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Patients Report 50 Percent Less Symptoms of Physical Dependence and Withdrawal Effects in Phase 3 Oxytrex Trial

SOUTH SAN FRANCISCO, Calif., March 24 /PRNewswire-FirstCall/ -- Pain Therapeutics, Inc. (NASDAQ:PTIE) , a biopharmaceutical company, today reported clinical results from the first of two Phase III trials with Oxytrex, a novel oral opioid painkiller.

In this Phase 3 study of 719 patients with severe chronic low-back pain, Oxytrex patients reported over 50% less symptoms of physical dependence and withdrawal effects (p<0.01) after cessation of prolonged, high-dose opioid therapy compared to patients on oxycodone. Oxytrex patients reported equal pain relief to patients on oxycodone and about 20% less overall opioid-related side-effects during treatment, including less somnolence (p<0.05), less pruritus (p<0.05) and 44% less moderate-to-severe constipation (p<0.05).

"This is the first time a large, rigorous trial shows a meaningful improvement in physical dependence," said Lynn Webster, MD, lead investigator on this study, medical director of Lifetree Clinical Research & Pain Clinic in Salt Lake City, board certified physician in pain management and anesthesiology and a specialist in addiction medicine. "Physical dependence is a predictable effect of prolonged opioid therapy. Physicians or patients often associate physical dependence with addiction and avoid opioid painkillers altogether. Many recreational drug users who become hooked on opioids due to physical dependence find it inescapable to discontinue drug use. I think a new drug that provides pain relief yet curbs dependency stands to gain rapid acceptance in the medical community."

"Drug safety continues to dominate the public health agenda, especially with chronic drug treatments," said Remi Barbier, president and chief executive officer of Pain Therapeutics. "The oxycodone market is about $2 billion in size and represents over 10 million scripts per year. Will a broad swath of this market adopt a new drug that offers less physical dependence, less side-effects or lower dosing requirements? We believe so and that's why we're excited about our Phase III results."

"We plan to discuss an NDA strategy for Oxytrex with the FDA in late 2005 after unblinding results of our second Phase III trial," added Nadav Friedmann, PhD, MD, chief operating and medical officer at Pain Therapeutics.

Pain Therapeutics plans to submit trial results at the World Congress on Pain (Australia), August 21-26. Management also plans to present at the Smith Barney Citigroup 2005 Healthcare Conference in Washington, DC on Wednesday, March 30, and at the 2005 CIBC World Markets Annual Biotechnology Conference in New York, Monday, April 4, followed by a non-deal roadshow with institutional investors in the upcoming weeks.

Phase III Design
This randomized, double-blind, placebo and active-controlled trial was conducted in multiple U.S. centers in ambulatory patients with persistent, moderate-to-severe low-back pain. After signing an informed consent form, all patients (N = 719) began a 4-10 day washout period. After the washout period, patients with severe pain scores (. 5 out of 10) were randomized to one of four treatment groups for dose titration: Oxytrex-QID (N=206), Oxytrex-BID (N=206), oxycodone-QID (N=206); or placebo (N=101). (Note: QID refers to four-times-a-day; BID refers to twice-a-day).

Treatment Period
During a six-week titration period, patients were dose-escalated with up to 80 mg of Oxytrex, oxycodone or placebo. Dose escalation stopped when patients reported adequate pain relief (< 2 out of 10) or an unacceptable level of opioid related side-effects. At that point the dose was fixed and patients continued their opioid therapy at that dose for a period of three months. The actual dose titration schedule was: 10 mg/day in week one; 20 mg/day week two; 30 mg/day week three; 40 mg/day week four; 60 mg/day week five; or 80 mg/day week six. Patients in the oxycodone group only received oxycodone. Patients in the Oxytrex groups received oxycodone formulated with ultra-low-dose naltrexone. Oxytrex-QID patients received a total daily dose of 4 nanograms of ultra-low-dose naltrexone; Oxytrex-BID patients received a total daily dose of 2 nanograms of ultra-low-dose naltrexone. Rescue medication was not allowed at any time during the study.

The primary and secondary endpoints were prospectively defined as superiority of Oxytrex to oxycodone. Pain intensity was measured on the Likert Pain Scale (0 = no pain; 10 = worst imaginable pain). Patients recorded their pain scores and side-effects in a daily diary immediately before their bedtime dose. Patients also visited the clinic initially each week and then every fortnight during the fixed dose period. Physical dependence is an expected response to prolonged opioid use and is characterized by a series of well-known clinical symptoms when opioid use is abruptly discontinued. At the conclusion of the study, patients were evaluated for opioid withdrawal effects using the Short Opiate Withdrawal Scale (SOWS).

Summary of Trial Results
-- Baseline. All patients reported similar baseline pain scores (7.3-7.7 out of 10).

-- Pain Scores. All drug groups separated from placebo (p -- Drug Dose. Patients in both Oxytrex groups required substantially less opioid drug dose (35 mg per day) to achieve equal pain relief compared to patients in the oxycodone group (39 mg per day) (p -- Side-effects. Opioid-related side-effects were about 20% lower overall in the Oxytrex-BID group compared to the oxycodone group. Oxytrex-BID patients reported 44% less moderate-to-severe constipation compared to the oxycodone group through the treatment period (p -- Physical Dependence/Withdrawal. The Oxytrex-BID group reported substantially lower mean SOWS scores (1.2) than patients in the oxycodone group (2.6) in the first 24 hours following drug discontinuation (p50%) reflects milder withdrawal events in the Oxytrex-BID group and more severe dependency and withdrawal effects in the oxycodone group.

-- Dose Frequency. Oxytrex-BID provided pain relief on par with oxycodone-QID without the use of a slow-release formulation. (Oxycodone has a peak effect within two hours of dosing and a clinical duration of action of 3-6 hours due to its short (2 to 4 hour) half-life in plasma. As a result, it is typically prescribed four-times-a-day for round-the-clock pain relief; slow-release formulation can provide more convenient forms of dosing, such as twice-a-day).

-- Drop-outs. As expected, the overall dropout rate was high (about 50%) due to the inclusion of a large placebo group (N= 101) and the length and complexity of the study. As expected, placebo patients dropped out earlier and more often than the drug groups.

A Unique Mechanism of Action
Opioid drugs can activate inhibitory or excitatory signals through opioid receptors. The well-known inhibitory action provides analgesia by dulling the transmission of pain signals to the brain. On the other hand, the opioid excitatory effect counteracts analgesia and contributes greatly to the adverse effects of chronic opioid use, such as physical dependence, tolerance and addiction. Recent data confirms that the activation of excitatory signals increases dramatically after chronic opioid use. Oxytrex is a unique oral painkiller that combines an ultra-low, nanogram dose of naltrexone (an opioid antagonist) with a clinical dose of oxycodone (an opioid agonist). The presence of ultra-low-dose naltrexone in Oxytrex is designed to minimize physical dependence, tolerance and enhance pain relief. We believe Oxytrex represents the first new mechanism of action of an opioid drug since morphine was discovered over 100 years ago.

Source: Pain Therapeutics, Inc.

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