Tramadol Versus Placebo in the Management of Postoperative Pain Following Bunionectomy

(Non-clinical summary)

Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol group with
opioidlike effects. Tramadol is extensively metabolized following administration, which
results in a number of enantiomeric metabolites that display different opioid-receptor
binding properties, and monoaminergic reuptake inhibition.

Key Inclusion Criteria:

- The patient is male or female 18-75 years of age undergoing unilateral first
metatarsal bunionectomy surgery

- Willing to give consent and able to understand the study procedures

- Female patients must be of non-childbearing potential or be practicing a highly
effective contraception

- The patient must be willing to be housed in a healthcare facility and able to receive
parenteral analgesia for at least 72 hours after surgery.

- The patient meets definition of American Society of Anesthesiologists (ASA) Physical
Class 1, or 2.

Exclusion Criteria:

- Patient is not expected to receive a continuous infusion nerve block as described in
the Post-Op anesthetic procedures protocol

- Patient is undergoing bilateral or revision bunionectomy surgery

- The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol
The patient has known physical dependence on opioids

- The patient has taken other prior/concurrent chronic medications that have not been at
a stable dose for at least 2 weeks prior to screening

- The patient is taking herbal or dietary supplements or medications that are moderate
or strong inhibitors of CYP2D6 or CYP3A4 or inducers of CYP3A4

- The patient has taken monoamine oxidase (MAO) inhibitors, trazodone, or
cyclobenzaprine within 14 days prior to surgery

- The patient cannot be withdrawn from medications (at least 7 days prior to surgery)
that may lower the seizure threshold (e.g. anti-psychotic agents, MAOI inhibitors) or
which increase serotonergic tone (e.g. selective serotonin reuptake inhibitors
(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic
antidepressants, triptans).

- The patient has a history of epilepsy, or is known to be susceptible to seizures

- The patient has a history of Long QT Syndrome or a relative with this condition

- The patient has expressed suicidal ideation or is considered to be at risk of suicide.

- The patient is morbidly obese (body mass index [BMI] ≥ 40 kg/m2) or has documented
sleep apnea requiring pharmacological or device intervention.

- Clinically significant abnormalities in the judgement of the Investigator

- The patient was administered an investigational product within 30 days prior to
Screening.

- The patient has previously participated in a clinical study with AVE-901.