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CRIA Study Results

Spring 2001

The results of two CRIA studies were presented recently (see below). Because of their potential practical applications, the study results were well received by both medical providers and people living with HIV.


Topical Aspirin for Peripheral Neuropathy

Patients who are experiencing painful peripheral neuropathy should consult with their primary care providers. Most pharmacies can compound this preparation of aspirin dissolved in ether with a prescription. Some pharmacists are concerned about the safety of people storing an ether preparation because of its flammable nature. Because of the positive results of this study and the frequency of painful peripheral neuropathy, CRIA is looking at other topical aspirin preparations.


Poster Presentation at the 8th Conference on Retroviruses and Opportunistic Infections, #601, February, 2001

Topical Application of Aspirin/Diethyl Ether in Treatment of Painful Distal Sensory Polyneuropathy in HIV-Positive Individuals: A Randomized, Double-Blind, Crossover Placebo-controlled Study.
I. Cergnul,1 J. Ernst,1 S. Blum,2 J. Cadman1
Community Research Initiative on AIDS (CRIA)1, New York, NY. Bronx-Lebanon Hospital Center,2 Bronx, NY.

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Introduction

With the increase in survival of people infected with HIV, many medical complications are occurring with increased frequency. Among these are the HIV-associated neuropathic disorders. Distal symmetric polyneuropathy (DSP) has been reported to be the most common neurological complication in patients with HIV. Patients commonly present with slowly progressive sensory loss and dysesthesias such as numbness, burning sensations, tingling and pain in the feet.

The Multicenter AIDS Cohort Study found that, between 1985 and 1992, DSP had the highest yearly increase in incidence among the neurologic complications of HIV infection, peaking at 2.81% in 1992. Treatment of DSP is problematic. Most treatments involve symptomatic pain control using nonopioid analgesics combined with a tricyclic antidepressant. Greater levels of pain require the use of opioids. Topical agents have also been used with varying degrees of success.

Topical nonsteroidal anti-inflammatory drugs have been used to treat local painful conditions of skin, joints and muscles. An advantage of a topical preparation is the ability to achieve high local concentrations of the agent with negligible systemic levels and, therefore, fewer adverse side effects or drug-drug interactions. Acetylsalicylic acid (aspirin), when applied topically, has been shown to have such a profile.


Objective

The aim of this investigation was to elucidate whether a topically applied solution of acetylsalicylic acid in diethyl ether (ASA/DE) provided adequate pain relief for HIV-infected people with distal symmetric polyneuropathy.


Patient Eligibility

  • HIV Infected

  • Age > 18

  • Presence of painful DSP as diagnosed by a comprehensive history and neuralgic examination

  • Duration of symptoms for >1 month

  • Grade 5 or higher on Brief Pain Inventory (BPI) scale


Methods

The study was a randomized, double-blind, crossover, placebo-controlled trial of a solution of acetylsalicylic acid dissolved in ether applied topically to the affected limbs of HIV infected patients with DSP. The primary outcome measure was the patients' description of pain as scored on the Brief Pain Index (BPI) using a 10 point scale.

43 HIV positive adults with DSP were randomized to one of two treatment arms. Patients in the first arm applied 7 ml. of a solution containing 375mg. ASA/DE three times a day to their distal extremities for 2 weeks. After a three-day washout period they then applied ether alone three times a day for an additional two weeks. Patients randomized to the second treatment arm self administered the placebo t.i.d. for two weeks, no treatment for three days and then two weeks of t.i.d. ASA/DE (375mg/dose). BPI was administered at the start of the study and then at the end of each week of treatment in each arm. All BPI questionnaires were administered, in person, by the same investigator (Dr. Cergnul).


Results

Of the 43 patients enrolled, 31 completed the study. Demographics and clinical characteristics were as follows: males were 55%, median age was 43, median length of HIV infection was 10 years, average time affected with DSP was 3 years. 90% of patients had an AIDS defining illness. The median CD4 cell count was 300 cells/ml. A median improvement in BPI of 30 % over baseline was present in the ASA/DE arm. The ASA/DE arm was also found to be 30% better than placebo. "Best" days on ASA/DE were 30 % better than baseline, and the "worse" days were 25% better on ASA/DE then at baseline. All results were statistically significant at p

Conclusions

Our study showed that the topical administration of aspirin in diethyl ether applied three times a day produced statistically significant pain relief when used in HIV infected patients with distal symmetric polyneuropathy. No side effects were reported by any of the study participants. Of note is the fact that 8 out of the 12 patients who dropped out of the study did so after the pain relief they felt in the first two-week period of the study disappeared when they were switched to the other solution in the second period These 8 patients were found at the close of the study to have received topical aspirin in the first two week period.

A solution of ASA/DE applied topically is a valuable alternative to other modalities of pain relief currently in use in the treatment of DSP in HIV infected individuals.


