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Anticachexic or antisarcopenic medications are pre- the safety of these medications being used in geriatric
scribed worldwide for geriatric patients with poor ap- population. This review looks at the evidence in rela-
petite and associated weight loss. They represent a tion to the benefits and risks of these medications and
valuable treatment option for managing cachexia. discusses what we know about their use in the geriat-
However, the well-publicized adverse reports about ric population. (J Am Med Dir Assoc 2007; 8: 363–377)
these medications in acquired immunodeficiency syn-
drome (AIDS) and in the cancer population has led to Keywords: Cachexia; elderly; pharmacotherapy; safety
some concern and much subsequent discussion over
To establish the optimal means of treating patients with PHYSIOLOGIC CAUSES OF WEIGHT LOSS IN THE
age-related cachexia, both the benefits and risks associated ELDERLY
with these presently available and potentially useful medica- Food intake regulation changes with age. The mechanisms
tions will be evaluated here. This review assesses the efficacy, regulating food intake in the elderly are complex and multi-
safety, and tolerability of medications that have been used in factorial, making treatment more challenging. Mecha-
cancer and AIDS-associated cachexia and gives a practical nisms10,11 involved in the process of weight loss and poor food
overview on maximizing the risk:benefit ratio for the use of intake are summarized in Table 1.
the particular class of drugs in the geriatric population.
Epidemiological evidence supporting the notion that sig- TREATMENT OPINIONS
nificant weight loss is associated with high mortality comes
from community studies and nursing home studies,1– 6 from Nutritional Supplementation
AIDS studies,7,8 and cancer study.9 Further evidence in sup- Rolls and colleagues12 found that even healthy elderly men
port of this notion comes from prospective longitudinal stud- consumed significantly less baseline energy compared with
ies of free-living and institutionalized elderly, which assessed younger men. Roberts and coworkers found that healthy elderly
the relationship between weight loss and survival.1,4 men had both a short-term (7 weeks), as well as long-term (6
The understanding of the pathophysiology of geriatric ca- months) impairment in adjusting their food intake after an
chexia has increased with effective and safe nutritional mea- episode of either overfeeding or underfeeding.13–15,16 –18 Encour-
surements. aging the elderly to take extra food (with verbal prompts, phys-
ical assistance) at mealtime over a period of time, then allowing
Northport VAMC, Geriatric division, Northport, NY (S.-S.Y., S.L.); Weill Medical them to eat at their own volition, can promote weight gain.
College of Cornell University and The New York Presbyterian Hospital, New Because the elderly are not able to adjust their food intake after
York, NY (M.W.S). a period of overfeeding, they will continue exceeding their
S.-S.Y. has received unrestricted research grants from Merck, Bristol-Myers eating needs, and thus, increase their weight. Providing an
Squibb, and Amgen Pharmaceuticals, and consulting fees from PAR Pharma- energy-dense nutritional supplement at least 30 minutes before
ceuticals. M.W.S. has been on advisory boards for GTX, Alder Pharmaceuticals,
Bristol-Myers, PAR and Amgen Pharmaceuticals, and has received research a meal can increase energy intake in elderly people. These
funding and lecture honoraria from Amgen and Par Pharmaceuticals. elderly men did not decrease food intake even when they were
Address correspondence to Shing-Shing Yeh, MD, PhD, Northport VAMC, Ge- given supplements before meals. They obtained 10% to 30%
riatric Division, Box 111, 79 Middleville Road, Northport, NY 11768. E-mail: extra energy from the “preload” (supplements given 30 minutes
shingshing.yeh@med.va.gov
before lunch) and still were able to take their usual amount of
Copyright ©2007 American Medical Directors Association food at mealtime.12 Wilson and colleagues19 found that admin-
DOI: 10.1016/j.jamda.2007.05.001 istration of dietary supplements between meals (⬎ 60 minutes
before the next meal), instead of with meals, may be more Parenteral Nutrition
effective in increasing energy consumption. Parenteral nutrition can be given to those elderly immedi-
McCrory and coworkers20 found that a wide variety of ately after acute disease who are not capable of taking ade-
sweets, snacks, condiments, and high-carbohydrate entrees quate calories or fluid.31,32 Peripheral parenteral nutrition can
coupled with a low variety of vegetables promoted long-term only provide a limited amount of calories, and the infusion
increase in energy intake and body fat. Providing nutritional site has to be changed frequently or a central, indwelling
supplements with a wide variety of sweets and carbohydrates catheter, with its risk of infection, may be placed. Marra and
may be helpful as the second step for the treatment of weight coworkers33 reviewed 47 patients who received long-term
loss. Medications and aging play a major role in taste loss and total parenteral nutrition and found that the incidence of
in distortions of taste.21 Because loss of taste and smell are catheter-related infections was high, and that a significant
common in the elderly, use of flavor-enhanced food has been proportion of catheter-related infections were polymicrobial
found to have a positive effect on food intake.22,23 and attributable to multidrug-resistant bacteria and fungi.
