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Development of Guidelines for the Use of Orexigenic Drugs in Long-Term Care

Course Authors

John E. Morley, M.D., and David R. Thomas, M.D.

Dr. Thomas is Professor of Medicine, St. Louis University School of Medicine.

During the last three years, Dr. Morley has received grant/research support from Vivus, Merck & Co., Pharmacia, B. Braun McGaw, Bayer Corp and Nestec, Ltd. He has also served on the Speakers' Bureau for LXN, Organon, Ross, Pharmacia, GlaxoSmithKline, Aventis, Searle, Merck & Co., Roche, Bristol-Myers Squibb, Novartis, Pratt, B.Braun McGaw, Pfizer and Solvay. During the last three years, Dr. Thomas has received grant/research support from Nestle.

This Cyberounds® is published simultaneously in the Supplement to the June 2003 issue of Annals of Long-Term Care, in cooperation with the Council for Nutritional Clinical Strategies in Long-Term Care, which received an unrestricted educational grant from Solvay Pharmaceuticals, Inc.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Evaluate outcomes of undernutrition in long-term care

  • Describe interventions for undernutrition in long-term care

  • Discuss options for use of orexigenic agents.

 

The Geriatric Anorexia Nutrition (GAIN) Registry clearly demonstrated that persons living in long-term care who are losing weight have a higher mortality compared to those who stop losing weight.(1) Those who gained weight had a lower mortality than those in whom weight stabilized.

Numerous other studies have shown that weight loss and protein energy malnutrition in older persons are associated with an increase in mortality.(2),(3),(4)Weight loss is also associated with a variety of other adverse effects (Table I).(5)

Table 1

In addition, protein energy malnutrition aggravates the deterioration in the immune system that is normally associated with aging and causes a decline in CD4+ T lymphocytes (Table II).(6)

Table 2

For these reasons, weight loss has been considered a sentinel event in the life of the nursing home resident.

Estimates of the prevalence of protein energy malnutrition in cross-sectional studies of nursing home residents range from 23-85%.(7) In a prospective study of admissions to a long-term care facility, 54% of the residents were malnourished at the time of admission.(8) Serum albumin levels below 3.5 g/dL occur in 6-43% of nursing home residents. While low serum albumin levels are often associated with protein deficiency, they are also caused by cytokine excess, which inhibits albumin production in the liver and causes albumin leakage into the extravascular space. The effects of cytokines on albumin make it a poor marker of nutritional status. Pyridoxine deficiency occurs in 65% of residents, thiamine deficiency in 19% and ascorbic acid deficiency in 2% of residents.(9)

Because of the importance of weight loss for residents in nursing homes, the Council for Nutritional Clinical Strategies in Long-Term Care has developed a series of guidelines for nutritional assessment and management in long-term care (Tables III and IV).(10)

At a recent meeting of the Council, it was felt that it would be useful to develop guidelines for the use of orexigenic agents in long-term care. In this Cyberounds®, we present a review of the efficacy and safety of orexigenic (appetite-stimulating) agents and the recommendations of the Council for Nutritional Clinical Strategies in Long-Term Care on the use of orexigenic agents in long-term care residents.

Protein and Energy Supplementation in Malnourished Older Persons

While there is a paucity of high-quality studies on liquid protein and energy supplementation in malnourished older persons, the Cochrane Database of Systematic Reviews found 31 trials with 2464 randomized participants that could be analyzed.(11) Based on their analysis, they found that supplements were associated with weight gain, decreased mortality (RR 0.67, 95% CI 0.52-0.87) and decreased length of hospitalization by 3.4 days. No decrease in the risk of non-nutritional morbidity was found, and there were inadequate numbers to judge the effects on function (e.g., grip strength, walking distance and Barthel index). Most studies were considered too short to have a realistic probability of detecting changes in function, quality of life or morbidity.

Based on the finding that glucose, when infused into the duodenum, increased hunger in older persons compared to younger persons,(12) Wilson et al.(13) studied the effect of a liquid caloric supplement administered concomitantly with the meal, or 60 minutes before the meal. They found that when a caloric liquid supplement was administered 60 minutes before a meal, it increased total caloric intake (supplement plus meal), but had no effect when given with the meal. It is, therefore, recommended that caloric supplements be given between meals and not with meals.

