Clinical trial NCT01053078
Conditions: Type 1 Diabetes Hypoglycemia Unawareness
Keywords: Type 1 diabetes Hypoglycemia unawareness low blood sugar
Sponsor: University of Minnesota
Start date: 2009-10-01; Completion date: 2014-06-01
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Low blood sugar is also called hypoglycemia. Usually, it is mild and can be treated quickly and easily by eating or drinking a small amount of a sugar-rich food. If low blood sugar is left untreated, it can get worse and cause confusion, clumsiness or fainting. Severe hypoglycemia can lead to seizures, coma, and even death.

Some people with diabetes do not have early warning signs of low blood sugar. This condition is called hypoglycemia unawareness. It happens when the body stops reacting to low blood sugar levels and the person does not realize that they need to treat their hypoglycemia. This can lead to more severe and dangerous hypoglycemia.

The purpose of this early study is to see if a drug called naltrexone should be studied more in people with Type I diabetes and hypoglycemia unawareness. This study will show whether naltrexone could reduce hypoglycemia unawareness. The study will also show, by using magnetic resonance imaging (also called MRI), whether naltrexone changes the way blood flows in the brain when a person is experiencing hypoglycemia.

Detailed description:
Visit 1

This visit is estimated to last approximately 1 hour.

At this visit, you will be asked to complete a questionnaire about hypoglycemia unawareness. Some questions about your medical history may be asked in order to make sure you are eligible to be in this study. You will also have some blood collected for tests that measure how your liver and kidneys are working. A blood test that measures muscle breakdown will also be done. If you are a female who could become pregnant, a pregnancy test will also be done. The amount of blood that will be collected at this visit is approximately three teaspoons. This visit is estimated to last approximately one hour.

You will be asked to wear a continuous glucose monitor (CGMS) around the clock for the seven days before the MRI study. This involves putting a small plastic sensor under the skin on your stomach and carrying the monitor that attaches to the sensor. The sensor measures your glucose and records the readings automatically on the monitor. The monitor is about the size of the palm of a woman's hand. The information stored on the monitor can be sent to a computer that the researcher uses. The researcher will insert the CGMS at visit 1.

Between Visit 1 and Visit 2

You will also be asked to keep careful records for the study every day for the next seven days. You will be asked to check your blood glucose before each of three meals and before you go to sleep at night. You will also be asked to write down your blood glucose levels and bring those records back for the researcher.

Visit 2

Seven days after visit 1 you will be asked to report to the Center for Magnetic Resonance Research (CMRR) at 7:30AM for your first MRI scan. The study will be done in the morning after an overnight fast. All subjects will be asked to fast for a minimum of 8 hours before arriving at the center. The researcher will advise you on how to adjust your insulin regimen during the 1-2 days before the MRI scan to be sure your blood sugar is in good control when you arrive at the CMRR.

Alternatively, you may be asked to come to the Clinical Research Unit the night before the MRI study You will be admitted to the Clinical Research Unit, and stay overnight there. You will not be given any food after your evening meal until your test is completed at about lunch time on the following day. Your evening dose of long-acting insulin or your pump will be held after 6:00 p.m. that evening. Your blood glucose will be measured every 1-2 hours. An intravenous (IV) catheter will be placed in your arm and will stay there until your test is over the next day. You will be given insulin and glucose as needed to keep your blood sugars between 100 and 150 mg/dl through the night leading to testing on the next day. In the morning, you will be transferred to the Center for Magnetic Resonance Research (CMRR) for an MRI.

At the CMRR, an IV will be placed in each of your arms. This will allow for giving insulin, glucose and potassium during the test. A third IV will be placed in one of your legs. This catheter will be put in so that blood can be collected during the test. After the catheter in your leg is placed you will rest for 30 minutes. After thirty minutes, blood will be collected from the catheter in your leg for laboratory tests. The test is then ready to begin.

You will be given insulin through the catheter in one arm and you will be placed in the MRI machine. Your glucose will be checked every five minutes throughout the study. Blood will also be collected every 30 minutes for other laboratory tests. When your glucose drops to 50 mg/dl it will be held at that level for approximately 30 minutes so the measures of blood flow and glucose concentrations in your brain can be taken. While your blood sugar is dropping, you will be asked about any symptoms you may feel. After the measures have been taken, the insulin given through the IV will be stopped and you will be given glucose to bring it back to a normal level.

You will be at the CMRR for 4-6 hours. After the test is completed, your IVs will be taken out, you will resume your usual diabetes treatments, and you will be fed a meal.