Additionally, resistance to eating at meal times in patients Thomas and colleagues34 found a benefit in treating pa-
with dementia is widely reported.24 Behavior disturbances tients with parenteral nutrition for a longer period of time in
also play a role in low body weight and weight loss in de- a single-center, prospective, randomized, parallel group design
mented patients.24 Providing feeding assistance with the reg- clinical trial that evaluated long-term safety of peripheral
ular use of feeding assistants may promote intake in the parenteral nutrition in postacute patients receiving inade-
demented population.25 quate enteral nutrition in the nursing home. They found that
the peripheral parenteral nutrition group demonstrated a
Tube Feeding trend toward improvement in nutritional and functional sta-
tus, and that it could be safely administered with a low
Tube feeding has been the treatment of choice in those
complication rate.34
with neuromuscular diseases (impaired swallowing or gag re-
flex), postoperative patients, those who are not able to eat, or Pharmacologic Interventions
patients using ventilators. Numerous studies have tried to
The effects of nutritional support on the prevention and
determine the benefits of tube feeding.26 –28 Mitchell et al27
treatment of cancer and AIDS cachexia have been investi-
found that there is no evidence that tube feeding prolonged
gated extensively.35–37 The review below looks at the evi-
survival. They found that advanced age and malignancy were
dence in relation to the benefits and risks of these medications
the most frequent reasons for having poorer survival with tube
and discusses proper use of these medications for geriatric
feeding. Tokuda and coworkers29 investigated the influence of
safety.
feeding tube placement on survival in hospitalized elderly
patients. In the multivariate survival model, which included PHARMALOGICAL AGENTS MOST COMMONLY
older age, hip fracture history, admitting diagnosis of pneu- USED FOR CACHEXIA
monia, and tube feeding placement, only feeding tube place-
ment (hazard ratio, 2.29; 95% confidence interval, 1.22– 4.33) Megestrol Acetate
was significantly associated with higher mortality. Feeding Megestrol acetate (MA) is a synthetic derivative of proges-
tube–associated side effects include aspiration, diarrhea, and terone. The literature supports that MA may act as a proges-
vomiting.28 Only a small subset of nursing home residents tational agent, an anti-inflammatory/glucocorticoid agent,
(stroke and head and neck cancer survivors) have been re- and an intrinsic androgen agent.38 – 46 It has been approved by
ported to benefit from tube feeding.30 the US Food and Drug Administration (FDA) as an appetite
The main side effects were masculinization in women, fluid Potential Problems
retention, and hepatic toxicity (jaundice, cholestatic hepati- Older men have lower testosterone clearance rates and a
tis, peliosis hepatitis, hyperplasias, and neoplasm).94,105–107 higher frequency of adverse effects.112 The frequency of a
Anabolic steroid abuse in athletes has been associated with a higher hematocrit (⬎54%), leg edema, and prostate events
wide range of adverse conditions, including hepatotoxic ef- (exacerbation of prostate cancer) were more significant in
fects, hypogonadism, testicular atrophy, impaired spermato- older men.112 Although older men can gain substantial mus-
genesis, gynecomastia, and psychiatric disturbances.108,109 cle mass and strength with supraphysiological testosterone
Anabolic steroids can also cause prostatic hypertrophy, which doses, they also experience a high frequency of the above
is already a common problem in elderly men. Likewise, an- noted adverse effects.112
drogens could stimulate a focus of prostate cancer if present. Selective androgen-receptor modulators that are preferen-
Concerns about long-term risks have restrained enthusiasm tially anabolic and that spare the prostate hold promise as
about their usage. We need more studies to determine anabolic therapies.