A number of recent caloric supplementation trials further support the positive conclusions of the Cochrane Database. Beattie et al.(14) examined 101 malnourished surgical patients and found that caloric supplements postoperatively retarded weight loss and improved grip strength, quality of life and morbidity compared to the control group. Lauque et al.(15) examined the effect of a daily 400-kcal oral supplement in persons at nutritional risk living in nursing homes. They noted an increase in daily protein and energy intake, body weight (1.4 ± 0.5 kg) and nutritional status in the supplemented group. In a 60-month randomized, placebo-controlled trial of 82 patients who had experienced a hip fracture (mean age, 80.7 years), protein repletion resulted in increased serum levels of insulin-like growth factor-1 (IGF-1), attenuation of proximal femur bone loss and decreased length of stay in the rehabilitation setting.(16)

These studies confirm the utility of protein-calorie supplementation to improve outcomes, but to a limited extent, suggesting the need for a more aggressive therapeutic effect. Caloric supplements should be given between meals. The utility of "med-pass" supplements (the giving of medications with a nutritional supplement) requires a controlled trial.

Depression

Depression is a common cause of severe weight loss in older persons, particularly those living in long-term care.(17),(18),(19) All persons losing weight should be screened for depression, using validated tools such as the Geriatric Depression Scale (if not demented) or the Cornell Scale for Depression in Demented Persons. At present, the drug of choice for treating depression in persons with weight loss is mirtazapine, since it has most often been associated with weight gain. However, weight gain may accompany improvement in depression despite the particular drug used.(20),(21),(22),(23),(24) There is some evidence that mirtazapine has specific orexigenic as well as antidepressant properties. However, any antidepressant that reverses depression will cause weight gain. If antidepressants are ineffective and the weight loss continues to be of significant concern, electroconvulsive therapy should be considered.

Anabolic Agents

Two types of anabolic agents have been utilized to increase weight in malnourished older persons (i.e., the anabolic steroids and growth hormone). Insulin growth factor-1 levels, which are regulated by growth hormone, decline to low levels in older persons and fall even further with the onset of malnourishment.(25) Thus, growth hormone was a reasonable agent to test in reversing protein energy undernutrition in older persons. Early studies demonstrated that in these individuals growth hormone caused nitrogen retention and produced weight gain.(26) Chu et al.(27) found that growth hormone could improve nutritional status in malnourished older persons. However, a large study on malnourished patients in intensive care units found that growth hormone increased length of hospitalization, ventilator dependence and death.(28) At present, growth hormone cannot be recommended for use in older malnourished persons.

Ghrelin is a peptide hormone produced by the fundus of the stomach. Ghrelin increases food intake and releases growth hormone.(29) It produces these effects by activating nitric oxide synthase in the hypothalamus. Ghrelin appears to be an excellent potential mediator for the development of drugs to treat anorexia and weight loss.

Testosterone levels decline in men and women with aging.(30),(31) Testosterone is an anabolic steroid. It increases strength, decreases fat mass, increases bone mineral density and improves visuospatial cognition.(31)(32) Low testosterone levels have been shown to be highly related to the development of arcopenia(33),(3)(4),(35) and to poor function (frailty).(36) Bakhshi et al.(37) showed that testosterone administration improved function in men during rehabilitation following hospitalization. While there are no studies conducted in long-term care on testosterone replacement, it would appear that this may be a reasonable option for malnourished men with low testosterone levels.

Other anabolic steroids have been used in malnourished ill patients. Nandrolone has been shown to enhance nutritional status in persons with renal failure.(38) Oxandrolone has been shown to decrease weight loss, nitrogen loss, time to healing and length of hospitalization in elderly burn patients.(39) In an open-label trial, oxandrolone 10 mg twice daily produced weight gain in patients with chronic obstructive pulmonary disease.(40) No trials on the effects of oxandrolone on residents in long-term care are available.

Megestrol Acetate

Megestrol acetate is a progestational agent that increases food intake. A number of studies on cancer patients have shown that megestrol acetate increases appetite and weight, and improves quality of life.(41),(42),(43) Similar findings have been reported in patients with AIDS.(44),(45)

There is limited experience of the use of megestrol in geriatric patients. Castle et al.(46) reported that two out of four patients receiving megestrol acetate had weight gain. In a retrospective study of 27 long-term care patients, 74% had an increase in body weight, with weight gain being greater in women than in men.(47) Karcic et al.(48) reported increased food intake, body mass index, albumin prealbumin, hemoglobin and lymphocyte count in a small number of nursing home residents who received megestrol.

Yeh et al.,(49) in a placebo-controlled, randomized, 3-month trial of megestrol, found that there was a significant increase in weight in the three months following megestrol administration. It is now well recognized that cytokines decrease food intake, inhibit albumin synthesis, cause muscle wasting, decrease nitrogen retention and provoke extravasation of albumin from intravascular spaces (Figure 1).(50),(51)

Figure 1. Effect of Cytokines on Nutrition.