Between the time you are admitted to the Clinical Research Unit and the time you are discharged after your MRI test, just less than one cup of blood will be collected.

You will be given a supply of naltrexone, the study medication, or placebo, with instructions for taking the medication over the next four weeks. You will be randomly assigned (like a flip of a coin) to naltrexone, or to a placebo (a pill that does not contain any medicine). Neither you nor your study doctor will know which study treatment (placebo or naltrexone) you are receiving. If it becomes necessary to know for medical reasons, the information will be made available.

Between Visits 2 and 3

While you are taking naltrexone or placebo you will be asked not to use Tylenol (or any other product containing acetaminophen), Advil (or any other product containing ibuprofen or a non-steroidal anti-inflammatory drug), or aspirin. You will also be asked to avoid alcohol while taking naltrexone. If you have any concerns or questions about using these substances during the time you are taking naltrexone please ask the study doctor or coordinator.

You should always take your naltrexone dose right after you eat a meal.

Days 1 - 5: Starting the day after your MRI test, you will be asked to take one 25 mg tablet of naltrexone or placebo each day for the next five days.

Days 6 - 10: On these days you will be asked to take one 50 mg tablet of naltrexone or placebo each day.

Days 11- 14: On these days you will be asked to take one 50 mg tablet of naltrexone or placebo twice each day. Visit 2 for the study will occur on Day 14.

Visit 3

This visit is estimated to last approximately 30 minutes.

You will come to the Clinical Research Unit for a short visit on this day. Blood will be collected for tests that measure how your liver and kidneys are working. A blood test that measures muscle breakdown will also be done. Just like at visit 1, the amount of blood collected from you at this visit will be approximately three teaspoons.

The study doctor or coordinator will also talk to you about how you are feeling. You will be asked about whether you have been taking naltrexone or placebo according to the study plan.

Between Visits 3 and 4

Days 15 - 21: On these days you will be asked to take one 50 mg tablet of naltrexone or placebo twice each day.

Visit 4

This visit is estimated to last approximately 30 minutes.

You will be asked to wear a continuous glucose monitor (CGMS) around the clock for the seven days before the MRI study. This involves putting a small plastic sensor under the skin on your stomach and carrying the monitor that attaches to the sensor. The sensor measures your glucose and records the readings automatically on the monitor. The monitor is about the size of the palm of a woman's hand. The information stored on the monitor can be sent to a computer that the researcher uses. The researcher will insert the CGMS at visit 4.

Between Visits 4 and 5

Days 22 - 28: On these days you will be asked to take one 50 mg tablet of naltrexone or placebo twice each day. You will take your last study dose of naltrexone or placebo on Day 28.

Starting on Day 22, just like in the first part of this study, you will also be asked to keep careful records for the study every day during this time. You will be asked to check your blood glucose before each of three meals and before you go to sleep at night. You will also be asked to write down your blood glucose levels and bring those records back for the researcher.

Visit 5

Just like in the first part of the study, you will be asked to report to the Center for Magnetic Resonance Research (CMRR) at 7:30AM for your first MRI scan. The study will be done in the morning after an overnight fast. All subjects will be asked to fast for a minimum of 8 hours before arriving at the center. The researcher will advise you on how to adjust your insulin regimen during the 1-2 days before the MRI scan to be sure your blood sugar is in good control when you arrive at the CMRR.

Alternatively, you will be asked to come to the Clinical Research Unit the night before the MRI study. You will come in the day before you take your last dose of naltrexone or placebo. You will be admitted to the Clinical Research Unit, and stay overnight there. You will not be given any food after your evening meal until your test is completed at about lunch time on the following day. Your evening dose of long-acting insulin or your pump will be held after 6:00 p.m. that evening. Your blood glucose will be measured every 1-2 hours. An intravenous (IV) catheter will be placed in your arm and will stay there until your test is over the next day. You will be given insulin and glucose as needed to keep your blood sugars between 100 and 150 mg/dl through the night leading to testing on the next day. In the morning, you will be transferred to the Center for Magnetic Resonance Research (CMRR) for an MRI.

Blood will be collected for tests that measure how your liver and kidneys are working. A blood test that measures muscle breakdown will also be done.

The procedures for Visit 5 will be exactly the same as the procedures in Visit 2. The only difference is that you will not be given any naltrexone or placebo at the end of the visit. When you complete Visit 5, your participation in the study has been completed.

