships between intake and palatability (Bellisle & Le Magnen, 1980; Bobroff & Kissileff, 1986; Guy-Grand et al., 1989). Thus our intake results also imply that endogenous opioid peptides are involved in processes underlying the determination of palatability. Although nalmefene reduced ratings of the attractiveness of the smell and taste of some foods, it did not alter the attractiveness of the appearance of any foods. This may be because these ratings reflect an association between the appearance of the foods and prior experience with the foods, all of which were familiar to the subjects. Such preconceptions may be modified by the subsequent smell and taste of foods. Nalmefene had most effect on the rated attractiveness of the smell and taste of pakora and Gouda, both of which have characteristically strong odours and flavours. Since the rated strength of smell of Gouda was also reduced significantly, it is possible that the effect on affective ratings was an indirect consequence of reduced olfactory sensitivity. It is unlikely that this was the case with taste since none of the sensory evaluations (bland, salty and sweet) was altered by nahnefene. Moreover, Fantino et al., (1986) found reductions in the pleasantness of sweet solutions and alimentary odours, but not of non-alimentary stimuli, suggesting that the effect of opioid blockade on sensory hedonics is restricted to ingestive stimuli. Some studies of effects of opioid antagonists on feeding have suggested that changes in eating were an indirect consequence of side-effects such as nausea (Spiegel et al., 1987; Wolkowitz et al., 1988). None of our subjects reported experiencing any such effects, however, and most considered they had been in the placebo condition. We did detect some small mood changes after nalmefene treatment, including a slight decrease in rated elation, which might be explained by nalmefene altering normal affect-related function. Previously, increases in affect-related measures were reported after administration of the exogenous opiates heroin and morphine (McAuliffe et al., 1985) and the specific opiate agonist fentanyl (Mattusek & Hoehe, 1989). There is also substantial evidence implicating endogenous opioid peptides in central reward (see Bozarth, 1988, for recent review), and that long-term depression of affective state can be associated with dysfunction in central processes associated with reward (Wilner, 1985). It therefore remains a possibility that the effects of nalmefene on hedonic components of eating were a consequence of a more general suppression of affectrelated processes, although this requires substantiation. To conclude, a nalmefene-treated group of young adults showed less attraction to and intake of palatable foods than a placebo group, lending further support to recent suggestions that endogenous opioid peptides are involved in orosensory reward mechanisms during feeding. REFERENCES

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