SAM-e to Treat Severe Depression in HIV-Positive Patients

Most health food stores and many buyers' clubs carry various brands of SAM-e (S-adenosyl-L-methionine). No independent agency regulates these products, so the quality may vary from brand to brand and even from bottle to bottle within a brand. Some bottles labeled as SAM-e may not even contain any active substance. As with any complementary therapy, talk with your healthcare provider before taking SAM-e.


Poster Presentation at the 13th National HIV/AIDS Update Conference in San Francisco, #3002, March, 2001

S-adenosylmethionine (SAM-e) in the Treatment of Depressive Disorders in HIV-Positive Individuals: Interim Results
I. Cergnul1, K. Jones,2 J. Ernst,1 D. Goldenberg,3 R. Brown4
Community Research Initiative on AIDS (CRIA),1 New York, NY; St. Vincent's Hospital,2 New York, NY; Weill Medical College of Cornell,3 NY; Columbia University,4 New York, NY.


Introduction

Depressive mood disorder is the most common reason for mental health assessments and interventions in HIV-positive individuals. Great strides have been made in the pharmacological treatment of depression and increasingly primary care providers are becoming proficient in the chemical treatment of depression. However, it is a major challenge in clinical research to identify a more efficient antidepressant, faster in onset of activity, with fewer side effects and few drug-drug interactions, which is especially important in HIV patients who are on complex antiretroviral regimens.


Rationale

SAM-e (S-adenosyl-L-methionine) is a naturally occurring molecule, present in almost every tissue and fluid in the human body. It has been extensively studied for over 25 years and is marketed in Europe as a prescription drug used in treatment of depression. The body uses this substance in a variety of biochemical reactions involving enzymatic transmethylation which is crucial to the proper functioning and structure of proteins, nucleic acids, lipids, hormones and neurotransmitters. In earlier placebo-controlled studies, treatment with SAM-e showed an increase in the metabolism of norepinephrine and serotonin (neurotransmitters implicated in the onset of depression). The likelihood of drug interactions (particularly important to HIV-patients on antiretroviral therapy) is significantly reduced because SAM-e is not metabolized by the liver, but rather used by the liver. Side effects reported in the literature prior to this study were mild and the SAM-e was well tolerated.


Methods

This was an open-label 8-week study that involved the enrollment of 20 HIV-positive patients with the diagnosis of Major Depressive Disorder (DSM- IV). Severity of depression was assessed by using the Hamilton Rating Scale for Depression (HAM-D) and Beck's Depression Inventory (BDI).Both scales are standard tools in assessing the level of depressed mood with the higher the score, the greater the severity of depression.

After the initial assessment by a study psychiatrist and baseline blood work, enrollees were started on 200mg of SAM-e twice a day with a daily supplementation of 1,000mcg B12 and 800mcg of Folic Acid (vitamins that assist the activity of SAM-e). During the study the oral dose of SAM-e was adjusted gradually on an individual basis up to 800mg twice a day. The doses were adjusted according to the severity of symptoms and rate of improvement. Patients were seen by the study psychiatrists at weeks 1, 2, 4, 6, and 8. At each visit the BDI was completed by the patient , the HAM-D, Karnofsky score, and HIV-symptoms checklist were administered by a study psychiatrist.


Eligibility Criteria

Inclusion Criteria:
  • HIV-positive serostatus

  • Major depression (DSM -- IV)

Exclusion Criteria:

  • Unstable medical illness

  • Pregnancy, lactation or refusal of participants to employ an acceptable method of contraceptive

  • History of substance abuse in the prior month

  • Treatment with another psychotropic medication within 2 weeks prior to initiation of SAM-e treatment

  • Concurrent treatment with MAO-inhibitors

  • Active suicidal ideation and/or psychotic symptoms

  • Reversible medical pathology thought to be causing depression

  • History of mania or diagnosed bipolar disorder


Results

This report includes the preliminary results from the first 15 patients that have completed the study to date. The blood results are not presented as they are still being evaluated.


Total Number of Patients15
males11
females4
Mean age (range)39 (24-56)
HIV positive15
AIDS14

The median dose of SAM-e given was 400mg b.i.d.

Patients showed significant clinical improvement at weeks 4 and 8 of 74 % and 87% on BDI, and 78% and 87% on HAM-D. No side effects were reported at any time by any study participant.


 BaselineWeek 4Week 8
BDI (0-63)35 95
HAM-D (0-79)2763


Conclusion

In our trial, SAM-e appears to significantly reduce depressive symptoms in HIV-positive individuals and to dramatically improve mood and quality of life with no sign of side effects. Continuation of this study as well as other longitudinal, randomized, double-blinded studies are justified to further assess the full spectrum of activity, elucidate the mechanism of action and the safety of SAM-e.





  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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