Oral delta-9-THC (Marinol) for AIDS-related anorexia/weight loss

Background Information of the Condition

Weight loss in AIDS patients results from loss of appetite (anorexia), wasting of muscle and adipose tissues (cachexia), and leads eventually in death.  Adequate treatments are needed to prevent malnutrition.  The goals of therapy in AIDS patients who are anorexic and cachexic are to increase appetite, increase or maintain weight, and increase quality of life.

Marinol, an oral Δ⁹-THC formulation, is a synthetic cannabinoid indicated previously as an anti-emetic in severe nausea and vomiting associated with cancer chemotherapy.  It is available as 2.5, 5.0, and 10.0 mg oral gel capsules.  Smoked medical marijuana is intended for general use and symptom management in HIV/AIDS patients.

Drug (Product Monograph)

Category: Marinol is categorized as an anti-emetic.  It is a psychotropic agent, which may produce physical and psychological dependence and has the potential for abuse. The active component THC is scheduled under the Controlled Drugs and Substances Act as a narcotic.

Mechanism of Action: Effects of Marinol are due to binding to the endogenous cannabinoid receptors (CB1 and CB2) thereby mimicking the pharmacological effects of the endocannabinoids, anandamide and 2-arachidonoylglycerol synthesized in humans.  The CB1 and CB2 receptors are found within the central and peripheral nervous systems, as well as in the cardiovascular, immune, and reproductive systems. 

Indications: for the treatment of AIDS-related anorexia associated with weight loss in adult patients.

Dose: Initial dose of 2.5mg b.i.d. to a maximum of 20mg/day in divided doses.
Caution is advised in prescribing Marinol in elderly patients because they are generally more sensitive to the psychoactive effects of drugs.

Duration: Marinol has not been systematically evaluated beyond 6 weeks in controlled clinical trials for AIDS-related anorexia associated with weight loss. The physician who elects to use it for extended periods in this indication should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Methodology of Systematic Review

Research Question(s):

1. In randomized controlled trials does Marinol monotherapy provide a therapeutic advantage over other formulations of cannabinoids or cannibis (smoked marijuana), other therapies such as megestrol acetate, anabolic agents (nandrolone and oxandrolone), testosterone replacement, recombinant human growth hormone, corticosteroids, thalidomide or pentoxifylline, or versus placebo in the treatment of anorexia associated with weight loss in AIDS patients?
2. In randomized controlled trials does Marinol in combination with other appetite stimulants/weight enhancers provide a therapeutic advantage over Marinol monotherapy in the treatment of anorexia associated with weight loss in AIDS patients?

Assessment principles:  We critically appraised single- or double-blind randomized controlled trials comparing Marinol to appropriate comparators in patients with AIDS-related anorexia associated with weight loss.  We examined results according to the following hierarchy of health outcome measures – all-cause mortality, non-fatal serious adverse events, general health and quality of life, withdrawals due to adverse events, surrogate outcomes (changes in lean body mass, weight, appetite, nausea, vomiting), and other adverse events such as CNS effects and sympathomimetic activity.

Search strategy: Databases searched were – Medline (1966- Dec. 2005), EMBASE (1988- Dec. 2005), the Cochrane database (issue 3, 2005) and the US FDA website.

Search Findings:
One DBRCT compared Marinol to smoked marijuana (Haney et al, 2005).  Three DBRCTs compared Marinol to placebo (Haney et al, 2005, Struwe et al, 1993 and Beal et al, 1995).  One open-label RCT compared combination therapy with Marinol and megestrol acetate versus Marinol alone or megestrol acetate alone (Timpone et al, 1997).

Results by trial:
Haney et al, 2005 is a dose ranging study which compared Marinol (10, 20, 30 mg Δ⁹-THC p.o.) vs. smoked marijuana (1.8%, 2.8% and 3.9% Δ⁹-THC) vs. placebo in a 4-week double-blind, RCT in 30 HIV positive patients with (N = 15) or without excessive muscle mass loss (N = 15) who were regular smokers of marijuana (smoked at least twice a week for the past 4 weeks).  This study used much higher doses of Marinol than is normally recommended for appetite enhancement.  This trial does not report on serious adverse events, functioning, quality of life, changes in weight, appetite, and nausea.  Caloric intake was found to increase significantly in patients with low muscle mass at all doses of Marinol and marijuana (except for the 2.8% dose) compared to placebo but the effect on weight is not reported. Adverse effects (sedation, stimulation, forgetfulness, withdrawn, dreaming more, nausea, vomiting, headache, and diarrhea) were more predominant in the oral Marinol and smoked marijuana groups (11 adverse events) compared to placebo (2 adverse events- nausea and dizziness). 

