Brain damage trial

 
A large pilot study on the effect of zolpidem after brain damage was completed by Nyakale et al, published in Arzneimittel Forschung Drug Research 2010, 60 (4): 177-81. Below are extracts from this publication. 
 

1. INTRODUCTION

 

Zolpidem (CAS 82626-48-0) is a sedative medicine that has been prescribed for insomnia for many years. It induces sleep by activating GABA(A) receptors in the brain which are inhibitory macromolecular complexes that mediate sedative, anticonvulsant, anxiolytic and myo-relaxant effects [1]. Zolpidem is a chemically distinct imidazopyridine that binds preferentially to the omega-1 subunit of the GABA (A) receptor [2,3].

 

The medical literature contains several well-documented reports of individual patients with brain damage who improved when they took zolpidem. In 2000 the first case report of an unexpected transient awareness after zolpidem describes a young male patient categorized to the vegetative state after a traumatic brain injury 3 years earlier, who regained consciousness thirty minutes after swallowing a 10mg zolpidem tablet [4]. Several similar cases have been reported since then [5-8]. Zolpidem has also been reported to improve neurological function in fully conscious patients with severe neurological disabilities due to stroke, traumatic brain injury or head injury and other causes [9-12]. In some reports, SPECT and PET scans detected an improvement of suppressed cerebral perfusion and metabolism in the brain after zolpidem [4,6,11]. Animal studies have also documented normalization of cerebral perfusion in injured brain after zolpidem [13].   

The aim of this study was to evaluate the effect of zolpidem in consecutive patients with neurological disability after brain damage, using established clinical rating scales and 99mTcHMPAO Brain SPECT scans.

 

 

2. PATIENTS AND METHODS

 

2.1 Project details

The study was registered through the Nuclear Medicine Department of the University of Pretoria (UP) as an M.Med. project of one of the participating co authors (NEN) and approved by the UP ethics committee under project registration number 80/2008.  

 

2.2 Patient population

During the last two years, all consecutive adult patients with brain damage of at least 6 months duration who applied to a co author’s practice (HWN) for zolpidem therapy were asked if they wanted to participate in the study. All were given full information regarding zolpidem and brain SPECT procedures and ample time to consider the information before they and their relatives gave written consent. All consented patients were fully examined clinically. There were 41 patients who could participate in the study. 

 

2.3 Patient selection

To determine neurological disability, all patients were rated according to the Barthel Index after interviews with their carers and families [14]. The top possible score on this index is 100/100. 23/41 patients scored less than the possible 100/100. These 23/41 patients were classed as neurologically disabled patients and selected for further study. There were 9 female and 14 male patients, aged between 20 and 77 (mean 45.8). Causes of their brain damage included stroke (n=12), traumatic brain injury (n=7), anaphylaxis (n=2), drugs overdose (n=1) and birth injury (n=1). Four were in the Minimally Conscious State, one had the Locked in Syndrome and the rest were fully conscious. 

 

2.4 Zolpidem application

Zolpidem tablets ( 10mg, Stilnox, Lot 8-64, expiry date July 2012), supplied by Sanofi Aventis South Africa (Pty) Ltd of 2 Bond Street, Midrand 165, South Africa  were provided by the Acadia Pharmacy in Pollock Park, Springs, South Africa. The 23 selected patients took 10mg zolpidem every morning for at least four months. On follow up, they were scored on the Tinetti Falls Efficacy Scale (TFES) which measures confidence in activities of daily living. The scores were based on interviews with their family and carers who rated the patient’s confidence according to the Tinetti criteria at baseline before zolpidem and after zolpidem therapy [15]. Patients and carers were asked whether any sedation was experienced after zolpidem. 

 

2.5 SPECT scan procedure and preparation

All selected patients had a baseline 99mTcHMPAO brain SPECT scan before starting zolpidem therapy and a second scan within the first two weeks after starting, performed 1 hour after 10 mg zolpidem, at peak effect. The radiotracer used for the Brain SPECT scan was 370 MBq of Technetium 99m Hydroxymethyl Propylamine Oxime (99mTcHMPAO). Before the SPECT scans, patients were required to abstain from caffeine or alcohol for 24 hours.  They were attached to an intra venous infusion line, kept patent by saline and adopted a comfortable position in a dimly lit, quiet room devoid of other people for thirty minutes, to become as calm and comfortable as possible.  A nurse then quietly entered the room and injected the 99mTcHMPAO through the patient’s intravenous line.

 

2.6 Acquisition protocol

Scans were conducted at least 30 minutes after 99mTcHMPAO injection in a supine position, using a Siemens Signature series Ecam Dual Head Gamma Camera. The imaging parameters were a 128x128 matrix, 360 degrees with 3 degree stops, 20 seconds per frame and less than 19 cm radial distance at a 140 keV photo-peak symmetrical 20% window, using low energy high resolution collimators.

