Pharmacologic Therapy for Hearing Loss

1
Pharmacologic Therapy for Hearing Loss

• Basic Science to Clinical Trials
• Ben J. Balough
• CAPT, MC, USN
• Naval Medical Center, San Diego

2
The Problem Military Noise

• Ubiquitous Hazard
• Conservation Programs since 1970s
• Universal Hearing Protection
• Monitoring and Tracking
• Continuously increasing disability rates
• gt22,000 new claims per year
• 2004 643 million
• 2005gt850 million

3
The Growing Noise Problem Cost of Hearing Loss
for All Veterans (1977-2006) Total
8,385,892,465 BILLION
Millions
901,472,784
Major VA Disability Only
Costs are approaching 1Billion annually
Navy Executive Safety Board
Data extrapolated from Dec 06 claims
4
The Problem Military Noise

• Center For Naval Analysis 2005
• 250,000 enlisted sailors, 25 year career
• 46 rate of hearing loss for surface ships
• 27 rate if shore duty
• Shore duty rate similar to sub and aviation
  communities

5
Cost of Hearing Loss for Navy Marine Corps
(1996-2006)
2006 Navy 161,180,364 Marine Corps
74,059,704

• Millions

Navy and Marine Corps Hearing Loss Facts FY06
costs 235,190,068 FY06 new cases 16,010
Total cases 123,758
Year
Navy Executive Safety Board
6
The Problem Military Noise

• Institute of Medicine Report 2005
• Congressionally mandated study
• Hearing Conservation Programs inadequate
• 2-5 times higher rates than civilian industry
• Recognized engineering and time limitations
• Improve hearing protection and compliance
• Official DoD response included study of
  alternative therapies!
• SECNAV 2007 GWON

7
NIOSH noise levels

• safe levels of noise
• Time weighted exposures
• 3dB increase cuts exposure time in half
• Current ear plugs offer 10-30dB of protection

8
THE GROWING NOISE PROBLEM Noise Levels in Navy
Marine Corps
No Hearing Protection Reqd
Max. Limit Double Hearing Protection
135 dB
84dB
109 dB
Technological Limit
Noise Level (Decibel)
Navy Executive Safety Board
9
AIRCRAFT NOISE What We Can and Cant Do About It
10
Carrier deck launch support personnel bow
catapult positions (F-35 noise contours)
11
Launch/ recovery support personnel exposed to
brutal acoustic loads
12
Military Aviation

• Problem
• 130 - 150 dB jet noise
• 12 - 24 hr. noise gt85 dB with little to no quiet
  recovery time
• 40 yr. helmet/hearing protector designs
• 30 dB noise attenuation at best
• Little effort to ensure good fit, performance, or
  maintenance
• Net Result
• Hazardous flight ops communications
• Reduced quality of life - increased stress and
  fatigue
• False sense of security

13
Military Noise Impact

• Threat detection critical for survival
• Members in small groups communication vital
• Tank crews at 25 increased risk if on member
  with hearing loss

14
NIHL Hypotheses

• Old Theory
• Noise creates mechanical damage to inner ear
• New Theory
• Cochlea has inherent defenses against noise
• Acoustic overexposure induces oxidative stress
• - toxic reactive oxygen species (ROS)
• If damage is severe enough hair cells die in a
  progressively over time (apoptosis)

15

Novel Approach Can we increase the ears
intrinsic defenses against noise?
X
MAKE the COCHLEA MORE NOISE RESISTANT!
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(No Transcript)
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Saline
Mitochondrial protectant
Glutamate antagonist
GSH replenisher
18
N-Acetyl Cysteine preserves almost all of the
OHCs
Acute noise trauma wipes out most of the outer
hair cells (OHCs)
19
Reproducible Results

• Kresge Hearing Research Inst. (U. Mich.)
• NAC decreases PTS, HC loss, lipid peroxidation
• Hearing Research Lab (SUNY Buffalo)
• NAC decreases PTS from impulse noise
• Karolinska Inst., Stockholm Sweden
• Oral NAC significantly increases
  perilymphatic/endolymphatic NAC levels
• NAC decreases damage from impulse noise

20
Timing of Hair Cell Loss After NoiseTherapeutic
Window
20
15
Missing IHC X 10
Missing OHC X 100
Hair Cell Loss
10
5
0
0.1
1
10
100
1000
Hours after injury
21
NAC Protection of Noise-induced Hair Cell Loss

• Saline controls

Antioxidant protection
22
NAC is effective in reducing permanent hearing
loss even if given shortly after the noise
exposure
23
NIHL Oxidative Stress Model

• Valid Hypothesis
• Decade of work in multiple labs
• Multiple Sites affected
• Chemical cascade
• Potential for Pharmaceutical intervention
• GSH replenishment via NAC
• Other potential targets/agents

24
N-acetylcysteine (NAC)

• Three decades of clinical use
• Safe, effective in acetominophen hepatotoxicity
• Minimal side effect profile
• GI upset, rash
• Used in high doses for prolonged periods
• 2-8 grams over months to years
• Poor bioavailability
• Inexpensive