At the CMRR, an IV will be placed in each of your arms. This will allow for giving insulin, glucose and potassium during the test. A third IV will be placed in one of your legs. This catheter will be put in so that blood can be collected during the test. After the catheter in your leg is placed you will rest for 30 minutes. After thirty minutes, blood will be collected from the catheter in your leg for laboratory tests. The test is then ready to begin.

You will be given insulin through the catheter in one arm and you will be placed in the MRI machine. Your glucose will be checked every five minutes throughout the study. Blood will also be collected every 30 minutes for other laboratory tests. When your glucose drops to 50 mg/dl it will be held at that level for approximately 30 minutes so the measures of blood flow and glucose concentrations in your brain can be taken. While your blood sugar is dropping, you will be asked about any symptoms you may feel. After the measures have been taken, the insulin given through the IV will be stopped and you will be given glucose to bring it back to a normal level.

You will be at the CMRR for 4-6 hours. After the test is completed, your IVs will be taken out, you will resume your usual diabetes treatments, and you will be fed a meal.

Between the time you are admitted to the Clinical Research Unit and the time you are discharged after your MRI test, just less than one cup of blood will be collected.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Naltrexone intervention 2: Placebo
Intervention descriptions: intervention 1: 1 month treatment; Naltrexone 25mg once daily for 5 days, then 50 mg once daily for 23 days intervention 2: 1 month treatment; placebo tablet once daily for 28 days

Protocol documents:
Prot_SAP_000.pdf: 
NCT01053078 
Naltrexone and Hypoglycemia in Type 1 Diabetes 
Protocol Approval Date: August 17th, 2012
PI: Elizabeth Seaquist, MD


Hypoglycemia unawareness is a limiting factor in the treatment of type 1 diabetes and is a very 
difficult problem to reverse.  Using positron emission tomography (PET), Dunn et al have recently 
demonstrated that patients with type 1 diabetes and hypoglycemia unawareness display a brain 
activation pattern during hypoglycemia that resembles the activation pattern seen following the 
administration of an addictive substance such as cocaine (1). In this response, the amygdala and 
hypothalamic regions associated with stress were less activated and the ventral striatum region 
associated with motivation and the lateral orbitofrontal cortex region associated with reward were not 
activated as strongly during hypoglycemia in the unaware compared to the aware subjects. These 
observations raise the question of whether one reason hypoglycemia unawareness is so difficult to 
reverse is that it is rewarding and not perceived as a stress to the patient, much like the response an 
addict has to a drug upon which he has grown dependent.  If so, therapies applied to the treatment of 
addictions might provide a novel approach to the treatment of hypoglycemia unawareness in type 1 
diabetes.  One such therapy could be the orally administered non-addicting opioid antagonist 
naltrexone that has been shown to be effective in the treatment of many addictions (2-4). 
 
The long-term goal of this project is to test the hypothesis that naltrexone therapy in subjects with 
type 1 diabetes and hypoglycemia unawareness will: 
• reduce the number of hypoglycemic events (defined as number of episodes of hypoglycemia 
that require the assistance of another to recognize/treat and as minutes during which blood 
glucose is < 70 mg/dl as measured by continuous glucose monitoring, both over a 7 day 
period),  
• improve recognition of hypoglycemia during experimental conditions, and  
• reduce activation in the ventral striatum and lateral orbitofrontal cortex and increase activation 
in the amygdala and hypothalamus during hypoglycemia.   
 
In this application, we describe a pilot study to determine if this treatment is of any benefit in treating 
hypoglycemia unawareness and to collect the observations necessary to develop a full-scale clinical 
trial of sufficient power to address our hypothesis.  Our specific aim is to perform a randomized 
double blind trial of four weeks of naltrexone or placebo therapy in twenty subjects with type 1 
diabetes and hypoglycemia unawareness and compare the outcome measures collected before 
treatment with those collected at the end of the treatment period. 
 
Background and significance 
Hypoglycemia unawareness is a limiting factor in the treatment of type 1 diabetes.  Lack of 
awareness of hypoglycemia increases the risk for severe hypoglycemia, coma, and death during 
insulin therapy (5) and fear of hypoglycemia may prevent patients from optimally controlling their 
blood sugars, thereby increasing their risk for the development of diabetes complications.  Strict 
avoidance of hypoglycemia has been known to partially restore awareness of hypoglycemia (6), 
however it is very difficult to achieve.  Using PET, Dunn et al (1) have reported an increase in glucose 
uptake (a measure of activation) in brain regions associated with motivation (ventral striatum) and 
reward perception (lateral orbitofrontal cortex) and decreased activation of stress related regions 
(amygdala) during hypoglycemia in hypoglycemia unaware subjects with type 1 diabetes relative to 
hypoglycemia aware subjects with type 1 diabetes.   This activation pattern resembles that seen in 
response to substances with addictive potential (7, 8), raising the question of whether one of the 
reasons that hypoglycemia unawareness is so difficult to reverse is that it is rewarding and not 
perceived as a stress to the patient.     