 

2.7 Image processing

Images were reconstructed on an e-soft viewing station using filtered back projection and Metz filtering. Coronal, sagittal and transverse images were constructed with similar alignment in the baseline and post zolpidem images.

 

2.8 Interpretation of the Brain SPECT scans

The scans were assessed visually by three independent, experienced nuclear medicine physicians who were unaware of the scan’s timing in relation to the zolpidem treatment. Scans were presented to them as within-patient pairs, but in a random order in relation to zolpidem. The assessors were required to state which scan depicted less damage, based on lesion size and uptake, or whether there was no difference. All patients who were rated as better (less damage) on the zolpidem SPECT by two or more assessors were designated improvers while those rated as better on the baseline SPECT or “no different” were designated non-improvers. When there was no agreement between assessors they were allowed to reach a consensus opinion while remaining blinded to zolpidem treatment (4/23 patients in total).

 

2.9 Statistical analysis

The statistical analysis was completed by Dr Olorunju from the MRC biostatistics department in Pretoria, SA. The overall TFES score was compared before and after zolpidem in all patients using the non parametric Wilcoxon signed rank test. The TFES scores in patients designated as improved and non improved after zolpidem according to their Brain SPECT scans were compared, using a two sample t test with unequal variance.

 

 

3. RESULTS

 

3.1 Patients

Table 1 shows the gender, age, causes of brain damage (Diagn.: CVA- Stroke, TBI- Traumatic Brain Injury, anaph- Anaphylaxis, Birth Inj- Birth Injury, Drugs OD- Drugs Overdose) the Barthel Index (BI), the Tinetti Falls Efficacy Scale before zolpidem (TFES), the TFES after zolpidem (TFESzlp), the change in the TFES after zolpidem (change), the state of consciousness (MCS-Minimally Conscious State, LIS- Locked in Syndrome, FC- Fully Conscious) Brain SPECT scan results (I-Improvers, NI- Non Improvers) and sedation effect (sed. y-yes, n- no) for 23 neurologically disabled patients scoring less than 100/100 on the BI, at least six months after their brain damage.

 

Table 1

 

 

 

 

 

 

 

 

 

 

 

Pt

Gender

Age

Diagn.

BI

TFES

TFESzlp

change

consciousness

SPECT

Sed

1

F

53

CVA

45

73

25

48

FC

I

n

2

M

18

TBI

60

81

47

34

FC

I

n

3

M

61

CVA

40

81

48

33

FC

I

n

4

F

56

CVA

20

100

71

29

MCS

I

n

5

F

53

CVA

90

43

23

20

FC

I

y

6

M

65

CVA

95

35

15

20

FC

I

y

7

M

42

Anaph

60

86

70

16

FC

NI

y

8

M

65

CVA

30

54

42

12

FC

NI

9

M

22

TBI

0

100

90

10

MCS

NI

n

10

M

38

CVA

95

36

26

10

FC

I

n

11

F

34

TBI

5

100

93

7

LIS

NI

y

12

M

53

CVA

90

44

37

7

FC

NI

y

13

F

48

Anaph

10

100

95

5

MCS

NI

y

14

M

27

TBI

15

91

86

5

FC

NI

y

15

M

39

TBI

20

95

93

2

FC

NI

y

16

M

53

CVA

80

71

69

2

FC

NI

n

17

M

32

TBI

0

100

100

0

FC

I

n

18

F

72

CVA

10

100

100

0

FC

NI

n

19

F

20

birth inj

45

66

66

0

FC

NI

n

20

M

65

CVA

60

36

36

0

FC

I

y

21

F

77

CVA

75

62

62

0

FC

I

y

22

M

23

TBI

80

34

34

0

FC

NI

n

23

F

38

drugOD

0

100

100

0

MCS

NI

y

 

 

3.2 Clinical scale

The overall mean improvement after zolpidem on the TFES was 11.3%, a reduction from 73.4/100  to 62.1/100 (p=0.0001). 10 out of 23 patients (43%) improved on Brain SPECT scan after zolpidem while there was no improvement on the SPECT scan in 13/23 patients. In the 10/23 improvers, the mean TFES score fell by 19.4% (± 16.75) compared with 5.08% (± 5.17) in the 13/23 non improvers (p=0.0081). Table 2 shows the confidence scores between 1 (most confident) and 10 (least confident) on the Tinetti Falls Efficacy Scale items before and after zolpidem, in 23 neurologically disabled patients after brain damage, scoring less than 100/100 on the Barthel Index.