25
Chinchillas to Marines
Rodent NAC in the basic science model shown to
prevent and treat NIHL dozens of abstracts, two
book chapters and five peer-reviewed publications
Human Can oral NAC prevent NIHL? Phase 1
Trial Prevention Marine Corp Recruit Depot, San
Diego 600 Marine recruits, double blinded
placebo controlled study before and after weapons
fire Mar-Oct 04
26
Clinical Trial Marine Recruit Training

• Controlled noise exposure
• 300 rounds of M-16 fire over 2 weeks
• No recreational noise exposures
• Uniform population
• Healthy males, highly screened
• Controlled administration
• Regulated meals at consistent times

27
MCRD Trial

• Prospective, Randomized, Placebo controlled study
  
• 900mg NAC TID during weapons training
• 566 patients
• Evaluation of NAC to augment hearing protection
• 300,000
• 6 months

28
MCRD Study timeline
29
MCRD Study Outcomes

• Will there be a difference in the numbers of
  significant threshold shift STS between NAC and
  placebo?(STS gt20dB worsening at any one test
  frequency, or gt15dB change at any two
  consecutive test frequencies in either ear (ASHA
  1994))
• Rate of STS in prior studies 10-15

30
MCRD Results

• Demographics
• no statistical differences between the two groups
  age, ethnicity, race, smoking history, previous
  noise exposure, handedness, recent cold or ear
  infection, Aspirin use, head injury, previous
  solvent exposure, or exposure to unusual noise
• Subjects in both groups were predominantly
  right-handed for use of a rifle trigger (95)

31
MCRD Results

• Side Effects
• The percentage of subjects reporting a side
  effect was 26.7 for the placebo group and 27.4
  for the NAC group (p0.4465)
• Average daily intensity, frequency and severity
  of side effects showed no differences between the
  NAC and placebo groups

32
MCRD Results

• Rate of STS
• Overall 37.4 rate of STS
• Right handed, Right ears
• 28.4 placebo vs. 21.4 NAC (p0.044)
• Greater shifts shown in either ear and both ears
  for placebo over NAC
• Results presented at COSM San Diego May 2007

33
MCRD Conclusions

• Safety
• 900mg NAC TID side effects similar to placebo and
  safe
• Efficacy
• Potentially a beneficial effect at this dose
  (25 reduction in STS in right ears)
• Conundrums
• Standard Hearing protection inadequate
• M-16, right ear-right hand exposure

34
Next Steps Phase 2 trials

• MCRD study useful but only impulse noise exposure
• Need to validate in real world noise
• Long term use deployment
• The aspirin and smoking effects
• 2.5 million DoD grant to conduct follow on
  studies
• MCRD 2 for dose response, salicylate effects and
  genetics
• 6 month at sea trial for continuous/kurtotic
  noise effects
• USMC combat training for higher intensity noise
  exposure and less controlled patient populations
• Basic Science
• Newer agents, multiple sites of intervention
• NIHL susceptibility genetics
• Blast

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Questions?
36
(No Transcript)
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Prevalence and Impact

• 50 million affected in US
• 12 million seek medical attention
• 1-4 debilitated
• Roughly 70 from NIHL
• Military Veterans
• Over 200,000 receive benefits
• 1 disability claim
• 643 million in compensation

38
Non-Pharmacological Treatments

• TRT, Biofeedback, Masking, and others
• Effective, but expensive
• Clinician intensive
• Difficult to widely implement
• Reserved for severe cases

39
Oral Pharmacological Therapy

• Non-intensive on medical resources
• Self administered, self monitored
• May provide benefit against the causes of
  Tinnitus
• Not just symptomatic relief
• Expensive to properly study

40
Pharmacological Therapy

• Wide variety of studies
• Non-randomized, non-controlled, low numbers
• Lack of uniform patient criteria
• Chronic, Acute
• Mild, Moderate, Severe
• Peripheral, Central, Mixed
• Lack of uniform reporting
• Subjective scales, audiometric analyses, Handicap
  Inventories

41
Pharmacological Therapy

• Included as secondary measure and results
  extrapolated
• High rate of placebo response
• Up to 40
• Otolaryngol Head Neck Surg. 1984 Dec92(6)697-9
• Ann Otol Rhinol Laryngol. 1988 Mar-Apr97(2 Pt
  1)120-3
• No good basic science models

42
Pharmacological Therapy

• Drugs vs. supplements
• Largely arbitrary distinction
• No drug with an indication for Tinnitus
• Side effects can be an issue
• Supplements
• Poorly regulated
• Use based on some science
• Side effects or interactions poorly characterized

43
Drugs commonly used for Tinnitus

• Tricyclic Anti-depressants
• GABA active drugs
• Benzodiazepenes
• Gabapentin
• Baclofen