whether anabolic steroids can induce meaningful improve-
ments in physical function and patient-important outcomes Potential Usage
in patients with physical dysfunction associated with chronic Testosterone may be given to hypogonadal or glucocorti-
illness or aging. coid-treated men114; it also may possibly be given as a lean
muscle enhancer for geriatric sarcopenic patients for a limited
Potential Usage period of time.112
In our opinion, the case report evidence is encouraging but Dr. Bhasin’s group112 suggested a low testosterone treat-
not yet sufficient to be reasonably confident that anabolic ment dose (125 mg/week), in patients with low normal tes-
agents will improve nonhealing wounds in any particular tosterone levels, and in combination with resistance training
patient group, despite Demling’s finding that oxandrolone exercise, had a lower frequency of adverse events and signif-
could increase wound closure.102–104 At the same time, we icant gains in fat-free mass and muscle strength; it’s use,
believe it would not be unreasonable for a clinician to try however, was not recommended by ISSAM (International
Anorexia
Catecholoamines Pyrogenic
IL-6 Disability
blocker APR
TNF-
ACE inhibitor CRP
IL-1
Recruitment of neutrophils
REE IL-1
Immunoglobulin production
Augment 1º
Thalidomide 2 ºAB response to inflammation
Glucocorticoid Primes PMN cytotoxicity
Cytokine Inhibitors ACE inhibitor
Protein via
Carbohydrate
metabolism PIF
metabolism
Lipid via blocker
metabolism LMF
NF-K
Cachex ia , Wa sting
via
Lipogenesis ( lipoproteins lipase activity
Anabolic agents Muscle proteolysis oxidation Lipolysis lipid synthesis
Hepatic protein synthesis ChREBp
Testosterone
GH, Ghrelin
Amino GH
acids,creatine, Ghrelin
protein
Amino acids
peptides
Gluconeogenesis Lose adipose tissue
Glucose Clearance
Glucogenlysis
Muscle wasting Glycogen-synthesis
ChRZBp= carbohydrate-responsive element-binding protein, GH =growth hormone, NPY = hypothalamic neuropeptide Y, EPA = Eicosapentaenoic acid, LMF = Lipid Mobilising Factor, PiF = Proteolysis-inducing Factor,
NF-K = nuclear factor kappaB , PMN = polymorphonuclear cells, APR = acute phase response, CRP = C-reactive protein , CRH = corticotropin-releasing hormone, ACTH = adrenocorticotropin, HPA =hypothalamic-
pituitary-adrenal axis, REE = resting energy expenditure, M = macrophage, IL-6 = interleukin-6, TNF- = Tumor necrosis factor alpha, IL-1 = interleukin-1, IL-1 = interleukin-1beta, = increase, = inhibition
ing selected groups of children with anorexia and reportedly attributable to decreased resting energy expenditure, inhibi-
affects central appetite centers. However, the results of clin- tion of lipolysis, and decreased insulin sensitivity.192 Beta
ical trials in cancer patients have been disappointing.189 blocker therapy has also shown to reverse excess protein
catabolism after severe burns and may increase skeletal muscle
Potential Side Effects mass.193 Hryniewicz and coworkers194 were able to partially
The side effects of sedation, dizziness, urinary retention, reverse cachexia through beta-adrenergic receptor blocker
and even possible extrapyramidal symptoms189,190 make it less therapy in patients with chronic heart failure.
likely to be a good drug to use in the geriatric population. Its
efficacy in the geriatric population is unproven despite its Potential Side Effects
surprising widespread usage in this group of patients. There is a higher percentage of elderly patients with sick
sinus disease, orthostatic hypotension, and bradycardia after
Potential Usage beta blocker therapy.195 The intrinsic property of beta block-
The side effects of cyproheptadine can be minimal with ers alone or in combination with other cardiac medications
lower dosage, short duration, and under close monitoring. taken by the elderly population can exacerbate their risk for
However, its benefit is questionable. It is unlikely that this sick sinus syndrome, cause bradycardia, hypotension, syncope,
drug will have a major effect on appetite. and even sinus arrest.196