Figure 1

Yeh et al.(52) reported that megestrol produced a decrease in interleukin-6, tumor necrosis factor receptor-p75 and soluble interleukin-2 receptor levels. Lambert et al.(53) also found that megestrol reduced interleukin-6 levels. These findings suggest that megestrol may be a useful drug in persons with cytokine excess. Cytokine excess may be gauged by measuring a C-reactive protein.

A major potential problem with megestrol is that it primarily produces an increase in fat mass rather than fat-free mass.(54) While an exercise program increased thigh muscle cross-sectional area, megestrol failed to do this. Megestrol acetate markedly decreased testosterone levels over a short time period. In addition to hypogonadism, megestrol acetate has been reported to produce hyperglycemia, adrenal suppression(55) and possibly deep vein thrombosis (Table V).(56) For the latter reason, megestrol acetate should not be used in immobile persons. The effective dose of megestrol acetate was 800 mg daily.

Table 5

Dronabinol

Cannabis was first recognized as an appetite stimulant in Aryuvedic medicine, and then in Arabic medicine by Al Badri in 1251. In 1838, O'Shaugnessy pointed out that cannabis made patients voraciously hungry and in The Lancet, in 1890, Reynolds wrote that cannabis "when pure and administered carefully is one of the most valuable medicines we possess." In the 1970s, during studies on the psychological effects of cannabis, it was noted to increase the intake of marshmallows and chocolate milk. In 1973, Morley et al.(57) reported that cannabis increased the desire for food, made substances taste better and smell richer, decreased pain and increased happiness. These are the ideal properties of a drug for palliative care.

Based on these findings, the active ingredient of cannabis, tetrahydrocannabinol, was isolated and a therapeutic agent, dronabinol, became available. Dronabinol has been shown to increase appetite in persons with cancer(58),(59),(60) or AIDS.(61),(62),(63)

Volicer et al.(64) studied 11 patients with Alzheimer's disease and disturbed behavior. They ranged in age from 65-82 years. Dronabinol, on average, produced a 3-pound weight gain compared to placebo. In addition, dronabinol improved scores on the Cohen-Mansfield Agitation Index. Jatoi et al.(58) found that dronabinol and megestrol improved appetite and produced weight gain. There was no advantage of utilizing the drugs in combination. Neither drug had any major side effects.

Another major benefit of dronabinol is its antiemetic effect.(65) It is a particularly potent agent in preventing anticipatory nausea and vomiting in chemotherapy patients. In addition to dronabinol's appetite stimulation effects and reduction of aggressive behavior in patients with Alzheimer's disease, it is also an antispasmodic and an analgesic.(66) As an analgesic, it is an excellent adjuvant therapy with opioids for use in central post-stroke pain and neuropathic pain.

Because dronabinol produces appetite stimulation, has antinausea properties, decreases pain and enhances general well being, it is considered the ideal drug for the management of end-of-life palliative care (Figure 2).

Figure 2. Use of Dronabinol for Palliative Care.

Figure 2

Because persons naïve to dronabinol may have mild delirium when first exposed to the drug, it should be initially given at a dose of 2.5 mg prior to bedtime. After one week, the 2.5-mg dose should be given before supper. After two weeks, if there has been no response, the nursing home resident should be given 2.5 mg before lunch and supper (Table VI).

Table 6

Council for Nutritional Clinical Strategies in Long-Term Care Recommendations for Use of Orexigenics

As weight loss is a sentinel event in the life of a nursing home resident, the Council recommends:

  • Previous recommendations of the Council for nonpharmacologic interventions should be instituted in persons at nutritional risk.
  • Persons who are depressed should receive treatment with an antidepressant that has orexigenic properties (e.g., mirtazapine). In depressed persons with severe weight loss, electroconvulsive therapy should be considered.
  • Orexigenics should be used when no obvious treatable cause of weight loss is present or when the above recommendations fail to reverse weight loss.
  • Use of anabolic steroids, preferably testosterone, should be used only to treat sarcopenia, not anorexia.
  • Megestrol acetate should be used in ambulatory persons with cytokine excess.
  • Because megestrol acetate reduces testosterone levels, it should be used in men only together with testosterone.
  • Megestrol acetate should be given for a maximum of 3 months.
  • Persons receiving megestrol acetate should be monitored for adrenocortical insufficiency.
  • Dronabinol should be used early when weight loss occurs without an apparent cause or when no reversible cause is present.
  • Dronabinol appears to be an ideal drug for end-of-life and palliative care.