 
Naltrexone, which can be delivered orally, has been shown to be safe and efficacious in the treatment 
of various addictive disorders such as alcoholism (4), opiate addiction (2) and pathological gambling 
(3). The drug binds primarily to the µ opioid receptor and is believed to block the binding of beta-
endorphins released from the nucleus accumbens and ventral tegmental areas upon exposure to an 
addicting drug like alcohol.  This blockade in turn ultimately affects downstream activation in regions 
associated with reward and craving (9).  Naltrexone is approved by the Food and Drug Administration 
for treatment of alcoholism at a dose of up to 50 mg a day for an indefinite period of time but has 
been used in higher doses to treat pathological gambling (10). Efficacy in reducing alcohol cravings 
increases with treatment periods longer than 60 days, but were reduced by approximately half after 
30 days of treatment (4).  The drug has a black box warning about hepatotoxicity at doses above 50 
mg/day, but in otherwise healthy out-patients, doses up to 200 mg a day were well tolerated and 
associated with normal liver function tests for more than a year (11).  
 
During hypoglycemia, intravenous administration of the µ opioid receptor antagonist naloxone 
enhances the epinephrine and cortisol secretory responses during hypoglycemia in both normal 
controls and in patients with type 1 diabetes (12).  More recently, naloxone infusion during an episode 
of hypoglycemia prevented the development of hypoglycemia associated autonomic failure in normal 
controls (13).  These observations suggest that a m opioid receptor antagonist might be of benefit in 
the treatment of hypoglycemia unawareness through a direct effect on cerebral glucose sensing 
and/or the coordinated counterregulatory response even if it does not prove to have an effect on the 
activation of centers involved in motivation and reward.   
 
Preliminary Data 
Our research group is very experienced in all aspects of the methodology required to complete this 
project.  We have a long track record of successfully recruiting subjects to participate in complicated 
metabolic studies (14-19).  In recent years, our work has focused on subjects with type 1 diabetes 
(20, 21), many with hypoglycemia unawareness, and we have developed a registry of such subjects 
interested in participating in future studies.  We also are skilled in the performance of clinical trials, 
having participated in the ACCORD trial since 1999 (22). 
 
Most relevant to this application is our experience performing hypoglycemic clamp studies while brain 
activation is studied using magnetic resonance techniques.  In our laboratory, we have used 
continuous arterial spin labeling (CASL) to identify brain regions that are activated in response to 
insulin-induced hypoglycemia in healthy human subjects (23).  Five men and five women (age 29 ± 
10 yrs, BMI 23.3 ± 2.1 kg/m2, mean ± SD) participated in this study. CASL images were acquired at 
euglycemia (99±5 mg/dl ) and again during hypoglycemia (52 ± 3 mg/d;) using 2D GE-EPI (labeling 
time=2500 ms, resolution =2x2x3mm, 100 label/control pairs).  In whole brain analysis, increases in 
regional cerebral blood flow, a measure of neuronal activation, were noted during hypoglycemia 
relative to euglycemia bilaterally in the medial thalamus, anterior cingulate, and posterior cingulate 
using BrainVoyager software, as has also been demonstrated by Teves et al using PET (TEVES 
PNAS 2004).   These increases coincided with the peak responses in counterregulatory hormones 
(glucagon = 110 ± 41 pg/ml, epinephrine = 519 ± 273 pg/ml, norepinephrine = 405 ±124 pg/ml), 
providing evidence that activation of these brain regions is involved in the counterregulatory response 
to hypoglycemia.  Focused region of interest analysis of specific regions such as the hypothalamus or 
amygdala was not performed in this study, but will be performed in the proposed project. 


 
Research Design and Methods: 
This study will be a randomized double blind placebo controlled trial involving 20 subjects with type 1 
diabetes and hypoglycemia unawareness.  Since the time necessary for the effect of naltrexone on 
our outcome variables to washout after a treatment period is unknown, each subject will serve as 
their own control and differences between the changes in the outcome measures will be evaluated 
between groups.  The study design is depicted in the figure below.   
 