44
Supplements frequently recommended

• Zinc
• Ginkgo biloba
• B-vitamins
• Anti-oxidants

45
The Present

• Pseudo science and supplements
• Tinnitus source variability
• Animal Models

46
Drugs

• TCAs
• Basic Science
• No studies
• Clinical Science
• May help in ameliorating co-morbidities in
  severe/chronic cases
• Depression, Insomnia
• Am J Otol. 1993 Jan 14(1)18-23
• May assist in reducing Tinnitus severity
• J Otolaryngol. 2001 Oct30(5)300-3
• SSRIs similarly effective
• Ear Nose Throat J. 2004 Feb83(2)107-8, 110, 112
  passim

47
Drugs GABA

• Basic Science
• GABA inhibition at IC prevents auditory seizures
• Hear Res. 2000 Jun 168(1-2)223-37
• Salicylate toxicity changes GABA(A) receptor
  binding at IC
• Hear Res. 2000 Sep147 (1-2)175-82
• Animal studies suggest complex drug interactions
  at brainstem
• Hear Res. 1996 Aug97(1-2)46-53.
• SPECT Imaging suggests central changes in chronic
  Tinnitus with loss of GABA inhibition
• Int Tinnitus J. 19962137-142

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Drugs GABA

• Clinical Science
• Short duration, small studies suggest benefit
• Demonstrate only activity, but not duration of
  therapy, holidays, or correct patient populations
• Arch Otolaryngol Head Neck Surg. 1993
  Aug119(8)842-5
• Ann Pharmacother. 1995 Mar29(3)311-2
• Highly effective in small group of patients with
  central Tinnitus
• Int Tinnitus J. 20028(1)30-6
• No studies using Neurontin alone

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Drugs Baclofen

• Baclofen
• Basic Science
• Animal studies suggestive
• Hear Res. 1996 Aug97(1-2)46-53
• Clinical Science
• No better than placebo
• Am J Otol. 1996 Nov17(6)896-903

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Drugs Others

• Prostaglandins, vasodilators
• Small studies, mixed results
• Arch Otolaryngol Head Neck Surg. 1993
  Jun119(6)652-4
• Auris Nasus Larynx. 2004 Sep31(3)226-32
• Otolaryngol Head Neck Surg. 2004
  May130(5)604-10
• Can be high rate of side-effects
• Otolaryngol Head Neck Surg. 1998 Mar118(3 Pt
  1)329-32

51
Supplements

• Zinc
• Zinc Deficiency Can Cause Tinnitus
• Am J Otol. 1989 Mar10(2)156-60
• Arch Otorhinolaryngol. 1987244(3)190-3
• Variable Rates of Zinc deficiency
• Otol Neurotol. 2003 Jan24(1)86-9
• Auris Nasus Larynx. 2002 Oct29(4)329-33
• Perhaps Useful in those with normal hearing
• Auris Nasus Larynx. 2003 Feb30 SupplS25-8
• Ann Otol Rhinol Laryngol. 1991 Aug100(8)647-9

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Supplements

• Ginkgo biloba
• Variable doses, variable extracts (LI1370,
  Egb761)
• Basic Science
• Reduction of salicylate Tinnitus
• 25-100 mg/kg/day EGb 761
• Audiol Neurootol. 1997 Jul-Aug2(4)197-212
• Clinical Science
• No benefit with LI 1370 in placebo controlled
  trial
• Large study, but only 150mg/day
• Meta analyses also negative
• BMJ. 2001 Jan 13322(7278)73
• Clin Otolaryngol Allied Sci. 2004
  Jun29(3)226-31
• Cochrane Database Syst Rev. 2004(2)CD003852
• Clin Otolaryngol 1999 24164167

53
Supplements

• B-vitamins
• No basic science
• Clinical Studies
• Increased relationship of B-12 deficiency in NIHL
  and Tinnitus vs. NIHL alone
• Am J Otolaryngol. 1993 Mar-Apr14(2)94-9
• B6 no better than placebo
• Clin Otolaryngol Allied Sci. 1987 Jun12(3)211-4

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Supplements Antioxidants

• Basic Science
• Animal data promising in preventing NIHL
• Acta Otolaryngol. 2005 Mar125(3)235-43
• Neurosci Lett. 2005 Jun 3380(3)234-8
• Hear Res. 2005 Apr202(1-2)200-8
• No data on tinnitus
• May prove useful in both centrally and
  peripherally generated tinnitus

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Supplements Anti-oxidants

• Clinical science
• Preliminary human data for NIHL, ISHL
• No link between hearing improvement and tinnitus
  improvement
• Kulak Burun Bogaz Ihtis Derg. 200412(5-6)107-14
• Currently no published large human trials for
  NIHL or tinnitus

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The Future

• Generally agreed standards for outcome
• THI, loudness matching, scaled scores
• Uniform Patient Reporting
• Hearing loss, acute or chronic, severity
• Study designs with sufficient power and clarity
• Laryngoscope. 1999 Aug109(8)1202-11
• Curr Opin Investig Drugs. 2005 Jul6(7)712-6
• Linkage of Basic Science with clinical studies