Footnotes

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2Liu LJ, Bopp MM, Roberson PK, Sullivan DH. Undernutrition and risk of mortality in elderly patients within 1 year of hospital discharge. J Gerontol A Biol Sci Med Sci 2002;57:M741-M746.
3Sullivan DH, Walls RC. Protein-energy undernutrition and the risk of mortality within six years of hospital discharge. J Am Coll Nutr 1998;17:571-578.
4Thomas DR, Verdery RB, Gardner L, et al. A prospective study of outcome from protein-energy malnutrition in nursing home residents. JPEN J Parenter Enteral Nutr 1991;15:400-404.
5MacIntosh C, Morley JE, Chapman IM. The anorexia of aging. Nutrition 2000;16:983-995.
6Kaiser JE, Morley JE. Idiopathic CD4+ T lymphopenia in older persons. J Am Geriatr Soc 1994;42:1291-1294.
7Abbasi AA, Rudman D. Undernutrition in the nursing home: Prevalence, consequences, causes and prevention. Nutr Rev 1994;52:113-122.
8Thomas DR, Zdrowski CD, Wilson MM, et al. Malnutrition in subacute care. Am J Clin Nutr 2002;75:308-313.
9Ritchie CR, Thomas DR. Aging. In: Handbook of Clinical Nutrition, third ed. Heimburger DC, Weinsier RL, eds. St. Louis, MO: Mosby; 1997.
10Thomas DR, Ashmen W, Morley JE, Evans WJ. Nutritional management in long-term care: Development of a clinical guideline. Council for Nutritional Strategies in Long-Term Care. J Gerontol A Biol Sci Med Sci 2000;55:M725-M734.
11Milne AC, Potter J, Avenell A. Protein and energy supplementation in elderly people at risk from malnutrition. Cochrane Database Syst Rev 2002;(3):CD003288.
12MacIntosh CG, Horowitz M, Verhagen MA, et al. Effect of small intestinal nutrient infusion on appetite, gastrointestinal hormone release, and gastric myoelectrical activity in young and older men. Am J Gastroenterol 2001;96:997-1007.
13Wilson MMG, Purushothaman R, Morley JE. Effect of liquid dietary supplements on energy intake in the elderly. Am J Clin Nutr 2002;75:944-947.
14Beattie AH, Prach AT, Baxter JP, Pennington CR. A randomised controlled trial evaluating the use of enteral nutritional supplements postoperatively in malnourished surgical patients. Gut 2000;46:813-818.
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36Perry HM, Miller DK, Patrick P, Morley JE. Testosterone and leptin in older African-American men: Relationship to age, strength, function, and season. Metabolism 2000;49:1085-1091.
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52Yeh SS, Wu SY, Levine DM, et al. The correlation of cytokine levels with body weight after megestrol acetate treatment in geriatric patients. J Gerontol A Biol Sci Med Sci 2001;56:M48-M54.
53Lambert CP, Sullivan DH, Evans WJ. Effects of testosterone replacement and/or resistance training on interleukin-6, tumor necrosis factor alpha, and leptin in elderly men ingesting megestrol acetate: A randomized controlled trial. J Gerontol A Biol Sci Med Sci 2003;58:165-170.
54Lambert CP, Sullivan DH, Freeling SA, et al. Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: A randomized controlled trial. J Clin Endocrinol Metab 2002;87:2100-2106.
55Goodman A, Cagliero E. Megestrol-induced clinical adrenal insufficiency. Eur J Gynaecol Oncol 2000;21:117-118.
56Bolen J, Andersen R, Bennett R. Deep vein thrombosis as a complication of megestrol acetate therapy among nursing home residents. Journal of the American Medical Directors Association 2000;(Nov/Dec):248-252.
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58Jatoi A, Windschitl HE, Loprinzi CL, et al. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: A North Central Cancer Treatment Group study. J Clin Oncol 2002;20:567-573.
59Berry EM, Mechoulam R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol Ther 2002;95:185-190.
60Walsh D, Nelson KA, Mahmoud FA. Established and potential therapeutic applications of cannabinoids in oncology. Supportive Care in Cancer 2001;11:137-143.
61Beal JE, Olson R, Lefkowitz L, et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 1997;14:7-14.
62Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10:89-97.
63Struwe M, Kaempfer SH, Geiger CJ, et al. Effect of dronabinol on nutritional status in HIV infection. Ann Pharmacother 1993;27:827-831.
64Volicer L, Stelly M, Morris J, et al. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer\'s disease. Int J Geriatr Psychiatry 1997;12:913-919.
65Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manage 1997;14:311-314.
66Clermont-Gnamien S, Atlani S, Attal N, et al. The therapeutic use of Delta 9-tetrahydrocannabinol (dronabinol) in refractory neuropathic pain. Presse Medicale 2002;31:1840-1845.