 

Table 2

 

pre zolpidem

post zolpidem

difference

p value

Taking bath or shower

7.4

5.96

1.43

0.0018

Answering the door or telephone

6.74

5.35

1.39

0.0049

Walking around the house

7.48

6.17

1.3

0.0084

Getting in and out of bed

6.26

5

1.26

0.0085

Getting in and out of a chair

6.17

5

1.17

0.0145

Reaching into cupboards

7.82

6.7

1.13

0.0462

Getting dressed or undressed

7.13

6

1.13

0.0146

Doing simple shopping

8.26

7.26

1

0.0146

Preparing a meal

8.17

7.21

0.96

0.0257

Doing light house keeping

7.91

7.39

0.52

ns0.0835

 

 

 

 

 

Overall score (all items)

73.39

62.09

11.3

0.0001

 

 

 

 

 

 

 

 

4. DISCUSSION

 

This is the first prospective, multi-patient, clinical study to demonstrate the beneficial effect of zolpidem in established brain damage.  Our patients’ injuries were severe, showing a degree of dependency by scoring less than 100/100 on the Barthel Index (BI). The BI is a widely used clinical tool to measure neurological disability, but is less sensitive for activities of daily living. We chose the equally established, but more sensitive Tinetti scale (TFES) for this purpose. It requires patients or carers to rate confidence in ten activities of daily living on a scale of 1 meaning most confident to 10 meaning least confident. The scale indirectly rates neurological disability because this is linked to lack of confidence in such activities [16].  We found a highly significant improvement (p=0.0001) in the mean TFES score after zolpidem in our 23 patients, 10 of whom improved by 10% or more and 6 by 20% or more. A 10% improvement is the equivalent of a patient progressing from inability to perform a task (1/10) to scoring full marks (10/10) which represents a clear and remarkable clinical improvement.

 

There were four patients in the Minimally Conscious State and one patient in the Locked in Syndrome included in this study. The chosen Tinetti Scale may not be the most sensitive way to evaluate these patients, but there are aspects of confidence in such patients which can be well rated on Tinetti criteria, for example “taking a bath or shower, getting in and out of bed and getting in and out of a chair”.

 

We included SPECT scans in this study as objective markers that would not be dependent on clinical rating or sensitive to placebo effects. We found a significant mean TFES improvement in the 10 patients with improved SPECT scans which contrasted with 13 non-improvers (19.4% versus 5.1%, p=0.0081). This indicates a link between clinical and SPECT scan improvements.

While placebo or positive controls are ideal markers for comparative studies, their role in this study appeared questionable due to the obvious sedative effect of zolpidem. In this study 11 of the 23 patients (48%) reported a sedative effect of zolpidem that would not have occurred on placebo, so rendering a statistical comparison between them invalid. A positive control in the form of another sedative would risk injuries from increased falls because daytime sedation would have been unavoidable for a period of several weeks. In patients who lack confidence for activities like descending steps we considered this to be ethically questionable during a proof of principle study when the beneficial effect of the test treatment remained in question. Having now established that zolpidem has an effect that probably decreases risk to further injury rather than increasing it in this patient group, our reservations for future trials will be diminished.

 

We think it improbable that the clinical and SPECT improvements were a placebo effect. Firstly, improvements on the Tinetti Scale were large and clinically more impressive than would be expected from placebos. They were 20% and over in 6 of the 23 patients which is the equivalent of patients recovering from no confidence whatsoever to full confidence in at least 2 activities.  Secondly, all patients were enrolled at least 6 months after their brain injury in a stable phase, which made spontaneous improvements most unlikely. Thirdly, apart from the objective nature of scans that detect perfusion changes within the brain, we ensured that scans were interpreted blindly and randomly by three independent assessors, who had no knowledge of the clinical rating scores.


We attempted to eliminate selection bias by enrolling consecutively presenting patients regardless of age, gender or cause of injury. This produced a wide variety of injury type and cause, which was not a major concern because previous anecdotal reports have shown beneficial zolpidem effects in a wide spectrum of clinical features and causes.  For example the first reported patient was categorized to the
Vegetative State after a traumatic brain injury, with a low Glasgow Coma Scale score of 9 that became a normal 15 after zolpidem [4]. By contrast, Hall et al found improvements after zolpidem in subtle impairments of word recognition and cognitive function in a fully conscious and independent stroke patient [17].

99mTc HMPAO SPECT scans can detect small changes in cerebral perfusion so they are often more sensitive than clinical rating scales. They detect changes regardless of the type of symptom. Improvements after zolpidem have been detected previously in SPECT and PET brain scans, correlating with clinical improvements [4,5,6].  The activated areas do not show a typical location or distribution pattern and vary between patients, probably because sites of injury are also highly variable. However, the timing and nature of the changes clearly indicate that they are part of the effect of zolpidem. This was shown pharmacologically in an animal study where the effect of zolpidem activation was blocked by flumazenil, an antagonist at benzodiazepine receptors, which includes the omega-1 sites at which zolpidem acts [18].  We did not find a perfect match between SPECT and TFES improvement, since there were 3 improvers on SPECT scan who had no detectable clinical improvement on the TFES. This may have been due to a lack of sensitivity to their symptoms in the TFES, which suggests that SPECT scans may be helpful in identifying possible responders when clinical changes are not obvious. 