Subjects 
Subjects between the ages 18 and 65 years of age will be recruited for participation from the 
University of Minnesota Endocrine Clinic and a registry of volunteers maintained by the investigators.  
Type 1 diabetes will be defined on clinical grounds.  To be categorized as experiencing hypoglycemia 
unawareness, subjects must first report at the time of initial contact an inability to recognize at least 
some blood glucose values less than 50 mg/dl during the prior 3 months.  At the time of the screening 
visit, subjects must then be defined as having hypoglycemia unawareness on a Cox questionnaire 
(24). Exclusion criteria will include concomitant use of acetaminophen, aspirin or ibuprofen (all may 
increase risk of naltrexone induced liver dysfunction), history of drug or alcohol abuse, current 
diagnosis or history of psychiatric illness, history of liver disease wiwth elevations in ALT/AST, history 
of renal insufficiency/failure (creatinine >1.5 mg/dL), pregnancy or breastfeeding, history of seizure or 
cardiac disease (both of which will increase risk of hypoglycemic clamp), history of stroke, head 
injury, or other chronic CNS disease, and presence of any characteristics that would preclude 
placement in the magnet (weight > 300 lbs, presence of metallic implants, etc.). 
 
Experimental protocol 
The screening visit will occur within two weeks of day zero, which will be the day of the first 
hypoglycemia study.  At the screening visit, informed consent will be obtained and a standardized 
form will be used to insure subjects meet inclusion/exclusion criteria.  Baseline labs for creatinine, 
ALT, AST, hemoglobin A1c, and CPK will be obtained.  The subject will be educated in the use of the 
continuous glucose monitor and sent home with sufficient supplies to collect data for the seven days  
before the clamp study on day zero.  During this period, subjects will also check their blood glucose 
before each of three meals and at bedtime and record the values as well as note any episodes in 
which another person was required to recognize and/or treat hypoglycemia.  The continuous glucose 
monitor display will be blinded to the subject so that it does not influence their diabetes management. 
 
Subjects will be admitted to the research center the afternoon before the hypoglycemic clamp study 
on day zero.  They will be allowed to take their short acting insulin or a bolus via their pump with their 
evening meal, but their evening dose of long-acting insulin or their pump will be held after 6 PM.  
Blood glucose values will then be monitored every 1-2 hours and an intravenous infusion of insulin 
and/or glucose will be provided to maintain blood sugars between 100-150 mg/dl.  Subjects will not 
be given additional food after their evening meal until the end of the hypoglycemic clamp on day zero. 
 
On the morning of the study, subjects will be transferred to the Center for Magnetic Resonance 
Research. After their arrival, they will be prepared for clamp study by the placement of one 
intravenous catheter into one vein in each antecubital fossa for the later infusion of glucose, insulin, 
and potassium.  A third intravenous catheter will be placed retrograde into a vein in the distal leg for 
later blood sampling.  Baseline blood samples for glucose, glucagon, catecholamines, cortisol, and 


growth hormone will then be collected no sooner than 30 minutes after catheter placement.  At time 0 
a constant infusion of insulin will be started at 2.0 mU/kg/min and the subject will be placed into the 
magnet. Plasma glucose be initially maintained at euglycemia (~100 mg/dl) while the baseline scan is 
done.  Plasma glucose will than be reduced to 50 mg/dl and maintained at this level of glycemia for 
approximately thirty minutes. During the final 15 minutes subjects will be asked to quantitate their 
symptoms using a standardized method (25).   Blood samples will be obtained every five minutes for 
measurement of plasma glucose concentration on a nearby analox machine and every twenty 
minutes for  later measurement of glucagon, catecholamines, cortisol, and growth hormone.   
 
Cerebral blood flow will measured 
on a Siemens 3 Tesla magnet when 
the subject is euglycemic and again 
during the final 15 minutes of the 
hypoglycemic period.   A T1 
mapping technique will be used in 
which a RARE sequence with etl=8 
echoes and an echo spacing of 7 
ms with center-out k-space sampling 
(effective TE = 7 msec) is employed.  
CBF contrast will be achieved using 
FAIR (26)with a 12 msec long HS8 
inversion pulse to generate a 6.6 Hz 
inversion bandwidth above a peak 
B1 of 500 Hz. A T1-image will be 
calculated at steady state from three 
acquired images on a pixel by pixel 
basis, as previously described (27).  
 