Struwe et al, 1993 is a 12-week double blind randomized cross over trial in 12 patients with HIV comparing Marinol (5.0 mg b.i.d. before lunch and supper) vs. placebo (5 weeks treatment followed by a 2-week washout period then 5 weeks on switched treatment).  7 (58%) patients withdrew and based on the results reported on the 5 remaining patients, no conclusions can be drawn. 

Beal et al, 1995 is a 6-week double blind RCT in 139 patients with AIDS-related weight loss comparing Marinol (2.5 mg to 20 mg oral daily) vs. placebo.  Since a large percentage of randomized patients were non-evaluable (43% in placebo group and 31% in treatment group), the results reported for the evaluable patients is too limited to draw scientificaly valid conclusions. Mortality, serious adverse events, and total adverse events were not reported.

Timpone et al, 1997 is a 12-week open label RCT in 52 anorexic patients with HIV wasting syndrome comparing Marinol (2.5 mg b.i.d.) in combination with megestrol acetate (250 mg/day or 750 mg/day) to Marinol (2.5 mg b.i.d.) monotherapy or megestrol acetate (750 mg/day) monotherapy.  47 patients returned for at least one visit and 39 completed the study.  There was significant mean weight gain with megestrol acetate 750 mg/day monotherapy (+ 6.5 + 1.1 kg) or when combined with Marinol (+6.0 + 1.0 kg).  The mean decrease in weight with Marinol monotherapy was – 2.0 + 1.3 kg and in the megestrol acetate 250mg + Marinol group was – 0.3 + 1.0 kg.  No significant difference was found between treatment groups in quality of life or withdrawals due to adverse events.  37/47 (79%) patients experienced one or more adverse events of grade 3 or 4 severity (7 in Marinol monotherapy group, 8 in megestrol acetate monotherapy group, 11 in each of the combination therapy groups).  10 patients experienced grade 3 or 4 neurological events (confusion, anxiety, depression, emotional lability, euphoria, hallucinations, somnolence, psychosis, amblyopia and seizure).

Critical appraisal Issues:
The included trials are of insufficient quality to determine the impact of marinol on weight gain or loss. The trials did not report  on other important outcomes including general health or quality of life. 

Conclusions:

Marinol versus other formulations of THC or Marijuana
Based on one double blind RCT (Haney et al, 2005) there is insufficient evidence to conclude that Marinol provides a therapeutic advantage over smoked marijuana in patients with AIDS-related anorexia associated with weight loss.

Marinol versus Megestrol acetate
Based on one 12-week open-label RCT (Timpone et al, 1997) comparing Marinol in combination with megestrol acetate with Marinol monotherapy or megestrol acetate monotherapy in patients with AIDS-related anorexia associated with weight loss there is insufficient evidence to conclude that Marinol provides a therapeutic advantage over megestrol acetate.

Marinol versus Placebo
Based on three double blind, RCTs (Haney et al, 2005, Struwe et al, 1993 and Beal et al, 1995) there is insufficient evidence to conclude that Marinol provides a therapeutic advantage over placebo in patients with AIDS-related anorexia associated with weight loss.

References:

1. Nemechek, P.M., et al.  Treatment guidelines for HIV-associated wasting.  Mayo Clin. Proc. Apr., 75(4): 386-394, 2000.
2. Electronic CPS, 2007. 
3. Marinol Product Monograph, Solvay Pharma, 2004.
4. Haney M, Rabkin J, Gunderson E and Foltin RW.  Dronabinol and marijuana in HIV+ marijuana smokers: acute effects on caloric intake and mood.  Psychopharmacology, 181; 170-175: 2005.
5. Struwe M, Kaempfer SH, Geiger CJ, et al.  Effect of dronabinol on nutritional status in HIV infection.  The Annals of Pharmacotherapy, 27(7-8): 827-831, 1993.
6. Beal, JE, Olson, R, Laubenstein, L, Morales, JO, et al.  Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS.  J. Pain and Symptom Management, 10(2): 89-97, 1995.
7. Timpone, JG, Wright DJ, Li, N, Egorin MJ, et al.  The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome.  AIDS Research and Human Retroviruses, 13(4): 305-315, 1997.