Brain SPECT scans can be interpreted visually by human observers or semi-quantitatively using computerized image comparisons such as BRASS, SPM or VOI techniques [19,20,21]. However, neither method provides an undisputed gold standard for accuracy and validity since necessary smoothing techniques for example may influence the accuracy of quantitative SPECT techniques [22]. For the unique purpose of this study, namely to identify a response after zolpidem in the same subject, a visual assessment by three independent, blind-to-treatment assessors was thought the most appropriate.

It is unusual that a sedative medication such as zolpidem can produce activation of suppressed brain tissue. It has been postulated that the observed long term physiological brain suppression that occurs after brain injury is a protective GABAergic effect, probably caused by oversensitive modified GABA receptors when GABA reserves become depleted after injury. Zolpidem counters this receptor modification and normalises brain function [5].


In conclusion our 23 patients produced a 43% response rate to zolpidem therapy according to the brain SPECT scans and clear, significant beneficial clinical effects. Further research should now be undertaken in the form of a placebo controlled trial, to confirm these results in established brain damage, whether it be due to stroke, traumatic brain injury or other causes.

 

 

5. ACKNOWLEDGEMENT

 

The authors wish to acknowledge Dr Andrew Sutton and Dr Shaun Kilminster for editorial and statistical considerations, the staff of the Nuclear Medicine Department of the University of Pretoria, the MRC statistics department and Mrs Ilse Myburgh and her team for organising the patient data collection.

 

 

6. CONFLICT OF INTEREST

 

This study was funded by the Nuclear Medicine Department of the University of Pretoria as part of an M.Med. Thesis. No external funding was received for this study. Co-authors R. P. Clauss and H.W. Nel are honorary consultants to ReGen Therapeutics who are the current holders of the intellectual property on zolpidem use in brain damage.

 

 

7. LITERATURE

 

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[4]        Clauss R P, Güldenpfennig W M, Nel HW, Sathekge M M, Venkannagari R R. Extraordinary arousal from semi-comatose state on zolpidem. S Afr Med J 2000; 90 (1): 68-72.

[5]        Clauss RP, Nel HW. Drug induced arousal from permanent Vegetative State. NeuroRehabilitation 2006; 21(1): 23-8.

[6]        Brefel-Courbon C, Payoux P, Ory F, et al. Clinical and Imaging evidence of zolpidem effect in hypoxic encephalopathy. Ann Neurol 2007; 62(1): 102.

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[12]      Shadan FF, Poceta JS, Kline LE. Zolpidem for Postanoxic Spasticity. Southern Med J 2004; 97(8): 791-92.

[13]      Clauss RP, Dormehl IC, Oliver DW, Nel HW, Kilian E, Louw WK. Measurement of cerebral perfusion after zolpidem administration in the baboon. Arzneim Forsch/Drug Res 2001, 51: 619-22.

[14]      Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Maryland State Medical Journal 1965; 14 : 56-61.

[15]      Tinetti ME, Richman D, Powell L. Falls Efficacy as a Measure of Fear of Falling. Journal of Gerontology: Psychological Sciences 1990; 45(6): 239-43.

[16]      Bandura A. Self-efficacy mechanism in human agency. American Psychologist 1982; 37: 122-47.

[17]      Hall SD,  Yamawaki N, Fisher AE, Clauss RP, Woodhall GL, Stanford IM. Desynchronization of pathological low-frequency brain activity by the hypnotic drug zolpidem. Nature Precedings 2008; hdl:10101/npre.2008.1966.1     

 [18]     Clauss RP, Dormehl IC, Kilian E, Oliver DW, Nel HW, Louw WKA. Cerebral blood perfusion after treatment with omega receptor drugs, zolpidem and flumazenil in the baboon. Arzneim Forsch/Drug Res 2002; 52: 740- 44.

[19]      Slomka PJ, Radau PE, Hurwitz G, Dey D. Automated three-dimensional quantification of myocardial perfusion and brain SPECT. Comput Med Imaging Graph 2001; 25: 153-64.

[20]      Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frith CD, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1965; 2: 165-189.

[21]      Van Laere K, Koole M, Versijpt J, Dierckx R. Non-uniform versus uniform attenuation correction in brain perfusion SPET of healthy volunteers. Eur J Nucl Med 2001; 28: 90-98.

[22]      Van Laere K, Warwick J, Versijpt J et al. Analysis of Clinical Brain SPECT Data Base don Anatomic Standardization and Referente to Normal Data: An ROC-Based Comparison of Visual, Semiquantitative and Voxel-Based Methods. J Nucl Med 2002; 43(4): 458-469.  

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