A Phase 2 Study to Evaluate Analgesic Effect of IV CR845 For Pain Following Bunionectomy Surgery

This is a single-center, randomized, double blind, placebo controlled, parallel group proof of concept study to evaluate the analgesic efficacy as well as the safety, tolerability and pharmacokinetic profile of CR845 in patients with pain following bunionectomy surgery.

Currently, the most widely used drugs to treat pain after surgery are opiates, such as morphine. Morphine works mainly by activating one of several types of opiate receptors that control some of our pain sensation - the so-called mu opiate receptors. These receptors are located in many areas of the brain and also outside of the brain. By activating these receptors, morphine provides significant pain relief, but also causes side effects that limit its use. Some of these side effects include: respiratory depression or arrest (slowed or stopped breathing), sedation (a state of calmness or extreme relaxation), euphoria (an exaggerated feeling of physical and mental well-being), constipation, nausea, vomiting, and drug addiction.

In order to avoid the side effects of morphine and other mu opiates, the present experimental drug CR845 was designed to work at a different type of opiate receptor - called kappa - that can also provide pain relief, by acting on sensory nerves outside the brain. CR845 was designed to penetrate the brain much less than other opiate drugs, which should result in pain relief similar to that of morphine, but with fewer side effects. Because CR845 activates kappa receptors instead of mu receptors, the side effects are different than with a morphine-type drug. In particular, kappa opiates, such as CR845, do not cause respiratory depression or arrest, euphoria, constipation, drug tolerance, physical drug dependence or drug addiction. For these reasons, CR845 may present a distinct advantage over other opiates that are currently used for pain relief and post-operative pain in particular.

Eligibility Criteria:
Inclusion Criteria:

1. Able to provide written informed consent prior to any study procedures;
2. Able to communicate clearly with the Investigator and staff;
3. Males and females aged 18 years or older;
4. Scheduled for elective primary unilateral first metatarsal bunionectomy surgery (osteotomy and internal fixation) with no collateral procedures;
5. Females physically incapable of childbearing potential (postmenopausal for more than 1 year or surgically sterile) or practicing an acceptable method of contraception (hormonal, barrier with spermicide, intrauterine device, vasectomized partner, or abstinence). Subjects using hormonal birth control must have received at least 1 cycle of treatment prior to randomization. All females of childbearing potential must have a negative pregnancy test and not be breast feeding at Baseline;
6. Negative urine drug screen for drugs of abuse at Screening and at Baseline; a positive drug screen result may be permitted if the patient has been on a stable dose of an allowed medication for \>30 days (antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective serotonin reuptake inhibitors \[SSRIs\], tricyclic antidepressants) or \>3 months (opioid analgesics or systemic steroids);
7. American Society of Anesthesiologists (ASA) risk class of I to II;
8. Body weight \<170 kg

Exclusion Criteria:

1. Has known allergies to opioids, unless has subsequently tolerated other opioids and in the opinion of the PI could tolerate study drug;
2. Has a known or suspected history of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-diagnosed alcohol, opiate or other drug abuse or dependence within 12 months prior to screening;
3. Is unable to refrain from alcohol consumption for a period beginning 24 hours prior to surgery through the end of the Treatment Period;
4. Has taken non-opioid analgesics (including cyclooxygenase-2 \[COX-2\] inhibitors) or nonsteroidal anti-inflammatory drugs (NSAIDs) within 12 hours of the Baseline assessments;
5. Has taken any opioid analgesics or used systemic steroids within 4 days of surgery OR has been using opiates chronically for a period of \< 3 months; (Note: Patients on stable chronic opioids for ≥ 3 months will need to discontinue them for 4 days prior to surgery);
6. Has used antipsychotics, antiepileptics, sedatives, hypnotics, or antianxiety agents, selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants for \< 30 days prior to surgery or had a dose change within the previous 30 days;
7. Has taken any prescription or over-the-counter medication within 4 days prior to surgery that, in the opinion of the Investigator, is expected to confound the analgesic response;
8. Has taken herbal agents or nutraceuticals (i.e., chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian) during any of the 7 days prior to surgery;
9. Has any clinically significant condition or a significant laboratory abnormality that would, in the Investigator's or designee's opinion, preclude study participation
10. Has received another investigational drug within 30 days of scheduled surgery.