A Study to Test the Use of Duloxetine for Pain in MS

Between 350,000 and 400,000 Americans have Multiple Sclerosis, a chronic neurological
disease characterized by demyelination and axonal degeneration. Pain is an important symptom
of MS, reported in 44% to 80% of patients.

Duloxetine is FDA apprBetween 350,000 and 400,000 Americans have Multiple Sclerosis, a
chronic neurological disease characterized by demyelination and axonal degeneration. Pain is
an important symptom of MS, reported in 44% to 80% of patients.

Duloxetine is FDA approved for use in treatment of diabetic painful neuropathy and
depression. Since the analgesic mechanism of action of Duloxetine is believed to occur in
the Central Nervous System, there is reason to believe that it may also be effective in
central pain conditions, such as MS.

Our study design includes a 1:1 randomization of Duloxetine to placebo. We hypothesize that
the Duloxetine group will experience reductions in the weekly 24 hour average and worst pain
scores that exceed 1.5 and that are significantly greater than reductions achieved in the
placebo group. We also hypothesize that Duloxetine will be well tolerated with no
significant group differences in adverse effects, sleep and quality of life as measured by
the SF-36 approved for use in treatment of diabetic painful neuropathy and depression. Since
the analgesic mechanism of action of Duloxetine is believed to occur in the Central Nervous
System, there is reason to believe that it may also be effective in central pain conditions,
such as MS.

Our study design includes a 1:1 randomization of Duloxetine to placebo. We hypothesize that
the Duloxetine group will experience reductions in the weekly 24 hour average and worst pain
scores that exceed 1.5 and that are significantly greater than reductions achieved in the
placebo group. We also hypothesize that Duloxetine will be well tolerated with no
significant group differences in adverse effects, sleep and quality of life as measured by
the SF-36.

Inclusion Criteria:

- Diagnosis of MS made at least 3 months prior based on McDonald or Proser criteria.

- Age over 17.

- Clinical stability defined as no MS exacerbation or change in disease modifying
therapy for 90 days prior to screening.

- Daily pain attributed to MS, present for a minimum of 2 months prior to screening.

- Minimum baseline score of 4 on the 24-h Worst Pain Score rated on an 11 point (0-10)
point Likert Scale within the identified region of central pain.

Exclusion Criteria:

- Pain that could not clearly be differentiated from causes other than Multiple
Sclerosis, such as diabetic neuropathy, PVD, arthritis or other musculoskeletal
condition, chronic headache, visceral pain.

- Transient pains such as dysesthetic L'Hermittes sign alone.

- Current or historical diagnosis of mania, bipolar disorder or psychosis.

- Concomitant use of monoamine oxidase inhibitors (MAOI) or thioridazine.(MAOI drug
must be discontinued 14 days prior to enrollment. At least 5 days must have passed
after study drug discontinuation before MAOI drug may be started.)

- Concomitant use of a serotonin reuptake inhibitor or venlafaxine or duloxetine within
4 weeks of baseline.

- Use of any analgesic medication except ibuprofen for neurogenic pain 7 days prior to
the baseline visit and until study termination.

- Use of an opioid, marijuana or dronabinol within 7 days of baseline.

- Narrow angle glaucoma.

- Depression with suicidality.

- Substantial alcohol use. Because it is possible that Duloxetine and alcohol interact
to cause liver injury, duloxetine should not be prescribed to patients with
substantial alcohol use. Potential subjects will be asked how much alcohol they
drink. If the answer is over 2 drinks a day this will generally constitute an
exclusion.

- History of chronic hepatic insufficiency or ALT or AST> twice the upper limit of
normal. Because it is possible thast Duloxetine may aggravate pre exisitng liver
disease, duloxetine should not be prescribed to patients with chronic liver disease.

- Renal insufficiency (Creatinine Clearance , 30mL/minor serum creatinine > 1.9).
Duloxetine is not recommended for patients with end stage renal disease (requiring
dialysis) or severe renal impairment. Population PK analyses suggest that mild to
moderate degrees of renal dysfunction (estimated CrCl 30-80ml/min)have no significant
effect on Duloxetine clearance. We will calculate creatinine clearance using the
Cockcroft-Gault calculation. This is the most common calculation used in FDA producy
labeling: Males=(140-age)(wt in kg)(serum creatinine)(72). Females= malesx 0.85.

- Uncontrolled hypertention (SBP>180, DBP>105)

- Females who are breast feeding, pregnant, or have potential to become pregnant during
the course of the study.(fertile and unwilling/unable to use effective contraceptive
measures)

- Any other serious and/or unstable medical condition.

- Allergy to ibuprofen or any other non steroidal anti inflammatory drug (NSAID)

- Any history of peptic ulcer disease within 2 years or lifetime history of
NSAID-associated gastritis or other toxicity.

- Patients taking low dose aspirin will be instructed to contact their primary
physicianto ask whether they may safely discontinue aspirin while participating in
this study. If the recommendation is to continue aspirin or if use of aspirin is for
secondary prevention of arteriosclerotic disease, then they will be excluded.