Cerebral blood flow maps will be calculated according to: 
 
 
 
where λ (ml/g) denotes the brain-blood partition coefficient of water, T1 (s) is the longitudinal 
relaxation time of tissue water, a is the efficiency of arterial spin labeling, and S0 and ST are signal 
intensities of control and arterial spin labeled images, respectively. Differences in whole brain 
cerebral blood flow measured during hypoglycemia and euglycemia will be determined for each 
subject.  The perfusion images will then be transformed into Talairach space using the anatomic 
images and differences between individual regions of interest (such as amydgala, ventral striatum, 
lateral orbitofrontal cortex, and hypothalamus) during hypoglycemia and euglycemia will be 
determined for each subject.  Dr. Silvia Mangia from the Center for Magnetic Resonance Research 
will be responsible for the collection and processing of the data collected using the 3 T magnet. 
 
At the completion of the clamp study, subjects will be removed from the magnet, the insulin infusion 
will be discontinued,glucose will be given to achieve euglycemia, and subjects will be fed a meal. 
Randomization will then be done  and subjects will be sent home with their assigned treatment.  An 
Study design.  CGMS= continuous glucose monitoring; 
BG=blood glucose; CASL = continuous arterial spin labeling; 
hypo= hypoglycemic; safety labs = ALT, AST, Cr, CPK 


Investigational New Drug (IND ) approval for the use of this medication for this study has already 
been obtained from the Food and Drug Administration.  The investigational pharmacy at the 
University of Minnesota Medical Center will insure that the naltrexone and placebo tablets are 
identical in appearance and will maintain the log of the treatment assignment.  Only the study 
pharmacist will have access to this log until the study is completed.  The dose of the drug will be 
titrated up over 10 days (25 mg daily x 5 days, then 50 mg daily x 5 days, then 50 mg BID x 18 days). 
Subjects will be asked to avoid use of acetaminophen, non-steroidal anti-inflammatory medications 
and alcohol while taking naltrexone.  At 14 ± 1 days, subjects will return to provide blood for 
measurement of ALT, AST, CPK, and creatinine.  Drug will be stopped in subjects who experience an 
increase that exceeds two times the upper limit of normal for ALT, AST, or CPK  or have a rise in their 
creatinine to 2.0 mg/dl or above in men or 1.5 mg/dl or above in women.   
 
At the 14 day visit, subjects will be reminded to wear the continuous glucose monitor for the seven 
days before the next hypoglycemic clamp study and will be sent home with sufficient supplies to do 
so.  On the night before the clamp study, they will be readmitted to the research center for 
preparation as outlined above.  Repeat samples for ALT, AST, CPK, and creatinine will also be 
collected.  On the day of the study, subjects will take their final dose of naltrexone/placebo and be 
transported to the Center for Magnetic Resonance Reserch to repeat the clamp study with 
measurement of cerebral blood flow described above. 
 
Statistical analysis 
This is a pilot study in which a sample size of 20 (10 subjects to receive placebo and 10 subjects to 
receive naltrexone) was arbitrarily selected to determine how large a sample size will be necessary to 
determine if naltrexone has an effect on our outcome measures.  Each subject will serve as his/her 
own control and changes in the outcome variables (number of hypoglycemic events defined as 
number of episodes of hypoglycemia that require the assistance of another to recognize/treat and as 
minutes during which blood glucose is < 70 mg/dl as measured by continuous glucose monitoring, 
both over a 7 day period); symptom scores collected during hypoglycemia’ and differences in regional 
blood flow noted between the euglycemic and hypoglycemic conditions for each study), will be 
compared between pre-treatment and end of treatment periods using Student’s t-test with correction 
for repeated measures.  Dr. Lynn Eberly from the Department of Biostatistics at the University of 
MInnesota will assist in the statistical analyses.  
 
Anticipated problems/potential solutions 
The most significant problem we may encounter is that our treatment outcomes will be unaffected by 
naltrexone treatment. Originally, we intended to focus on the effect of naltrexone on cerebral blood 
flow as a measure of regional activation during hypoglycemia, but since we are unaware of data that 
demonstrate naltrexone alters brain activation patterns in addicts, we have broadened our outcome 
measures to include more clinically relevant information such as frequency of hypoglycemia and 
symptom scores during controlled hypoglycemia.    We are hopeful that naltrexone will have an effect 
on at least one of the outcome variables and will use the data collected from this pilot to design a 
larger study.   
 
 
 


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